CN101123878A - amino acid prodrug - Google Patents

Abstract

This invention relates to a prodrug comprising an amino acid linked to a pharmaceutical agent or drug having a hydroxyl, amino, carboxyl, or acylated derivative thereof. The prodrug can be used in the same manner as the pharmaceutical preparation, but with enhanced therapeutic properties. In fact, the prodrug of this invention enhances at least two therapeutic properties, as defined. This invention also relates to pharmaceutical compositions containing a prodrug.

Description

amino acid prodrug

field of invention

The present invention relates to amino acid derivatives of drug compounds, and methods for treating specific diseases, which can be improved by administering these drugs and pharmaceutical compositions containing these drugs. The present invention relates to the enhancement of many physicochemical, biopharmaceutical and clinical potencies of various drugs using amino acids as covalently bonded carriers for these drugs.

Background technique

The development of chemical compounds for the treatment of disorders, conditions and diseases is becoming increasingly difficult and expensive. The probability of success for such development is often discouragingly low. Furthermore, the time for development can approach or exceed ten years, leaving a large number of patients untreated for a prolonged period of time.

Even when effective pharmaceutical compounds are developed, disadvantages accompany their administration. These disadvantages can include aesthetic and pharmacokinetic barriers to the effectiveness of these existing pharmaceutical ingredients, for example, the unpleasant taste or odor of a pharmaceutical compound or composition is a significant barrier to patient compliance with a dosing regimen. Undesirable solubility characteristics of pharmaceutical compounds can make it difficult to formulate uniform compositions. Other disadvantages associated with known pharmaceutical compounds include: poor absorption in oral formulations; low bioavailability of pharmaceutical compounds in oral formulations; lack of proportionality; low stability of pharmaceutical compounds in vivo and in vitro; Brain barrier; excessive first-pass metabolism of drug compounds across the liver; excessive enterohepatic recirculation; poor absorption; release of ineffective compounds at the site of action; allergic reactions, e.g., gastro-intestinal inflammation and and/or ulcers; painful injections of parenterally administered pharmaceutical compounds and compositions; excessively high doses required for some pharmaceutical compounds and compositions, and other objectionable properties. Some pharmaceutical compounds are processed by the body to produce toxic byproducts with deleterious effects.

The art is constantly searching for new compounds for the treatment of a wide range of different diseases, with improved properties to overcome the aforementioned disadvantages of existing pharmaceutical compounds.

The present invention overcomes many of the problems associated with drugs currently on the market by making prodrugs. The concept of prodrugs is well known and numerous examples of such prodrugs are listed in the literature and a large number of prodrugs are available on the market, including different types such as statins, ACE inhibitors, drugs such as Antiviral drugs of Acyclovir, and analogs. However, the present invention uses amino acids as part of making prodrugs. The prodrugs of the present invention have a number of advantages. For example, when amino acid prodrugs are administered by various routes such as oral, IV, rectal, or other such methods, these prodrugs are converted into active drug molecules. A significant advantage of this amino acid prodrug is that it is non-toxic and thus can be absorbed into the body or excreted safely. This is quite different from the behavior exhibited by a large number of prodrugs available on the market, the pro-parts of which are inherently toxic, such as statins, enalapril, benzodiazepines, etc. Benazapril and similar groups of ace inhibitors, and also a large number of antibiotics such as pivoxils, isopropyls, axetils, cilexetils and similar groups , are highly toxic, thereby reducing the therapeutic index of the active drug.

On the other hand, the amino acid prodrugs of the present invention also confer many advantages as shown below.

Summary of the invention

The present invention is directed to a pharmaceutically active prodrug having an amino acid covalently linked to a pharmaceutical compound to form the acid prodrug, administered in this form to a patient, such as a mammal.

Amino acids are ideal models for use as prodrugs because of their ability to form various types of linkages between themselves and the drug. By definition, amino acids have at least two functional groups, amino (NH ₂ ) and carboxyl (COOH). For example, α-amino acids have the well-known structure

是氨基酸的主链。这样，例如，除了在主链上的氨基和羧基外，侧链上也可以具有官能团。氨基酸部分上的官能团允许在氨基酸和药物之间产生共价键。Here _R is the side group or side chain of an amino acid. as defined here

is the backbone of amino acids. Thus, for example, besides amino and carboxyl groups on the main chain, functional groups may also be present on the side chains. Functional groups on the amino acid moiety allow for a covalent bond between the amino acid and the drug.

The drugs or agents used in the present invention contain functional groups on them that allow the drugs to react with amino acids and form covalent bonds with amino acids. Examples of functional groups on drugs include _NH2 , OH, COOH or acid derivatives thereof, such as esters, amides or the like.

The link between the drug compound and the amino acid can be through:

1) From the ester bond (-CO-O-) formed by the condensation or transesterification reaction of carboxylic acid with alcohol or phenolic hydroxyl group, for example:

a) when the drug compound has an aliphatic or aromatic hydroxyl group, under esterification conditions, it can form an ester bond with the main chain carboxylic acid group of the amino group; or

b) when the pharmaceutical compound has an aliphatic or aromatic hydroxyl group and the amino acid has a side chain carboxylic acid group, an ester bond can be formed between them under esterification conditions; or

c) when the pharmaceutical compound has a carboxylic acid group and the amino acid has a side chain aliphatic or aromatic hydroxyl group, under esterification conditions, an ester bond can be formed between them; or

d) When the pharmaceutical compound has a substituted or unsubstituted acyloxy (eg, alkoxy- or arylalkoxy-, aryloxycarbonyl) substituent (compound-O-CO-substituent) ester group, and when the amino acid has a main-chain carboxylic acid group, an ester bond can be formed therebetween by a transesterification reaction; or

e) When the pharmaceutical compound has a substituted or unsubstituted acyloxy (eg, alkoxy- or arylalkoxy-, aryloxycarbonyl) substituent (compound-O-CO-substituent) ester group, and when the amino acid has a side chain carboxylic acid group, an ester bond can be formed therebetween by a transesterification reaction; or

f) When the pharmaceutical compound has an ester group with a substituted or unsubstituted alkoxy- or arylalkoxy- or aryloxycarbonyl substituent (compound-CO-O-substituent), and the amino acid has a side chain aliphatic or aromatic hydroxyl groups, ester linkages may be formed therebetween by transesterification; or

g) The alcohol and carboxylic acid moieties can be on the same molecule so that they can form lactones. Also included within the scope of the invention are certain compounds which, for example like Gabapentin, are capable of forming lactones under ester-forming conditions.

2) From the amide bond (-CO-NH-) formed by the condensation of carboxylic acid and amine, for example:

a) when the pharmaceutical compound has an amino group and the amino acid has a main-chain carboxylic acid group, under amide-forming conditions, an amide can be formed; or

b) when the pharmaceutical compound has an amino group and the amino acid has a side chain carboxylic acid group, an amide bond can be formed therebetween under amide forming conditions; or

c) when the pharmaceutical compound has a carboxylic acid group and the amino acid has a backbone amino group, an amide bond can be formed between them under amide forming conditions; or

d) When the pharmaceutical compound has a carboxylic acid group and the amino acid has a side chain amino group, an amide bond can be formed therebetween under amide forming conditions.

Accordingly, the present invention relates to the prodrugs so formed. As shown below, the prodrugs so formed have advantages not achieved with prodrugs not linked to the amino acid. For example, it improves bioavailability, improves potency, is less toxic, exhibits greater solubility in water and/or improves the ability of the drug to enter cell membranes or cross the blood-brain barrier, exhibits lesser adverse effects such as gastro-intestinal sensitization Other side effects, improved therapeutic index and similar advantages.

Thus, the present invention relates to a method of improving the therapeutic properties of a drug selected from the group consisting of increased potency, increased therapeutic index, increased concentration in mammalian body fluids, relative to administration of the corresponding drug in non-prodrug form to a patient. solubility in, improved penetration of cell membranes, improved performance across the blood-brain barrier, reduced side effects such as significantly reduced irritation and/or ulceration, less toxicity, increased absorption rate, and the like, the method comprising combining the drug with The amino acids react to form a covalent bond between them and the product (hereinafter "prodrug") is administered to the patient. The prodrugs of the present invention have at least one improved property. In fact, it is preferred that they exhibit at least two of the improved properties mentioned above. Additional advantages of prodrugs include the broad range of amino acids available and the ease of reaction. The amide-forming reaction is generally efficient and highly productive, probably greater than about 70%, more preferably greater than about 80%, and most preferably greater than about 90%.

Description of drawings

Figure 1 graphically compares L-serine ester (F1) to (±) ibuprofen (Ibuprofen), (±) cloth based on the antagonistic properties of albino mice to acetylcholine-induced writhing after 1 hour of dosing. L-threonine ester (F2) of profen and (±) L-hydroxyproline ester (F3) of ibuprofen, (±) ibuprofen (i.e., racemic mixture) and ibuprofen ( S) (+) potency.

Figure 2 is a graph comparing the anti-property of albino mice to acetylcholine-induced writhing after 3 hours of dosing, to (±) L-serine ester of ibuprofen (F1), (±) ibuprofen L-threonine ester (F2) and (±) L-hydroxyproline ester of ibuprofen (F3), potency of (±) ibuprofen and (S)(+) ibuprofen.

Figure 3 illustrates the dose response relationship of L-serine ester of acetylsalicylic acid (Formulation 1) versus mean clotting time (MCT) in minutes.

Figure 4 is a graphical representation of the dose-response relationship of L-hydroxyproline ester of acetylsalicylic acid (Formulation 2) versus mean clotting time (MCT) in minutes.

Figure 5 is a graphical representation of the dose-response relationship of L-threonine ester of acetylsalicylic acid (Formulation 3) versus mean clotting time (MCT) in minutes.

Figure 6 is a graphical representation of the dose-response relationship of the control group (acetylsalicylic acid) to the mean clotting time (MCT) in minutes.

Figure 7 graphically compares L-serine ester of acetylsalicylic acid (F.1), L-threonine ester of acetylsalicylic acid (F.2), L-hydroxyproline ester of acetylsalicylic acid (F.3), and relative potency of acetylsalicylic acid (PC) as a function of mean clotting time in minutes.

Detailed Description of the Invention

As used herein, the terms "drug", "medicament", and "drug" are used interchangeably and refer to the active compound administered to a patient without the amino acid. Also, as used herein, the drug contains functional groups that are capable of reacting with the amino acid, such as _NH2 , OH, COOH, or acylated derivatives thereof (e.g., esters, anhydrides, amides, and the like) and its analogues. When the drug is linked to an amino acid, the term "amino acid prodrug" or "prodrug of the invention" or words equivalent thereto is used.

Among the amino acids useful as promoieties (ie, reactive with drugs) are those containing free amino and/or carboxylic acid groups of all conventional amino acids. Of these, some preferred embodiments include those amino acids that have relatively high solubility in aqueous media, such as at least 100 g/L, more preferably at least 250 g/L, and even more preferably at 25°C in unbuffered deionized water At least 500g/L. For example, the solubility of glycine and proline in deionized water at 25°C is approximately 250 g/L and 1620 g/L, respectively.

Other amino acids that can be used as the promoiety are those containing a basic amino side chain, such as lysine. For example, the solubility of lysine in deionized water at 25°C is about 700 g/L.

Other amino acids that can be used as the promoiety are those containing a hydroxyl side chain, such as hydroxyproline, serine and threonine. For example, the solubilities of threonine, hydroxyproline, and serine in deionized water at 25°C are approximately 100 g/L, 369 g/L, and 420 g/L, respectively.

Other preferred embodiments include those amino acids that have relatively low solubility in aqueous media, for example, a solubility in deionized water at 25°C of at most 10 g/L, or such as at most 2 g/L, or such as at most 0.6 g/L . For example, the solubility of tyrosine in deionized water at 25°C is about 0.5 g/L. Due to the limited solubility of these prodrugs, these prodrugs can be used to produce formulations with sustained release properties.

Other amino acids that can be used as the promoiety are those containing a carboxylic acid side chain, such as glutamic acid and aspartic acid. Other amino acids that can be used as promoieties are non-essential amino acids and non-naturally occurring amino acids.

其中R₀是下文列出的氨基酸的侧链：The following reaction schemes illustrate the reactions of the above-discussed drugs containing hydroxyl, carboxyl and amino groups with various amino acids. In the diagram below, when any functional group of OH, COOH or NH ₂ appears, R is a drug without this functional group, and R ₁ is

where _R0 is the side chain of the amino acid listed below:

Reaction Scheme A: where the hydroxyl group of a drug reacts with the carboxyl group of an amino acid to form an ester prodrug.

R-OH + HOOC-R ₁ -NH ₂ → RO-(C＝O)-R ₁ -NH ₂

Drug Amino Acid Amino Acid Ester Prodrug

Reaction Scheme B: where the carboxyl group of the drug reacts with the hydroxyl group of a hydroxyamino acid to form an ester prodrug, where the hydroxyl group is on the side chain.

Reaction Scheme C: where the amino group of a drug reacts with the carboxyl group of an amino acid to form an amide prodrug.

R-NH ₂ + HOOC-R ₁ -NH ₂ → R-NH(C＝O)-R ₁ -NH ₂

Drug Amino Acid Amino Acid Amide Prodrug

Reaction Scheme D: where the carboxyl group of the drug reacts with the carboxyl group of the amino acid to form an anhydride prodrug.

R-COOH + HOOC-R ₁ -NH ₂ → R-(C=O)-O-(C=O)-R ₁ -NH ₂

Drug Amino Acid Amino Acid Anhydride Prodrug

Reaction Scheme E: where the amino group of a drug reacts with the amino group of an amino acid to form an azo prodrug derivative.

R-NH ₂ + NH ₂ -R ₁ -COOH → RN＝NR ₁ -COOH

Drug Amino Acid Amino Azo Prodrug

Reaction Scheme F: where the carboxyl group of a drug reacts with the amino group of an amino acid to form an amide prodrug.

R-COOH + NH ₂ -R ₁ -COOH → R-(C=O)NH-R ₁ -COOH

Drug Amino Acid Amino Acid Amide Prodrug

In the A-F scheme above, the preferred amino acids used are as follows:

Glycine Sarcosine r-aminobutyric acid Alanine Valine Isoleucine Leucine

Serine Homoserine Threonine Carnitine Choline Aspartate Glutamate

Ornithine Lysine Paracanavanine Canavanine Arginine

Proline Asparagine Glutamine Histidine Carnosine

Phenylalanine Tyrosine Tryptophan

As used herein, the term "amino acid" refers to an organic compound or a salt thereof having a carboxyl group (COOH) and an amino group (NH ₂ ) therein. In solution, the two end groups ionize to form a diionized, neutral overall that can be considered a zwitterion. The amino group donates electrons to the carboxyl group, and its ionized end is stabilized in aqueous solution by polar water molecules.

It is the side groups that distinguish amino acids from one another. Some amino acids, such as lysine, have amino groups on their side chains; others have side chains containing hydroxyl groups, such as threonine, serine, hydroxyproline, and tyrosine; some amino acids have carboxyl groups on the side chains , such as glutamic acid or aspartic acid. These functional groups on the side chains can also form covalent bonds with drugs, such as esters, amides, and the like. When these side chain groups participate in the formation of these bonds, such as hydroxyl groups, the association can be described by OAA, where AA is an amino acid residue with a hydroxyl group on the side chain, but no hydroxyl group itself. Thus, AA therein refers to an amino acid that does not have a side hydroxyl group because it participates in the ester-forming reaction. Also, when an ester is formed between the hydroxyl group of an amino acid and the OH group of a drug, the hydroxyl group on the carboxyl group forms a by-product with the hydrogen on the hydroxyl group, therefore, the resulting product does not have an OH group on the carboxyl group, only the acyl moiety . When the combination is described as C(=O)-NHAA, it means that the amino acid forms an amide bond between the carboxyl group of the drug and the amino group of the amino acid. However, as mentioned above, since the NH of the amide bond comes from an amino acid, AA is an amino acid without an amino group.

Preferred amino acids are naturally occurring amino acids. More preferred amino acids are α-amino acids. Also preferred amino acids are in the L-configuration. Preferred amino acids include the twenty essential amino acids. Preferred amino acids are Lysine (Lys), Leucine (Leu), Isoleucine (Ile), Glycine (Gly), Aspartic Acid (Asp), Glutamic Acid (Glu), Methionine (Met), alanine (Ala), valine (Val), proline (Pro), histidine (His), tyrosine (Tyr), serine (Ser), norleucine (Nor ), arginine (Arg), phenylalanine (Phe), tryptophan (Trp), hydroxyproline (Hyp), homoserine (Hsr), carnitine (Car), ornithine (Ort ), canavanine (Cav), asparagine (Asn), glutamine (Gln), carnosine (Can), taurine (Tau), S-methylcysteine (Djk), γ-amino Butyric acid (GABA), cysteine (Cys), cystine (Dcy), sarcosine (Sar), threonine (Thr), and the like. More preferred amino acids are the twenty essential amino acids, Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser .

Prodrugs are prepared from drugs having groups capable of reacting with amino acids.

Preferred drugs that can react with amino acids according to different reaction schemes are as follows:

reaction diagram

Drugs A B C D D E E

Cyclosporins Yes

Lopinavir Yes Yes Yes

Ritonavir Yes Yes Yes

Cefdinir Yes Yes Yes Yes Yes

Zileuton Yes Yes Yes

Nelfinavir Yes Yes Yes

Flavoxate Yes Yes Yes

Candesartan Yes Yes Yes Yes Yes

Propofol Yes

Nisoldipine Yes Yes Yes Yes Yes

Amlodipine Yes Yes Yes Yes Yes

Ciprofloxacin Yes Yes Yes Yes Yes

Ofloxacin Yes Yes Yes Yes Yes

Fosinopril Yes Yes Yes

Enalapril Yes Yes Yes

Ramipril Yes Yes Yes

Benazepril Yes Yes Yes

Moexipril Yes Yes Yes

Trandolapril Yes Yes Yes

Cromoglycate Sodium (Cromolyn) Yes Yes Yes Yes

Amoxicillin Yes Yes Yes Yes Yes Yes

Cefuroxime Yes Yes Yes Yes Yes Yes Yes

Ceftazimide Yes Yes Yes Yes Yes Yes

Cefpodoxime Yes Yes Yes Yes Yes Yes

Atovaquone Yes

Gancyclovir Yes Yes Yes

Penciclovir Yes Yes Yes

Famciclovir Yes Yes Yes

Acyclovir Yes Yes Yes

Niacin Yes Yes Yes

Bexarotene Yes Yes Yes

Propoxyphene Yes

Salsalate Yes Yes Yes Yes

Acetaminophen Yes

Ibuprofen Yes Yes Yes

Lovastatin Yes Yes Yes Yes

Simavastatin Yes Yes Yes Yes Yes

Atorvastatin Yes Yes Yes Yes

Pravastatin Yes Yes Yes Yes Yes

Fluvastatin Yes Yes Yes Yes Yes

Nadolol Yes

Valsartan Yes Yes Yes

Methylphenidate Yes Yes Yes Yes

Sulfa Drugs Yes Yes

Sulfasalazine Yes

Medroxyprogesterone Yes

(Medroxyprogesterone)

Methylprednisolone Yes

(Methylprednisolone)

Estramustine Yes

Miglitol Yes

Mefloquine Yes Yes

Capacitabine Yes

Danazol Yes

Eprosartan Yes Yes Yes

Divalproex Sodium (Divalproex) Yes Yes

Fenofibrate Yes Yes Yes

Gabapentin ^* Yes Yes Yes Yes Yes

Omeprazole Yes

Lansoprazole Yes

Megestrol Yes

Metformin Yes

Tazorotene Yes Yes Yes

Sumitriptan Yes

Naratriptan Yes

Zolmitriptan Yes

Aspirin Yes Yes Yes

Olmesartan Yes Yes Yes

Sirolimus Yes

Tacrolimus Yes

Clopidogrel Yes Yes Yes

Amphotericin B Yes Yes Yes Yes

(Amphotericin B)

Tenofovir Yes

Unoprostone Yes Yes Yes

Fulvestrant Yes

Cefditoren Yes Yes Yes

Efavirenz Yes

Eplerenone Yes Yes Yes

Treprostinil Yes Yes Yes Yes

Adefovir Yes

The prodrugs of the present invention contain amino groups and are therefore basic in nature. They are capable of forming various pharmaceutically acceptable salts with various inorganic and organic acids. Acids which can be used to prepare the pharmaceutically acceptable acid addition salts of these basic compounds are those acids which form non-toxic acid addition salts, i.e., those containing a pharmaceutically acceptable anion. Salts such as hydrochlorides, hydrobromides, hydroiodides, nitrides, sulfates, hydrogensulfates, phosphates, formates, acetates, citrates, tartrates, lactates, and its analogues.

As indicated herein, in one embodiment, the present invention relates to a prodrug, wherein the prodrug comprises a drug such as cyclosporine A (cyclosporine) and esterified to MeBmt (xy=CH=CH) or dihydro Amino acids of _the MeBmt moiety (xy= _CH2CH2 ). Amino acids are linked to cyclosporine A and to other drugs by covalent bonds.

The compounds of the present invention are prepared by techniques well known in the art. For example, if the drug contains an OH group, such as cyclosporine, the amino acid or its acylated derivative or amino acid alkyl ester reacts with the carboxyl group of the drug, such as cyclosporine A, under esterification conditions, the amino acid Acylated derivatives such as acid halides, such as amino acid fluoride, amino acid chloride, and the alkyl group in the amino acid alkyl ester contains 1-6 carbon atoms. Preferably, the reaction takes place in the presence of an acid such as hydrochloric acid, hydrobromic acid, p-toluenesulfonic acid and similar acids. Alternatively, as described above, if the drug has an amino group, the amino acid can react with the drug under amide forming conditions to form an amide as a covalent bond. Or if the drug has a carboxyl group or an acylated derivative, the carboxyl group or acylated derivative can react with the amino group of the amino acid under amide forming conditions to form an amide to form an amide bond between the amino acid and the drug. In addition, as mentioned above, if the drug has a carboxyl group, the hydroxyl group of the side chain of the amino acid can react with the carboxyl group or an acylated derivative under esterification reaction conditions to form an ester bond between the amino acid and the drug.

If the amino acid has a reactive group under the reaction conditions, it can be protected by a protecting group well known in the art. After the reaction is complete, the protecting group is removed. Examples of protecting groups that can be used are described in the book entitled "Protective Group in Organic Synthesis" by Theodora W. Greene, John Wiley & Sons, 1981, the contents of which are incorporated by reference.

For example, if amino acids have carboxyl groups on their side chains, such as aspartic acid and glutamic acid, which can be used in the aforementioned synthesis, they usually require protection of the side chain carboxylic acid. Suitable protecting groups may be esters such as cyclohexyl ester, tert-butyl ester, benzyl ester, allyl ester, 9-fluorophenyl-methyl or adamantyl such as 1- or 2 - an adamantyl group, which can be protected after completion of the esterification reaction using techniques well known to those of ordinary skill in the art.

If the amino acid has a hydroxyl group on the side chain, such as serine, threonine, hydroxyproline, etc., and an amino acid with a phenol group on the side chain, such as tyrosine, etc., when used in the aforementioned esterification reaction, They will desirably require protection of the side chain hydroxyl or phenol groups. Suitable protecting groups for hydroxy side chain groups may be ethers such as benzyl ether or tert-butyl ether. Benzyl ether is removed by the action of liquid hydrogen fluoride, while tert-butyl ether can be removed by treatment with trifluoroacetic acid. Suitable protecting groups for the phenol side chain group may be ethers, as described above, including benzyl ether or tert-butyl ether or 2,6-dichlorobenzyl, 2-bromobenzyloxycarbonyl, 2, 4-Dinitrophenyl, etc.

Furthermore, the product may be purified to render substantially pure by techniques well known to those of ordinary skill in the art, for example, by chromatography such as HPLC, crystallization and the like. Substantially "pure" means that the product contains no more than about 10% impurities.

Prodrugs can be made into pharmaceutical compositions, including said prodrugs, or pharmaceutically acceptable salts, pharmaceutically acceptable solvates, esters, enantiomers, diastereoisomers, N-O compounds, The polymorphs, as described herein, are accompanied by a pharmaceutically acceptable carrier, and optionally, but desired, pharmaceutically acceptable excipients using techniques well known to those of ordinary skill in the art.

Prodrugs for use in the present methods are used in therapeutically effective amounts.

The physician will determine the most suitable dosage of the prodrugs of the present invention, and the dosage will vary with the form of administration and the particular compound chosen, and further, it will vary depending on various factors including, but not limited to, receiving The patient to be treated and the patient's age, severity of the disease being treated, etc. and knowledge of the prodrug being administered. Physicians will generally desire to initiate treatment with small doses substantially less than the optimum dose of the compound and to increase the dose by small increments until the optimum effect under the circumstances is achieved. It will generally be found that when the composition is administered orally, larger amounts of active agent will be required to produce the same effect as smaller amounts administered by injection. These compounds can be administered in the same manner as the corresponding non-prolonged forms of the drug, and at dosage levels of the compounds of the same order of magnitude normally employed with other therapeutic agents. When administered by injection, the compound is usually administered at a dose of, for example, about 0.001 to about 10,000 mg/kg/day, which also depends on the subject and the severity of the disease to be treated and the compound used.

In a preferred embodiment, the compound employed is administered orally in an amount of from about 0.01 mg to about 1000 mg per kilogram of body weight per day, depending on the particular mammalian subject or disease to be treated, more preferably from about 0.1 to about 500 mg /kg body weight per day. This dosage regimen can be adjusted by the physician to obtain the optimum therapeutic response. For example, several divided doses may be administered daily or, as indicated, the dose may be reduced accordingly as the exigencies of the therapeutic situation manifest.

Prodrugs may be administered in any convenient manner, such as orally, intravenously, intramuscularly or subcutaneously.

Prodrugs can be administered orally, for example, with an inert diluent and an absorbable edible carrier, or sealed in hard or soft shell capsules, or compressed into tablets, or added directly to recipes in food. For oral therapeutic administration, the prodrugs can be combined with excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, wafers and the like. Such compositions and preparations should contain at least 1% prodrug. The percentages of compositions and formulations can, of course, vary, and will generally range from about 5 to about 80 percent by weight of the unit. The amount of prodrug used in such therapeutic compositions is such that a suitable dosage will be obtained. According to the present invention, preferred compositions or formulations contain between about 200 mg and about 4000 mg of prodrug. Tablets, lozenges, pills, capsules, etc. may also contain the following ingredients: a binder such as tragacanth, acacia, cornstarch or gelatin; excipients such as dicalcium phosphate; , potato starch, alginic acid, etc.; lubricants such as magnesium stearate; sweeteners such as sucrose, lactose, or saccharin may be added, or flavoring agents such as peppermint, oil of wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier.

Other various materials may serve as coatings or to modify the physical form of the dosage unit. For example, tablets, pills, or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and employed in substantially nontoxic amounts. In addition, the active compounds can be incorporated into sustained release formulations and formulations. For example, sustained release dosage forms can be designed in which the active ingredient is bound to an ion exchange resin, which can optionally be coated with a diffusion barrier layer to adjust the release properties of the resin, or where the prodrug of the invention is combined with an ion exchange resin well known in the art. A sustained release polymer such as hydroxypropylmethylcellulose and similar substances.

Prodrugs can also be administered injectably or intraperitoneally. It is especially advantageous to formulate injectable compositions in dosage unit form for ease of administration and uniformity of dosage. Dispersions in glycerol, liquid polyethylene glycols, such as PEG 100, PEG 200, PEG 300, PEG 400 and the like, and mixtures thereof and in oils can also be prepared. Under ordinary conditions of storage and use, these products contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. In all cases the pharmaceutical form is generally sterile and fluid to the extent that it can be syringable. It must be stable under the conditions of manufacture and storage and usually must remain free from the contamination of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and one or more liquid polyethylene glycols, as disclosed herein, and the like), its suitable mixture, and vegetable oil. Proper fluidity can be maintained, for example, by using a coating such as lecithin, by maintaining the desired particle size in the dispersion, and by using surfactants. Microbial activity can be prevented by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, such as sugars and sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents which delay absorption, such as aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the prodrug in the required amount in an appropriate solvent with various other ingredients enumerated above as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders, the above solutions are vacuum-dried or freeze-dried as necessary.

Prodrugs may also be administered topically, such as, for example, from patches using techniques well known to those of ordinary skill in the art. Prodrugs may be administered buccally by preparing suitable formulations of the prodrugs of the invention and using procedures well known to those skilled in the art. The formulations are prepared with suitable non-toxic pharmaceutically acceptable ingredients. The ingredients used in the preparation of elixirs are well known to those skilled in the art. Some of these ingredients are described in the literature (Remington's Pharmaceutical Sciences, ^17th edition, 1985), a standard reference in this field. The choice of a suitable carrier will depend considerably on the precise nature desired for the buccal formulation, such as tablets, lozenges, gels, plasters and the like. All such formulations are considered to be within the scope of the present invention, and they are prepared by conventional methods.

Pharmaceutical composition formulations can be prepared using conventional methods using one or more physiologically and/or pharmaceutically acceptable carriers or excipients. Thus, the compounds and their pharmaceutically acceptable salts and solvates can be prepared for inhalation or insufflation (through the mouth or nose) or for oral, buccal, injectable, or rectal administration. For oral administration, the pharmaceutical composition may take the form of, for example, tablets or capsules prepared by conventional methods in combination with pharmaceutically acceptable excipients such as binders (e.g., pre- gelatinized cornstarch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose), fillers (e.g., lactose, microcrystalline cellulose, or dibasic calcium phosphate), lubricants (e.g., magnesium stearate, talc, or dibasic silicon oxide), disintegrants (eg, potato starch, or sodium starch glycolate), or wetting agents (eg, sodium lauryl sulfate). Tablets can be coated by methods well known in the art.

Liquid preparations for oral administration may take the form of, for example, solutions, syrups, or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional methods together with pharmaceutically acceptable additives such as suspending agents (for example, sorbitol syrup, corn syrup, cellulose derivatives or hydrogenated edible oils and fats), emulsifying agents (for example, lecithin or acacia), no-aqueous vehicle (for example, almond oil, oily esters, regular alcohol, or rectified vegetable oil), and preservative (for example, methyl or propyl parabens or sorbic acid). The formulations may also contain suitable buffer salts, flavouring, coloring and sweetening agents. Formulations for oral administration may be suitably formulated to provide controlled release of the active prodrug.

The prodrugs of the invention may be prepared for parenteral administration by injection, such as bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, eg, in ampoules, or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, prodrugs may be in powder form for constitution with a suitable vehicle, eg sterile pyrogen-free water, before use.

The prodrugs of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the prodrugs of the invention can also be prepared as a depot formulation. Such long-acting formulations may be administered by implantation (eg, subcutaneously or intramuscularly), or by intramuscular injection. Thus, for example, prodrugs may be prepared with suitable polymeric or hydrophobic materials (eg, emulsions in acceptable oils) or ion exchange resins, or sparingly soluble derivatives such as sparingly soluble salts.

The pharmaceutical compositions containing the prodrugs of the invention may, if desired, be presented in a pack or dispenser device which may contain one or more unit doses containing the active ingredient. The pack may for example comprise a foil of metal or plastic, for example a blister pack. The pack or dispenser device can provide instructions for administration.

In tablet form, it is desirable to include a lubricant, which facilitates the method of manufacturing the dosage unit; the lubricant may also optimize erosion and drug flow rates. If present, lubricants are present in an amount of about 0.01 wt.% to about 2 wt.%, preferably about 0.01 wt.% to 0.5 wt.% of the dosage unit. Suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, sodium stearylfumarate, talc, hydrogenated vegetable oils and polyethylene glycols. However, as will be appreciated by those skilled in the art, adjusting the particle size and/or unit density of the ingredients in the dosage unit can provide similar effects, namely improved manufacturability and improved manufacturability, without the addition of lubricants. Optimize erosion rate and drug flow.

Other ingredients may optionally be incorporated into dosage units. Such additional optional components include, for example, one or more disintegrants, diluents, binders, enhancers, and the like. Examples of disintegrants that may be used include, but are not limited to, cross-linked polyvinylpyrrolidones, such as crospovidone (e.g., Polyplasdone-XL, available from GAF), cross-linked carboxymethylcelluloses, such as Croscanmelose (e.g., Ac-di-sol_, available from FMC), alginic acid, sodium carboxymethyl starches (e.g., Explotab_, available from Edward Medell Co., Inc. .obtained), bentonite agarose and alginic acid. Suitable diluents are those commonly used in formulations prepared using compression techniques, e.g. dibasic calcium phosphate dihydrate (e.g., Di-Tab®, available from Stauffer), sugars crystallized with dextrin (eg, co-crystallized sucrose, dextrins such as Di-Pak® available from Amstar), calcium phosphate, cellulose, kaolin, mannitol, sodium chloride, dried starch, powdered sugar, and the like. Adhesives can be used to enhance adhesion. Examples of such binders include, but are not limited to, starch, gelatin, and sugars such as sucrose, glucose, molasses, and lactose. Penetration enhancers may also be present in the novel dosage units to increase the rate at which the active agent crosses the oral mucosa. Examples of penetration enhancers include, but are not limited to, dimethylsulfoxide ("DMSO"), dimethylformamide ("DMF"), N,N-dimethylacetamide ("DMA"), decane Methyl sulfoxide ("C ₁₀ MSO"), polyethylene glycol monolaurate ("PEGML"), glycerol monolaurate, lecithin, 1-substituted azepan-2-ones, especially 1 -n-dodecylcycloazepan-2-one (sold under the trademark Azone.RTM. from Nelson Research & Development Co., Irvine, Calif.), lower alkanols (e.g., ethanol), SEPA_ (sold Macrochem Co., Lexington, Mass.), cholic acid, taurocholic acid, bile salt type enhancers, and surfactants such as Tergitol_, Nonoxynol-9_ and TWEEN-80_.

Flavoring agents may optionally be included in various pharmaceutical formulations. Any suitable flavoring agent may be used, for example mannitol, lactose or artificial sweeteners such as Aspartam. Colorants can be added, although these agents are not required. Examples of colorants include any water soluble FD&C pigments, mixtures thereof, or corresponding lakes.

In addition, if desired, the dosage unit may be formulated with the addition of one or more preservatives or bacteriostatic agents, such as methylparaben, propylparaben, chlorocresol, benzalkonium chloride, or the like .

As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents known in the art for pharmaceutically active substances. Their use in therapeutic compositions is envisioned in addition to any conventional media or agents incompatible with the prodrugs. Supplementary active ingredients can also be incorporated into the compositions.

Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of prodrug calculated to produce the required pharmaceutical carrier, in association with the required pharmaceutical carrier. The desired therapeutic effect of the prodrug.

For convenient and effective administration, an effective amount of the prodrug is combined with a suitable pharmaceutically acceptable carrier in dosage unit form as previously described. For example, a unit dose may contain from about 10 mg (eg, for humans) or as low as 1 mg (for small animals) to about 2000 mg of the principal active compound. If formulated as a solution, the concentration of the prodrug preferably ranges from about 10 mg/mL to about 250 mg/mL. For compositions containing auxiliary active ingredients, the dosage is determined with reference to the usual dosage and the way of administering the composition. In the case of buccal administration, the amount of prodrug present in a buccal unit dosage form is from about 10 to about 50 mg.

The prodrugs of the present invention are effective for the treatment of diseases or conditions, wherein corresponding drugs (without the amino acid prodrugs of the present invention) are commonly used.

As used herein, the term "treating" when used refers to reversing, alleviating or inhibiting the progress of a disease, disorder or condition, or one or more symptoms of such a disease, disorder or condition. As used herein, "treating" can also refer to reducing the probability or incidence of a disease, disorder or condition in a mammal compared to an untreated control population, or compared to the same mammal before treatment. For example, as used herein, "treating" can refer to preventing a disease, disorder or condition, and can include delaying or arresting the onset of, or delaying or preventing the symptoms of, the disease, disorder or condition. As used herein, "treating" can also refer to lessening the severity of, or the symptoms accompanying, a disease, disorder, or condition before a mammal is afflicted by the disease, disorder, or condition. Such prevention and lessening of the severity of a disease, disorder or condition before the patient is afflicted by the disease, disorder or condition, as described herein, involves administering a composition of the invention to a patient for a period of time and Not when the patient is afflicted by the disease, disorder or condition. As used herein, "treating" can also refer to preventing the recurrence of a disease, disorder or condition, or arresting the recurrence of symptoms that accompany such a disease, disorder or condition. As defined above for "treatment," the terms "treatment" and "therapeutically" are used herein to refer to the act of treatment.

"Patient" or "subject" as used herein refers to a warm-blooded animal, preferably a mammal, such as cats, dogs, horses, cows, pigs, mice, rabbits and primates including humans. Preferred patients are humans.

The prodrugs of the present invention exhibit the same potency as their counterparts without amino acid linkages. Prodrugs exhibit enhanced therapeutic properties. That is, the prodrugs of the invention exhibit at least one, and more preferably at least two, enhanced therapeutic properties relative to drugs that are not converted to the prodrugs of the invention prior to administration. These therapeutic properties include (but are not limited to):

a. Improved taste, smell

b. Desired octanol/water partition coefficient (ie, solubility in water/oil)

Various amino acids have different solubility in aqueous solution. By choosing specific amino acids, the octanol-water partition coefficient can be influenced. For example, many of the drugs listed below are highly hydrophobic. Amino acids are highly hydrophilic. For example, suppose propofol is the drug and lysine is the amino acid. Propofol is completely insoluble in water, while lysine can be dissolved to the extent of 700mg/ml. When these two different molecules are esterified by an ester bond, the resulting lysine ester of propofol has a solubility in water of more than 250 mg/ml.

On the other hand, cromolyn sodium is highly water soluble. In fact, it is not absorbed when administered orally. Absorption can be enhanced by affecting its water solubility. In this case, the opposite of propofol would be looked for, ie, the goal is to reduce water solubility. By choosing a suitable amino acid of low water solubility, such as tyrosine, a proper hydrophilic/lipophilic balance can thus be achieved.

c. Improved in vitro and in vivo stability

d. Increase the permeability of the blood-brain barrier

e. Elimination of the hepatic first-pass effect, i.e., the drug is not metabolized in the liver and thus more drug is in the systemic circulation

f. Reduction of entero-hepatic recirculation (improved bioavailability)

g. Painless injection of parenteral preparations

h. Improved bioavailability

i. Changes that increase absorption (ratio of increase to lack)

j. Reduce side effects

k. Dose proportionality

Dose proportionality requires that when the drug is administered in increasing doses, proportionally increasing amounts of the active drug are released into the blood. Dose proportionality is measured by determining the area under the plasma concentration and drug-time curve obtained after administration by any route other than the IV route, and measuring the concentration in plasma/blood at the same The area under the plasma concentration and drug-time curves. The simple mathematical procedure is as follows: For example, the drug is administered at eg 3 different doses, 10, 100 and 1000 mg, the patient is orally administered, and the area under the plasma concentration and drug-time curve (AUC) is measured. Each total AUC is then divided by the dose and the result should be the same for the 3 doses. If so, then there is dose proportionality. Dose disproportionality indicates that any one or more of the pharmacokinetic/pharmacological mechanisms are saturable, including absorption, metabolism, or the number of receptor sites available for pharmacological response.

For example, in the above study, given the resulting AUC values of 100, 1000, and 10,000, dose proportionality is not appropriate. In the absence of dose proportionality, there will be greater or lesser amounts of drug in the plasma, depending on which mechanism is saturable. Here are a few possibilities:

Saturable absorption. If this is the case, as the dose increases, the proportionality decreases and less drug is absorbed, so the total AUC will decrease as the dose increases.

Saturable elimination metabolism. If this is the case, then more and more of the drug will be circulating in the blood and the AUC will increase with the dose.

Saturable pharmacological receptor sites: In this case, any additional drug will not increase the response since all receptor sites will eventually be occupied by the drug. Therefore, dose increases do not result in increased responses.

Dose proportionality is an excellent response state because pharmacological response and therapeutic efficacy can be accurately predicted at all doses. Such dose proportionality is a desirable property for any drug. Furthermore, achieving dose proportionality also depends on formulation and fed/fasted differences.

l. Selective hydrolysis of prodrugs at the site of action

m. Controllable release performance

n.Targeted drug delivery

o. Reduced toxicity, thereby increasing the therapeutic rate

p. to reduce the dose

q. Altering metabolic pathways to release more drug at the site of action

r. Increase solubility in aqueous solution

s. enhance potency

Therefore, prodrugs of amino acids are available in various dosage forms and are prepared by conventional methods:

i. Oral liquid formulations (controlled-release and immediate-release liquids, with or without sugar, with or without coloring, with or without alcohol, including chewable tablets)

ii. Oral solid preparations (controlled-release and immediate-release tablets, capsules and capsule-shaped sugar-coated tablets)

iii. Intravenous administration (injection, ready-to-use and lyophilized powder)

iv. Intramuscular administration (injection, ready-to-use and lyophilized powder)

v. Subcutaneous administration (injection, ready-to-use and lyophilized powder)

vi. Transdermal administration (mainly ointment)

vii. Nasal administration (spray, formulation for spray therapy)

viii. Topical administration (cream, ointment)

ix. Rectal administration (creams, ointments, and suppositories)

x. Vaginal administration (creams, ointments, and pessaries)

xi. Eye administration (drops and ointments)

xii. Oral Administration (Chewable and Instant Chewable Tablets)

Many of the drugs discussed herein, especially the tablets described below, are characterized by being highly hydrophobic and prone to sedimentation in the presence of small amounts of water, such as when in contact with the body (eg, gastric fluids). It is therefore particularly difficult to provide, for example, oral dosage forms which are acceptable to the patient in form and taste, which are stable on storage and which can be routinely administered to provide suitable and manageable dosages.

The proposed liquid formulations shown in the table here, like many drugs for oral administration, have hitherto been mainly based on the use of ethanol and oils or similar excipients as carrier media. Therefore, drinking solutions of many drugs offered on the market employ ethanol and olive oil or corn oil as a carrier medium in combination with a solvent system comprising, for example, ethanol and LABRIFIL and equivalent excipients as a carrier medium. For example, cyclosporine drinking solutions available on the market use ethanol and olive oil or corn oil as a carrier medium in combination with the surfactant Labroid. See, eg, US Patent No. 4,388,307. However, a number of difficulties are associated with the use of drinking solutions and similar compositions proposed in the art.

Furthermore, the palatability of known oil-based systems is problematic. In particular, the taste of known drinking solutions of various drugs is unpleasant. Mixtures with an appropriately flavored drink which is added to a pharmaceutical preparation in high dilution before ingestion into the body, such as a chocolate drink preparation, have been used to make conventional therapy fully acceptable. Employing an oil-based system also requires the use of high ethanol concentrations, so that this in itself is inherently undesirable, especially foreseeable when administered to children. In addition, volatilization of ethanol, such as from capsules (which has been heavily employed to address the palatability issues discussed or other issues (eg, when opening)), will lead to the generation of drug precipitation. For example, when such compositions are in the form of soft gelatin microcapsules, this particular difficulty necessitates the encapsulation of such microcapsule products in airtight elements, for example, air-tight blisters (blisters) or aluminum - Foil blister. This makes the product bulky and more expensive to produce. Furthermore, the storage properties of the aforementioned formulations are far from ideal.

For the large number of drugs described herein, the levels of bioavailability achieved using existing oral drug delivery systems are also low, and show large variability between individuals, across patient types, and even within the same individual at different times during treatment. difference. Literature reports show that the average absolute bioavailability obtained by adopting the existing treatment scheme of the drug drinking solution sold on the market is only about 10-30%, and there are significant differences between each group, such as in the liver (relatively low bioavailability degree) and bone marrow (relatively high bioavailability) transplant recipients. Inter-subject variability in bioavailability has been reported from one or a few percent in some patients to 90% or more in others. As already noted, significant changes in individual bioavailability over time are often observed. Thus, there is a patient need for more uniform and higher bioavailability of many of the drugs described herein.

The use of such dosage forms is also characterized by wide variation in the desired patient dosing. For effective treatment, drug blood or serum levels must be within a specific range. This desired range can in turn vary depending on the particular condition being treated, such as whether the treatment prevents one or more pharmacological effects of a particular drug, and whether alternative treatments are employed when accompanied by the primary treatment. Because of the considerable variability in the resulting bioavailability of conventional dosage forms, the daily dosage required to achieve the desired serum level will also vary significantly from one individual to another and even within the same individual. Therefore, blood/serum levels must be monitored at regular and frequent intervals in patients receiving drug therapy. Monitoring of blood/serum levels must be done routinely. This is inevitably time-consuming and inconvenient, and adds significantly to the overall cost of treatment.

Blood/serum levels achieved with existing drug delivery systems also exhibit wide variation between peak and trough values for a number of drugs described herein. That is, for each patient, the level of effective drug in the blood varies widely between administrations of individual doses.

A water-soluble form for injection is also required for a large number of drugs described herein, in particular beta-lactam antibiotics, cyclosporins, cephalosporins, steroids, quinolone antibiotics and cyclosporine. It is well known that Cremaphore L_ (CreL) currently used in formulations is a polyethoxylated derivative of castor oil and is a toxic excipient for a large number of drugs described herein below. A large number of allergic reactions have been reported due to this castor oil component. Due to the low water solubility of the drugs, there are currently no formulations that would allow many of the drugs in this condition to be present in aqueous solutions at the required concentrations.

In addition to these very obvious practical difficulties with existing oral dosage forms, undesired side effects have also been implicated.

Many proposals have been made in the art to address the various problems described, including solid and liquid oral dosage forms. A major difficulty that remains, however, is the inherent insolubility of many of the drugs shown in the table below in aqueous media, thus preventing the dosage form from containing the drug at a level that meets the criteria for ease of use and desired bioavailability. Sufficiently high concentrations, eg, to enable efficient absorption from the stomach or intestinal lumen and to achieve consistently and appropriately high blood/serum levels.

The particular difficulties encountered with regard to the oral administration of these drugs will inevitably impose limitations on the use of specific drugs for the treatment of relatively less serious or less dangerous disease conditions. A particular area of difficulty with cyclosporine as a test drug, for example, is the use of cyclosporine in the treatment of autoimmune diseases and other conditions affecting the skin, such as the treatment of atopic dermatitis and psoriasis, and in this It is widely proposed in the field for stimulating hair growth, such as for treating alopecia caused by aging or disease.

Thus, although oral cyclosporine treatment represents a considerable potential benefit of this drug for patients with conditions such as psoriasis, the risk of side effects associated with oral treatment prevents the general use of this drug. A number of proposals have been made in the art for the application of cyclosporine, eg topical cyclosporine and numerous topical delivery systems have been described. However, attempts at topical application have not yet provided any definitive effective therapy.

However, the present invention overcomes the above-mentioned problems. More specifically, the prodrugs of the present invention significantly increase the solubility of the drug in aqueous solutions relative to the non-prodrug form of the drug, thereby eliminating the need to employ carriers such as ethanol or castor oil when administered in solution. Furthermore, according to the present invention, the prodrugs of these drugs do not exhibit the side effects of the formulations of the prior art. Further, it has been found that oral absorption is increased for many of the drugs in the table below when administered in the form of prodrugs according to the invention, thereby significantly enhancing its bioavailability and potency.

Preferred drugs that combine with amino acids to form prodrugs are listed in the table below, with the benefit shown in the penultimate column of the table. In the form, the retrieval table is as follows:

a) Improved taste and smell

b) desired octanol/water partition coefficient (i.e. solubility in water)

c) Improved stability in vitro and in vivo

d) blood-brain barrier permeability

e) Elimination of liver first-pass effect

f) Decreased enterohepatic recirculation

g) Painless injection of parenteral preparations

h) Improved bioavailability

i) Increase absorption rate

j) Reduce side effects

k) Dose proportionality

l) Selective hydrolysis of the prodrug at the site of action

m) Controlled release properties

n) targeted drug delivery

o) Reduced toxicity, thereby increasing therapeutic rates

p) reduce dose

q) Altering metabolic pathways to release more drug at the site of action

Also, the table shows the potency of the prodrugs. The utility of a prodrug is the same as that of the corresponding drug (without the linked amino acid moiety). The utility is described in documents such as "The Physicians Desk Reference, 2004 edition", the contents of which are incorporated herein by reference.

Amino acid prodrugs of Applicable dose range Preferred Dosage Range The most preferred dose range Amino acids that can react with drugs to form ester/amide/azo/anhydride prodrugs preferred amino acid most preferred amino acid Improving immune potency of prodrugs effect Cyclosporine Preferred Formulation Oral Tablet/Capsule Oral Liquid Intravenous Injection All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar or a dipeptide consisting of any two amino acids, especially AA-Gly, where Gly is the spacer attached to cyclosporine and AA is the amino acid listed above . Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar or any two amino acids Dipeptides, especially AA-Gly, where Gly is the spacer attached to cyclosporine and AA is the amino acid listed above. Dipeptides of Lys, Pro, , Gly and Lys-Gly, Pro-Gly, Gly-Gly b, e, f, g, h, k, l, o, and p Prevention of organ rejection such as kidney, liver and heart allografts, treatment of rheumatoid arthritis and psoriosis 5-1000mg1-25mg/ml10-250mg/5ml 20-250mg5-15mg/ml25-100mg/5ml 25-100mg10mg/ml50mg/5ml Lopinavir Preferred Dosage Form Oral Tablet/Capsule Oral Liquid All dosages are indicated on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Pro, Gly, and Ala b, h, j, k, and o Treatment of human immunodeficiency virus (HIV) infection, such as acquired immunodeficiency syndrome (AIDS, AIDS) 0.1-1mg0.1-1mg/5ml 200-800mg0.2-0.8g/5ml 400-500mg400mg/5ml

Cefdinir preferred dosage form Oral tablet/capsule Oral liquid IV infusion         All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Lle, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Tyr, and Thr a, b, e, f, h, i, o, and p For Haemophilus influenzae, including β-lactamase-producing strains, eg, Haemophilus parainfluenzae (including β-lactamase-producing strains) and Moraxella (including β-lactamase-producing strains ), and Streptococcus pyogenes; antibiotic treatment for conditions such as pneumonia, bronchitis, and sinusitis, pharyngitis, and tonsillitis 0.1-1mg0.1-1mg/5ml0.01-1mg/100ml 0.2-0.5mg0.2-0.5mg/5ml20-500mg/100ml 200-400mg0.2-0.4mg/5ml50-150mg/l00ml Zileuton Preferred Formulation Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Gly, Lys, Sar, Ala, Pro b, h, i, j, k, o, p treat asthma 200-1200mg200-1200mg/5ml 200-800mg200-800mg/5ml 300-400mg200-400mg/5ml Nelfinavir Preferred Dosage Form Oral Tablet/Capsule Oral Powder Intravenous Formulation All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Gly, Lys, Sar, Aia, Pro b, h, i, j, k, o, p Treat human immunodeficiency virus (HIV) infections such as AIDS 0.05-1mg10-250mg/gm10-250mg/100ml                0.1-0.5mg20-200mg/gm20-200mg/100ml 0.2-04mg40-100mg/gm40-100mg/100ml

Flavoxate preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Tyr, and Thr b, h, i, j, k, l, o, and p Treatment of urinary spasms   10-1000mg10-1000mg/5ml 20-500mg20-500mg/5ml             50-250mg50-250mg/5ml              Candesartan preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Tyr, and Thr b, c, e, f, h, i, j, k, l, o, p, q treat high blood pressure   1-100mg1-100mg/5ml 2-75mg2-75mg/5ml 4-504-50mg/5ml Propofol Preferred Dosage Form Intravenous Infusion              All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Gly, Lys, Sar, Pro, Ala, and Val b, c, d, g, h, j, k, l, m, n, o, p, q anesthetize the central nervous system 1-25mg/ml 2.0-20mg/ml                    5-15mg/ml                  Nisoldipine Preferred Dosage Form Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Gly, Lys, Ser, and Hyp b,e,h,i,j,o Calcium channel blockers for the treatment of high blood pressure 2-100mg2-100mg/5ml 2.5-75mg2.5-75mg/5ml 5-50mg5-50mg/5ml

  Amlodipine Preferred Dosage Form Oral Tablet/Capsule Oral Liquid All doses are expressed on a drug basis IV Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Gly, Lys, Ser, and Hyp b, e, h, i, j, o Calcium channel blockers for the treatment of high blood pressure 0.1-20mg0.1-20mg/5ml               1-10mg             1-10mg/5ml             2.5-5mg      2.5-5mg/5ml      Ciprofloxacin Preferred Formulation Oral Tablet/Capsule Oral Liquid IV Bulk (Sterile) All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Thr, Gly, and Lys a,b,c,g,h,i,j,k,o,p Antibiotics; inhibit various bacteria such as Pseudomonas aeruginosa, Staphylococcus aureus or Proteus mirabilis; treat corneal ulcers, conjunctivitis, acute otitis externa 0.1-1.5mg0.05-1mg/5ml2-25mg/ml             0.1-1.0mg0.08-1mg/5ml3-20mg/ml             0.2-0.8mg0.12-1g/5ml5-15mg/ml           Preferred dosage form of ramipril oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Thr, Gly, and Lys j, o treat high blood pressure 0.1-20mg0.1-20mg/5ml 0.5-12mg0.5-12mg/5ml 1-10mg1-10mg/5ml

Trandolapril Preferred Form Oral Tablet/Capsule Oral Liquid                All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly, and Lys j, o treat high blood pressure   0.1-10mg0.1-10mg/5ml 0.5-7.5mg               0.5-7.5mg/5ml                  1-4mg             1-4mg/5ml              Fosinopril preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly, and Lys j, o treat high blood pressure   1-100mg1-100mg/5ml 2-75mg2-75mg/5ml 5-50mg5-50mg/5ml  Enalapril preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly, and Lys j, o treat high blood pressure 0.5-100mg0.5-100mg/5ml               1-50mg1-50mg/5ml             2-25mg2-25mg/5ml              Benazepril preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Orr, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Thr, Gly, and Lys j, o treat high blood pressure 1-100mg1-100mg/5ml           2-75mg2-75mg/5ml            2.5-50mg2.5-50mg/5ml          

Perindopril preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Thr, Gly, and Lys j,o treat high blood pressure 0.1-20mg0.1-20mg/5ml 0.5-15mg0.5-15mg/5ml 1-10mg1-10mg/5ml Moexipril preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly, and Lys j,o treat high blood pressure 1-30mg1-30mg/5ml 2-20mg          2-20mg/5ml              5-15mg               5-15mg/5ml            Cromolyn sodium preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, and Pro b, c, h, i, j, k, l, n, o, p, q Inhibit the secretion of histamine and leukotrienes from mast cells; treat mastocytosis, asthma 10-200mg10-200mg/5ml             20-100mg20-100mg/5ml 20-50mg20-50mg/5ml

Amoxicillin Preferred Form Oral Tablet/Capsule ^* Oral Liquid Oral Powder ( ^* Chewable also available) All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly and Lys a, b, c, h, i, j, k, l, o, p Antibiotics effective against beta-lactamase-negative strains that cause ear, nose, and throat infections, such as Streptococcus, Staphylococcus, or Haemophilus influenzae; treatment of genitourinary tract infections caused by Escherichia coli, Proteus mirabilis, and Enterococcus faecalis , skin infections caused by Streptococcus, Staphylococcus, or E. coli, lower respiratory tract infections caused by Streptococcus, Staphylococcus, Haemophilus influenzae, and gonorrhea 0.1-1.5mg         0.1-1.5mg/5ml         0.1-0.75mg          0.2-1.2mg             0.2-1.2mg/5ml           0.1-0.6mg 0.25-1mg           0.25-1mg/5ml          0.125-0.5mg Cefuroxime preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Thr, Gly, and Lys b, c, e, f, h, i, j, k, o, p Antibiotics; for streptococcal pharyngitis/tonsillitis, acute bacterialotitis media due to streptococcus, Haemophilus influenzae, moraxella catarihalis, or streptococci, urinary tract due to Escherichia coli or Klebsiella pneumoniae Infections, gonorrhea and skin infections caused by staph or strep bacteria 10-1000mg10-1000mg/5ml           50-750mg50-750mg/5ml            100-600mg            100-600mg/5ml             

Ceftazidime preferred dosage form powder for intravenous administration oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Thr, Gly, and Lys a, b, c, g, h, i, j, k, l, o, p, q Antibiotics for the treatment of lower respiratory tract infections, including pneumonia caused by Pseudomonas, Haemophilus influenzae, Klebsiella, Enterbacter, Escherichia coli, Proteus mirabilis, Staphylococcus, Streptococcus; Pseudomonas aeruginosa Skin and skin tissue infections caused by bacteria, Klebsiella, Escherichia coli, Proteus enterbacter, Staphylococcus, Streptococcus, Pseudomonas aeruginosa, enterbacter proteus, Gram Urinary tract infections caused by Lebsiella spp., E. coli; bone and joint infections caused by Pseudomonas, eruginosa, Klebsiella spp., Enterbacter spp., or staphylococci; gynecologic infections including those caused by E. coli Endometritis, pelvic cellulits, and female genital tract infections caused by Escherichia coli, intra-abdominal infections, and central nervous system infections, including meningitis 0.1-5mg0.1-1mg0.1-2.5mg/5ml 0.25-4mg0.25-1mg0.25-2mg/5ml 0.5-2mg0.5-1mg0.5-1mg/5ml cefpodoxime              Preferred Dosage Form Oral Tablet/Capsule Oral Liquid                 All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly, and Lys a, b, c, g, h, i, j, k, l, o, p, q Antibiotics especially against Streptococcus, Haemophilus influenzae, Moraxella catarrhalis; treatment of acute otis media, pharyngitis, tonsillitis, pneumonia, bronchitis, gonorrhea, and female rectal infections 10-500mg10-500mg/5ml 25-350mg25-350mg/5ml              50-250mg50-250mg/5ml            

Atovaquone Preferred Dosage Form Oral Tablet/Capsule Oral Liquid For Pediatrics               All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Sar, Ala, Pro and Ser a,b,h,i,j,k,o,p Treatment of malaria caused by the Plasmodium parasite More than 50-1000mg/5ml10-150mg/5ml More than 100-500mg/5ml25-100mg/5ml More than 200-300mg/5ml50-75mg/5ml Acyclovir Preferred Formulation Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Sar, HypPro and Ser b, c, h, i, j, k, o, p Treatment of Human Cytomegalovirus (HCMV) 50-1000mg50-1000mg/5ml             100-750ml100-750mg/5ml                150-500mg150-500mg/5ml                Ganciclovir Preferred Form Oral Tablet/Capsule Oral Liquid IV Infusion All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Thr, Gly, and Lys b, c, e, f, h, i, j, k, o, p Treatment of Human Cytomegalovirus (HCMV) 0.1-1mg0.1-1mg/5ml10-200mg/ml              0.2-0.8mg0.2-0.8mg/5ml25-100mg/ml              0.2-0.6mg0.2-0.6mg/5ml30-60mg/ml              

Penciclovir preferred dosage form Oral liquid Powder for intravenous use Topical cream Oral tablet/capsule All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Thr, Gly, and Lys b, c, e, f, h, i, j, k, o, p Treatment of Human Cytomegalovirus (HCMV) 10-1000mg/ml0.1-5%10-500mg 25-750mg/ml0.25-3％20-300mg 50-500mg/ml0.5-2.5%25-250mg Niacin Extended Release Preferred Formulation Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Tyr, Gly, and Lys a, b, h, i, j, l, m, n, o, p, q lipid control 0.2-2mg0.2-2mg/5ml 0.25-1.5mg          0.25-1mg/5ml          0.5-1mg         0.5-1mg/5ml           Bexarotene Preferred Form Oral Tablet/Capsule Oral Liquid Topical Gel All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly, and Lys b, c, h, i, j, k, l, o, p Treatment of skin disorders, especially those requiring retinoid X receptor activation Above 10-500mg/5ml0.1-5% More than 25-250mg/5ml0.25-2.5% More than 50-100mg/5ml0.5-1.5%

Propoxyphen preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly, and Lys a,b,c,h,i,j,k,l,o,p treat pain 20-400mg20-400mg/5ml            25-250mg25-250mg/5ml              30-150mg30-150mg/5ml                Salsalate Preferred Formulation Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Thr, Gly, and Lys b, c, h, i, j, k, o, p Treat inflammatory conditions 0.2-2mg0.2-2mg/5ml                 0.25-1.5mg0.25-1.5mg/5ml             0.3-1mg0.3-1mg/5ml                  Paracetamol Preferred Dosage Form Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Sar, Gly, and Lys a, b, c, e, h, i, j, k, o, p treating pain or fever 20-1000mg20-1000mg/5ml           50-800mg50-800mg/5ml                100-600mg100-600mg/5ml              ibuprofen            Preferred Dosage Form Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Tyr, Gly, and Lys a, b, h, i, j, l, m, n, o, p, q Treat pain, fever, or inflammation 20-1000mg20-1000mg/5ml            50-800mg50-800mg/5ml            100-600mg100-600mg/5ml               

Lovastatin Preferred Dosage Form Oral Tablet/Capsule Oral Liquid                  All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly, and Lys b, c, e, f, h, i, j, k, l, o, p Decreases cholesterol concentration; inhibits hydroxymethylglutaryl-CoA (HMG-CoA) reductase 1-100mg1-100mg/5ml 2-80mg2-80mg/5ml 5-50mg5-50mg/5ml Simvastatin preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly, and Lys b, c, e, f, h, i, j, k, l, o, p Decreases cholesterol concentration; inhibits hydroxymethylglutaryl-CoA (HMG-CoA) reductase 1-200mg1-200mg/5ml               2-150mg             2-150mg/5ml            2.5-100mg             2.5-100mg/5ml             Atorvastatin preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly, and Lys b, c, e, f, h, i, j, k, l, o, p Reduce cholesterol (chlolesterol) concentration; inhibit hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase 1-250mg1-250mg/5ml                2-125mg            2-125mg/5ml                  5-100mg           5-100mg/5ml              Pravastatin preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly, and Lys b, c, e, f, h, i, j, k, l, o, p Reduces cholesterol (chlolesterol) concentration; hydroxymethylglutaryl-CoA (inhibits HMG-CoA) reductase 1-250mg1-250mg/5ml               2-125mg            2-125mg/5ml                5-75mg               5-75mg/5ml               

Fluvastatin preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Tyr, Gly, and Lys b, c, e, f, h, i, j, k, l, o, p Reduce cholesterol (chlolesterol) concentration; inhibit hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase 1-250mg1-250mg/5ml              2-125mg2-125mg/5ml                    5-75mg5-75mg/5ml                  Nadolol preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Sar, Ser, and Pro b, h, i, j, k, l, o, p Treatment of angina and hypertension; beta-adrenoceptor antagonist 1-250mg1-250mg/5ml               5-225mg5-225mg/5ml             10-200mg10-200mg/5ml                Valsartan Preferred Formulation Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Ser, Thr, Lys, Gly, and Sar b, f, i, j, k, l, o, p For hypertension, angiotensin II antagonists 10-500mg10-500mg/5ml                 25-250mg25-250mg/5ml                  50-200mg50-200mg/5ml                  Methylphenidate Preferred Formulation Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Hyp, Sar, and Ser a, b, c, h, j, k, l, o, p Treating attention deficit disorder and narcolepsy 1-50mg1-50mg/5ml                2-40mg2-40mg/5ml                 2.5-25mg2.5-25mg/5ml             

——————————————————— Trovafloxacin preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Ser, Pro, Hyp and Thr a, b, e, h, j, k, o, p Antibiotics; inhibit bacteria such as Escherichia coli, Pseudomonas aeruginosa, Haemophilus influenzae, Streptococcus, Klebsiella, Staphylococcus, Mycoplasma pneumoniae, Peptostreptococcus, Prevotella; treatment of pneumonia and Post-surgical infections; treatment of gynecological and pelvic infections such as endomyositis, parametritis, abortion infections, and postpartum infections; treatment of skin infections such as diabetic foot infections   10-500mg10-500mg/5ml 50-300mg50-300mg/5ml 80-250mg80-250mg/5ml 5-AS ^* preferred dosage form oral tablet/capsule oral liquid ( ^* 5-aminosalicylic acid)            All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Glu, Gly, Tyr and Lys b, c, i, j, l, m, n, o, p, q Treat tuberculosis 1-200mg          1-200mg/5ml               5-150mg5-150mg/5ml              10-125mg10-125mg/5ml              Methylprednisolone preferred dosage form intramuscular injection topical cream All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Pro, Sar and Ser b, c, g, j, l, m, n, o, p, q Treat inflammation, especially those resulting from infection, tissue trauma, anaphylaxis (allergic reaction), and autoimmune disease   2-200mg/ml0.001-5% 5-150mg/ml0.01-2.5%   10-100mg/ml0.1-2%

The preferred dosage form of medroxyprogesterone is intramuscular injection All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Pro, Sar and Ser b, c, g, j, l, m, n, o, p, q provide contraception 1mg-4mg/ml 10mg-2mg/ml 40mg-1mg/ml Estramustine Preferred Dosage Form Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Orr, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Gly, Lys, Pro, Ala, Sar and Val b, c, h, i, j, k, l, o, p Treatment of cancer, especially metastatic or progressive (growing) prostate cancer 10-500mg           10-500mg/5ml              25-250mg25-250mg/5ml              50-200mg               50-200mg/5ml                  Miglitol Preferred Formulation Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Sar, Pro, and Ser b,c,i,j,n,q Treat type 2 diabetes 1-250mg           1-250mg/5ml                 2-150mg2-150mg/5ml              10-125mg             10-125mg/5ml              Mefloquine Preferred Form Oral Tablet/Capsule Oral Liquid                    All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Sar, Pro, Val, Ala a, b, c, h, i, j, k, l, o, p, q treat malaria 10-500mg              10-500mg/5ml               100-400mg25-400mg/5ml                 150-300mg             150-300mg/5ml              

Danazol Preferred Formulation Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Hyp, Pro, Ala, Val, Ser and Thr a, b, c, e, f, g, h, i, j, k, l, n, o, p, q Treatment of endometriosis and fibrostatic breast disease 2-500mg2-500mg/5ml                10-350mg              10-350mg/5ml               25-250mg            25-250mg/5ml                 Eprosartan preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Lys, Gly and Val b, c, h, i, j, k, l, o, p Angiotensin-converting enzyme inhibitors, for the treatment of high blood pressure 0.1-1mg0.1-1mg/5ml                 200-800mg          200-800mg/5ml                300-750mg           300-750mg/5ml            Divalproex Sodium Preferred Formulation Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Lys, Gly, and Val a, b, c, f, h, i, j, k, l, o, p treatment of epilepsy 50-800mg50-800mg/5ml              75-750mg              75-750mg/5ml               100-600mg             100-60mg/5ml              Fenofibrate Preferred Formulation Oral Tablet/Capsule Oral Liquid                 All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Lys, Gly, and Ala b, c, h, i, j, k, l, o, p, q treat hypercholesterolemia 10-800mg10-800mg/5ml                 20-750mg          20-750mg/5ml              100-600mg100-600mg/5ml           

gabapentin preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Cyclic Derivatives and Tyr b, c, d, e, f, h, i, j, k, l, n, o, p, p treatment for convulsions   10-800mg10-800mg/5ml 25-750mg25-750mg/5ml 50-500mg50-500mg/5ml Lansoprazole preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Gly, Lys, Pro, Sar, Ser and Val b, e, f, h, i, j, k, l, o, p Inhibits gastric acid secretion by inhibiting secretion of the H+-K+-ATPase (proton pump) system on the surface of parietal cells; treats hyperacidity 1-60mg            1-6mg/5ml               2-50mg            2-50mg /5ml 10-40mg10-40mg/5ml                  Omeprazole preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Val, Pro and Sar b, e, f, h, i, j, k, l, o, p Inhibits gastric acid secretion by inhibiting secretion of the H+-K+-ATPase (proton pump) system on the surface of parietal cells; treats hyperacidity 1-200mg            1-200mg/5ml               2-100mg          2-100mg/5ml                5-60mg5-60mg/5ml            Megestrol preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Gly, Lys, Sar, Pro, Ser and Ala b, c, h, i, j, k, l, n, o, p Treating Anorexia; Stimulating Appetite in Anorexia and AIDS Patients 2-100mg        2-100mg/5ml             4-80mg           4-80mg/5ml               20-60mg20-60mg/5ml              

Metformin Preferred Dosage Form Oral Tablet/Capsule Oral Liquid               All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Dimers of Asp, Glu, Lys and Azo o, p Treats hyperglycemia; promotes insulin to transport glucose to cells 0.2-3mg            0.2-1mg/5ml                0.25-1.5mg0.25-1.5mg/5ml                 0.5-1mg               0.5-1mg/5ml               Tazarotene preferred dosage form topical gel                All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Lys, and Gly B, c, h, l, j, k, l, o, p Treatment of psoriasis and acne mainly caused by pathogenic microorganisms, allergies and inflammation 0.01-0.3% 0.02-0.25% 0.025-0.125% Sumatriptan Preferred Dosage Form Oral Tablet/Capsule Oral Liquid Intramuscular Injection All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Ala, Pro, Sar and Val b, c, d, g, h, i, j, k, l, n, o, p, q Serotonin subtype receptor agonists for the treatment of migraine 5-250mg            5-250mg/5ml                1-36mg/ml                10-200mg               10-200mg/5ml                2-24mg/ml              20-125mg20-125mg/5ml4-20mg/ml               Naratriptan preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Sar, Val, Ala, and Pro b, h, i, j, k, l, o, p serotonin subtype receptor agonists for the treatment of migraine 0.1-10mg             0.1-10mg/5ml              0.25-5mg            0.25-5mg/5ml                 0.5-4mg0.5-4mg/5ml                  

Zolmitriptan Preferred Formulation Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Sar, Val, Ala, and Pro b, h, i, j, k, l, o, p serotonin subtype receptor agonists for the treatment of migraine 0.1-12mg            1-12mg/5ml                  0.5-10mg0.5-10mg/5ml               1-7.5mg             1-7.5mg/5ml               Aspirin Preferred Form Oral Tablet/Capsule Oral Liquid              All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Lys, Gly, and Ala a, b, c, e, f, g, h, j, k, l, m, n, o, p, q Antipyretic, Anti-inflammatory, Analgesic, Thrombolytic; Treatment of Hyperthermia, Myocardial Infarction, and Thrombolysis 10-1000mg         10-1000mg/ml            20-800mg20-800mg/ml                25-600mg           25-600mg/ml               Olmesartan preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Lys, Gly, and Ala b, h, i, j, k, l, o, p Angiotensin-converting enzyme inhibitors, for the treatment of high blood pressure   1-100mg1-100mg/5ml 2-80mg2-80mg/5ml 4-50mg4-50mg/5ml Sirolimus Preferred Formulation Oral Tablet/Capsule Oral Liquid Intramuscular Injection All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Lys, Gly, and Ala b, h, i, j, k, l, o, p Immunosuppressants for patients undergoing surgical transplantation; antibiotics; treatment of vitiligo, psoriasis, acne 0.1-20mg            0.1-20mg/5ml               0.5-10gm0.5-10mg/5ml                1-8mg           1-8mg/5ml             

Tacrolimus preferred dosage form Oral tablet/capsule Oral liquid IV infusion All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Ala, Thr, Sar and Pro b, c, g, h, i, j, k, l, o, p Immunosuppressants for patients undergoing surgical transplantation; antibiotics; treatment of vitiligo, psoriasis, acne 0.1-20mg              Above/5ml             1-20mg/ml                        0.2-15mg or more/5ml2-15mg/ml           0.25-10mg          Above/5ml             2.5-8mg/ml                      Pimecrolimus Preferred Formulation Oral Tablet/Capsule Oral Liquid Ointment Cream All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Ala, Thr, Sar and Pro b, c, g, h, i, j, k, l, o, p Immunosuppressants for patients undergoing surgical transplantation; antibiotics; treatment of vitiligo, psoriasis, acne 0.1-20mg              Above/5ml                0.01- 10%                        Above 0.2-15mg/5ml0.1-5%              0.25-10mg            Above/5ml           0.5-2%                       Clopidogrel preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis                               20-125mg20-125mg/5ml            25-100mg25-100mg/5ml               Ser, Hyp, Thr, Lys, Ala, and Gly b, c, h, i, j, k, l, m, o, p, q Treat heart muscle infection 10-250mg        10-250mg/5ml             20-125mg20-125mg/5ml            25-100mg            25-100mg/5ml              Amphotericin B Preferred Formulation Intravenous Topical Cream               All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Lys, Ala, and Gly b, c, g, i, j, l, m, n, o, p, q against fungi, especially those that act on the cell membrane and alter cell permeability 0.5-20mg/kg/day0.01-10%           1-15mg/kg/day0.1-5%            2-10mg/kg/day0.5-2%            

Tenofovir preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Lys, Gly, Ala, Pro, Ser and Sar b, c, h, i, j, k, l, o, p Human immunodeficiency virus (HIV) inhibitors, to treat AIDS infection 10-900mg10-900mg/5ml 50-750mg50-750mg/5ml 100-500mg100-500mg/5ml Unoprostone Optimal Dosage Eye Drops All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Tyr, Pro, and Lys b, c, h, i, j, k, l, n, o, p, q Treatment of glaucoma primarily caused by aging; lowers intraocular pressure 0.01-1%             0.05-0.5%               0.01-0.25%            Fulvestrant preferred dosage form intramuscular injection All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Gly, Lys, Pro, Ala, Val and Sar B, c, g, j, l, o, p Treating cancer, especially breast cancer 2-1250mg/5ml         10-1000mg/5ml                20-500mg/5ml              Cefditoren Preferred Form Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Gly, Lys and Ala b, c, h, i, j, k, l, o, p Antibiotics, especially against Haemophilus influenzae, Haemophilus parainfluenzae, Streptococcus, Moraxella catarrhalis; treatment of bronchitis, pharyngitis, tonsillitis, skin infections 20-500mg           20-500mg/5m             100-400mg         100-400mg/5ml             150-300mg           150-300mg/5ml           

Efavirenz Preferred Form Oral Tablet/Capsule Oral Liquid            All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Gly, Lys, Pro, Ala, Sar, and Val b, c, h, i, j, k, l, o, p Human Immunodeficiency Virus Type 1 (HIV-1), Specific, Nonnucleoside Reverse Transcriptase Inhibitor; Treatment of AIDS Infection 0.2-1.2mg0.2-1.2mg/5ml             300-800mg             300-800mg/5ml                  400-750mg             400-750mg/5ml              Eplerenone Preferred Formulation Oral Tablet/Capsule Oral Liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dc y, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Ser, Hyp, Thr, Lys, Gly, and Val b, c, h, i, j, k, l, o, p Treatment of hypertension, blocking the binding of aldosterone to mineralocorticoid receptors Treprostinil preferred dosage form oral tablet/capsule subcutaneous infusion All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and Sar Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, Sar Gly, Lys, Val, Hyp, Thr and Ser b, c, g, h, i, j, k, l, o, p Inhibit platelet aggregation and vasodilation in systemic and pulmonary vascular beds, and treat cardiovascular-related diseases 0.1-100mg/ml10-1000mg           0.2-50mg/ml               20-800mg                    0.5-20mg/ml25-500mg            Adefovir preferred dosage form oral tablet/capsule oral liquid All dosages are expressed on a drug basis Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cav, Asn, Gln, Can, Tau, Djk, GABA, Cys, Dcy, Thr, and SarLys, Leu, Ile, Gly, Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Thr, Arg, Phe, Trp, Gln, Asn, Cys and Ser, Hyp, SarGly, Lys, Gly, Val, Ser, Hyp, and Prob, c, h, i, j, k, b, c, h, i, j, k, l, o, p1 human immunodeficiency disease Human Immunodeficiency Virus (HIV) Reverse Transcriptase Inhibitor; Treatment of HIV Infection and AIDS (AIDS) 1-100mg1-100mg/5ml             Efavirenz 2-50mg          2-50mg/5ml            All dosages are expressed on a drug basis 5-20mg5-20mg/5ml           Lys, Leu, Ile, Gly, Asp, Glu, Met,

The following non-limiting examples further illustrate the invention:

Synthesis of various amino acid derivatives of selected drugs

I. Propofol Derivatives

Propofol (2,6-diisopropylphenol) is a low molecular weight phenol that is widely used as a central nervous system anesthetic and possesses sedative and hypnotic activity. It is administered intravenously to induce and maintain anesthesia and/or sedation in mammals. The main advantages of propofol are the rapid induction of anesthesia with few side effects, and once the drug is stopped, the patient wakes up quickly without prolonged sedation.

Propofol has been shown to have a number of therapeutic applications, which are varied and somewhat surprising. For example, it has been shown to be a potent antioxidant, antiemetic, antipruritic, antiepileptic, anti-inflammatory, and even appears to have anticancer properties.

Mechanism:

The mechanism of action of propofol has been extensively studied. Its central nervous system anesthetic activity appears to be associated with its high affinity for a specific subclass of GABA receptors (Collins G.G.S., 1988, Br. J. Pharmacology. 542, 225-232). However, a large number of different receptors in the brain are substrates for propofol, so it has a variety of activities.

Propofol also has important biological effects as an antioxidant. Due to its broad activity, propofol is theoretically useful for treating a number of inflammatory processes in which oxidation is an important factor. For example, cyclooxygenase, which mediates the synthesis of prostaglandins, leads to inflammation. By inhibiting oxidation in the airways, propofol can be used to treat aspirational acid, adult/child respiratory distress syndrome, obstructive airway disease, asthma, cancer and a host of other similar pathologies.

Because oxidative tissue damage is common, propofol has been suggested for the treatment of Parkinson's disease, Alzheimer's disease, Friedrich's disease, Huntington's disease (Huntington's disease), multiple sclerosis, amyotrophic lateral sclerosis, spinal cord injuries, and various other neurodegenerative diseases.

Propofol is currently commercially available in the United States as an intravenous emulsion sold by Astra Zenaca under the trade name Diprivan®. It is one of the most widely used short-acting central nervous system anesthetics on the market. Propofol is present in a pyrogen-free sterile emulsion at a concentration of 10 mg/mL in a formulation containing soybean oil, glycerin, lecithin, edetate disodium, and sodium hydroxide.

A significant disadvantage of propofol is that it is completely insoluble in water. Even at a low concentration of 10 mg/mL, the drug precipitates from aqueous solutions at room temperature. Manufacturers of such preparations therefore use exceptionally complex and toxic emulsifiers to emulsify this product in water in a special way. For example, manufacturers of intravenous formulations use lecithin, Cremaphor L_, castor oil, and other similar emulsifiers.

However, the use of such emulsifiers poses many problems. Various types of emulsifiers in Cremaphor L_ are known to contribute to allergic reactions. Some patients have demonstrated anaphylactic shock to lecithin and castor oil. Furthermore, maintaining the stability of propofol in these emulsions is temporary and more expensive. Furthermore, the presence of lecithin and castor oil renders the emulsion susceptible to microbial growth. It is also possible to complex propofol with cyclodextrins to make it soluble in water, but cyclodextrins have not been approved by the FDA for intravenous therapy.

So far, no one has made a safe prodrug of propofol. British Patents 1,102,011 and 1,160,468 and US Patent 3,389,138 describe phenolic esters of various amino acids in which propofol is attached to numerous side chains which can produce toxic effects when released in vivo.

US Patent No. 6,451,854 describes a number of α-aminoacetate substituted propofols in which the propofol and the side chains are substituted with a number of different chemical groups. All of these N,N-disubstituted glycinate esters of propofol are not represented as non-toxic, and many of the compounds described therein are derivatives of propofol. Thus, when released in vivo, after enzymatic cleavage of the ester, many of the active drugs released are not propofol, and therefore without any toxicity data on them, they are entirely new molecules with unknown therapeutic efficacy in humans.

In another publication on water-soluble salts of amino acid esters of the anesthetic propofol (Int.J.Pharmaceutics, 175[2]: 195-204, 1998), the author synthesized many water-soluble salts of propofol derivative. However, when these prodrugs are cleaved by esterases, substituted unnatural amino acids with completely unknown toxicity are released into the body.

Until now there are no pharmaceutical formulations on the market that deliver propofol without harmful side effects. However, the present invention leads to a number of water-soluble, non-toxic derivatives of propofol which are suitable for releasing propofol in vivo without any harmful side effects and without the need for toxic and expensive additives, solubilizers and emulsifiers .

Thus, in one aspect, the present invention relates to a class of prodrugs of propofol. The prodrug contains the carboxyl group of an amino acid that is esterified to the free hydroxyl group present on the propofol molecule.

More specifically, one aspect of the present invention relates to a compound of the following formula or a pharmaceutically acceptable salt thereof

Wherein AA is an amino acid, and the carboxyl group of AA reacts with the hydroxyl group of propofol.

In another aspect, the present invention also relates to a pharmaceutical composition, which includes a therapeutically effective amount of the above-mentioned various propofol prodrugs and pharmaceutical carriers thereof.

In another embodiment, the present invention is directed to a method of treatment of a patient in need of treatment with propofol, the method comprising administering to said patient an effective amount of propofol.

In yet another embodiment, the present invention is directed to a method of increasing the solubility of propofol in an aqueous solution comprising reacting hydroxyl functional groups of propofol and isolating the product thereof.

In still further embodiments, the present invention is directed to a method that substantially and in a therapeutically effective manner mitigates or eliminates the potential of current formulations containing toxic excipients when administered to a patient. toxic side effects, the method comprising separately reacting the hydroxyl functional group of the propofol molecule with the carboxyl functional group of selected amino acids to form an ester covalent bond, isolating the product thereof, and administering the product to a patient.

The present invention shows that when an unsubstituted naturally occurring amino acid is esterified with propofol, the resulting prodrug is highly water soluble (>200 mg/L in water), releases a nontoxic amino acid after cleavage in vivo, and does not require Toxic emulsifiers, additives and other excipients.

Furthermore, it has been shown that the present invention also results in drugs which are prodrugs of propofol of the present invention and are highly effective central nervous system anesthetics. The current amino acid prodrugs are therefore potent CNS anesthetics, regardless of release of the active parent drug.

The solubility of the amino acid ester of the present invention in water at room temperature is at least 10 times that of propofol. In particular propofol has a solubility range of greater than 100 mg/mL for glycinate, proline and lysine esters and greater than 250 mg/mL for lysine.

Since the phenolic group responsible for antioxidant activity is blocked, the prodrugs of the present invention are not believed to exhibit any antioxidant activity; however, the inventors have found that prodrugs of propofol are effective whether or not releasing propofol of anesthetics. The described propofol prodrugs release propofol when administered in vivo, and the resulting drug retains the pharmacological and antioxidant properties of the prodrug.

The prodrugs of propofol of the present invention clearly offer many advantages over propofol, for example, all side chains cleaved from these prodrugs are naturally occurring essential amino acids and are therefore non-toxic. This leads to a high therapeutic index. Second, all of these prodrugs are readily cleaved in vivo to release propofol. Moreover, due to the high water solubility of these prodrugs, they can be easily administered by using sterile lyophilized powders to form solutions in situ prior to intravenous administration, or by providing prefilled syringes or bottled infusions for injection. Amino acid esters are more stable than propofol because the OH groups of propofol are blocked from oxidation. Thus the propofol prodrugs of the present invention are more effective than propofol itself, and do not have the toxicity and other pharmaceutical problems associated with current marketed formulations.

The propofol prodrug of the present invention has properties of anti-inflammation, anti-oxidation, anti-cancer, anti-convulsant, antiemetic and antipruritic.

The propofol prodrugs of the present invention are effective in the treatment of diseases or conditions for which propofol is commonly used. The prodrugs disclosed herein are transformed in vivo to release the active compound and facilitate propofol therapy by alleviating or eliminating their attendant biopharmaceutical and pharmacokinetic barriers. It should be noted, however, that these prodrugs themselves are sufficiently active in mammals without releasing any active drug. Because the prodrug is more soluble in water than propofol, it does not require carrier excipients such as ethanol or castor oil which may be toxic or produce deleterious side effects. Furthermore, oral formulations containing propofol prodrugs are absorbed into the blood and are quite effective.

In this way, the prodrugs of the present invention facilitate therapy by eliminating the biopharmaceutics and pharmacokinetic barriers of existing drugs.

Moreover, these prodrugs can be easily synthesized in high yields using commercially readily available reagents.

Overview:

The steps of synthesizing glycine ester, L-proline ester and L-lysine ester of propofol are as follows. However, these are examples and any amino acid prodrug of propofol can be prepared using the following method. See the Experimental section for complete procedures and analyzed data. In general, propofol (10 g) reacts with N-Boc-protected amino acids (1 equivalent) in the presence of catalytic amounts of 4-(N,N-dimethylamino)pyridine (DMAP) as shown in the following scheme , 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) reaction. EDC is removed by water extraction. After drying over sodium sulfate and filtration, the crude protected amino acid ester of propofol was concentrated and purified by flash chromatography to give the protected ester in 50-60% yield. The protecting group was then removed by stirring the protected ester in ether saturated with hydrochloric acid (g) at room temperature. The yield of the deprotection step is typically 60-95%. After the glycinate and L-proline ester hydrochlorides of propofol were processed by filtration and drying, no further purification was required. L-lysine propofol hydrochloride was crystallized once from ethanol to remove traces of mono-protected L-lysine propofol.

Composition order:

1. SPI0010

2. SPI0011

3. SPI0013

diagram

Synthesis of glycine, L-proline and L-lysine esters of propofol: a) EDC, DMAP, _CH2Cl2 ; b) HCl( _g ), _Et2O .

Experimental part:

The synthesis of SPI0010, SPI0011 and SPI0013 was performed in batches. Usually small-scale experiments are performed first followed by larger batches. Reagents mentioned in the experimental section were of the highest commercially available purity and were purchased from Aldrich, Aeros, or Bachem, except that solvents were purchased from Fisher Scientific or Mallinkrodt.

1) SPI0010

Propofol (9.98 g, 55.97 mmol) was dissolved in dichloromethane (200 mL) at room temperature under argon atmosphere. Add N-tert-butoxycarbonylglycine (11.2 g, 63.91 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 11.1 g, 57.9 mmol ) and 4-(N,N-dimethylamino)pyridine (DMAP, 1.5 g, 12.27 mmol). After stirring at room temperature under argon atmosphere for 21 hours, water (200 mL) was added and the layers were separated. The dichloromethane layer was washed with water (200 mL) and dried by adding sodium sulfate (5 g) for 1 hour. After filtration and concentration under reduced pressure, the remaining oil was purified by flash chromatography on silica gel (250 g), eluting with hexane/ethyl acetate (10:1). This step yielded the protected N-BOC protected glycinate ester of propofol (11.34 g, 60% yield) as a white solid.

tert-butoxyformylaminoacetic acid-2,6-diisopropylphenyl ester:

¹ H NMR (300 MHz, CDCl ₃ ): δ=7.25-7.13 (m, 3H), 5.18 (br s, 1H), 4.22 (d, 2H, J=5.7Hz), 2.89 (m, 2H), 1.46 (s, 9H), 1.18 (d, 12H, J=6.9Hz).

¹³ C NMR (75 MHz, CDCl ₃ ): δ=169.35, 155.75, 145.22, 140.35, 126.90, 124.14, 80.32, 42.66, 28.54, 27.79, 23.57.

Propofol-Boc-glycine ester (11.28 g, 33.6 mmol) was dissolved in anhydrous ether (200 mL) at room temperature. Stir for 45 minutes while bubbling hydrochloric acid (g) into the solution. The mixture was stirred at room temperature under an argon atmosphere for 48 hours. After 48 hours hexane (200 mL) was added and the precipitate was filtered. The white solid was dried under high vacuum at 88°C for 5 hours. This experiment produced SPI0010 (8.73 g, 95% yield, 99.9% purity by HPLC analysis) as a white solid.

2,6-diisopropylphenyl ester hydrochloride of amino-acetic acid:

¹ H NMR (300MHz, CDCl ₃ ): δ=8.77(br s, 3H), 7.20-7.08(m, 3H), 4.14(m, 2H), 2.87(m, 2H), 1.11(d, 12H, J = 7Hz).

¹³ C NMR (75 MHz, CDCl ₃ ): δ = 166.42, 144.84, 140.42, 127.10, 124.06, 40.47, 27.61, 23.55.

CHN elemental analysis:

Calculated: C 61.87, H 8.16, N 5.15; Found: C 61.14, H 8.20, N 5.14.2) SPI0011

Propofol (10.03 g, 56.23 mmol) was dissolved in dichloromethane (100 mL) at room temperature under argon atmosphere. Add N-tert-butoxycarbonyl-L-proline (14.04 g, 65.22 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 11.95 g , 62.33 mmol) and 4-(N,N-dimethylamino)pyridine (DMAP, 1.1 g, 9.0 mmol). After stirring at room temperature under an argon atmosphere for 3 hours, water (100 mL) was added and the layers were separated. The dichloromethane layer was washed with water (100 mL) and dried over sodium sulfate (5 g) for 1 hour. After filtration and concentration under reduced pressure, the remaining oil was purified by flash chromatography on silica gel (250 g), eluting with hexane/ethyl acetate (10:1). This step yielded the N-BOC protected L-proline ester of propofol (11.34 g, 66% yield) as a clear oil, which solidified upon standing in the refrigerator.

Pyrrolidine-1,2-dicarboxylic acid-1-tert-butyl ester-2-(2,6-diisopropyl-phenyl) ester:

¹ H NMR (300MHz, CDCl ₃ ): δ=7.3 1-7.20(m, 3H), 4.73(m, 1H), 3.70-3.50(m, 2H), 3.20-2.94(m, 2H), 2.46-2.20 (m, 2H), 2.20-2.0 (m, 2H), 1.55 (m, 9H), 1.25 (m, 12H).

¹³ C NMR (75MHz, CDCl ₃ ): δ=171.87, 171.01, 154.34, 153.93, 145.35145.23, 140.06, 140.21, 126.69, 126.53, 123.95, 80.28, 79.89, 59.14, 46.67, 16.10, 38.38 28.56, 28.56, 27.44, 27.18, 23.47.

Propofol-Boc-L-proline ester (13.95 g, 37.14 mmol) was dissolved in anhydrous ether (100 mL) at room temperature. Stir for 60 minutes while bubbling hydrochloric acid (g) into the solution. The mixture was stirred at room temperature under an argon atmosphere for 22 hours. After 22 hours hexane (50 mL) was added and the precipitate was filtered. The white solid was dried under high vacuum at 88°C for 5 hours. This experiment produced SPI0011 as a white solid (9.1 g, 95% yield, 99.1% purity by HPLC analysis).

Pyrrolidine-2(S)-carboxylic acid-2,6-diisopropyl-phenyl ester hydrochloride:

¹ H NMR (300 MHz, CDCl ₃ ): δ=10.15 (br s, 2H), 7.27-7.14 (m, 3H), 4.78 (t, 1H, J=7.8Hz), 3.56 (m, 2H), 2.85 (m, 2H), 2.64(m, 1H), 2.40(m, 1H), 2.20(m, 1H), 2.05(m, 1H), 1.18(m, 12H).

¹³ C NMR (75 MHz, CDCl ₃ ): δ=168.30, 144.23, 139.74, 126.98, 123.96, 51.58, 38.21, 29.32, 26.64, 26.18, 23.71, 23.02, 21.67.

CHN elemental analysis:

Calculated: C 65.48, H 8.40, N 4.49; Found: C 65.50, H 8.43, N 4.50.

3) SPI0013

Under ice/water bath cooling, the dicyclohexylamine salt of di-N-boc-L-lysine (23.62 g, 0.0447 mmol) was added to water containing diethyl ether (200 mL) and potassium bisulfate (9.14 g) ( 200mL). After stirring for 20 minutes, the solution was separated. The ether layer was extracted three times with cold water (100 mL). The ether layer was then dried over sodium sulfate (15 g) for one hour, filtered and concentrated under reduced pressure. This series of steps yielded the free acid of N,N'-di-boc-L-lysine (15.5 g, 100% recovery).

Propofol (8.0 g, 45 mmol) was dissolved in dichloromethane (100 mL) at room temperature under argon atmosphere. Add N,N-di-tert-butoxycarbonyl-L-lysine (15.5 g, 44.7 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( EDC, 8.62 g, 45 mmol) and 4-(N,N-dimethylamino)pyridine (DMAP, 0.55 g, 4.5 mmol). After stirring at room temperature under an argon atmosphere for 3 hours, water (100 mL) was added and the solution was separated. The dichloromethane layer was washed with water (100 mL) and dried over sodium sulfate (5 g) for 1 hour. After filtration and concentration under reduced pressure, the remaining oil was purified by flash chromatography on silica gel (250 g), eluting with hexane/ethyl acetate (9:1). This step produced a white foamy L-lysine ester of propofol protected by the protecting group N-BOC (12.42 g, 55% yield).

2(S),6-di-tert-butoxycarboxamidocaproic acid-2,6-diisopropylphenyl ester:

¹ H NMR (300MHz, CDCl ₃ ): δ=7.28-7.1 5(m, 3H), 5.22(d, 1H, J=8.4Hz), 4.70(m, 1H), 4.59(m, 1H), 3.17( m, 2H), 2.93(m, 2H), 2.09(m, 1H), 1.86(m, 1H), 1.67-1.54(m, 4H), 1.48(s, 9H), 1.46(s, 9H), 1.20 (m, 12H).

¹³ C NMR (75MHz, CDCl ₃ ): δ=171.82, 156.10, 155.65, 145.25, 140.30, 126.80, 124.03, 80.14, 79.28, 53.76, 40.29, 32.09, 28.66, 28.54, 27.48, 23.91, 23.

Propofol-di-Boc-L-lysine ester (12.34 g, 24.37 mmol) was dissolved in anhydrous ether (250 mL) at room temperature. While stirring for 60 minutes under cooling in an ice/water bath, hydrochloric acid (g) was bubbled into the solution. The mixture was stirred at room temperature under an argon atmosphere for 48 hours. After 48 hours the precipitate was filtered and crystallized from ethanol (100 mL). The resulting white solid was dried under high vacuum at 90°C for 4 hours. SPI0013 produced in this experiment was a white solid (5.5 g, 60% yield, 98.6% purity by HPLC analysis).

2(S), 6-diaminocaproic acid-2,6-diisopropylphenyl ester dihydrochloride:

¹ H NMR (300MHz, CDCl ₃ ): δ=9.05(br s, 3H), 8.35(br s, 3H), 7.26-7.13(m, 3H), 4.43(t, 1H, J=6Hz), 3.0- 2.6 (m, 4H), 2.09 (m, 2H), 1.80-1.50 (m, 4H), 1.10 (d, 12H, J=7Hz).

¹³ C NMR (75 MHz, CDCl ₃ ): δ=168.30, 144.23, 139.74, 126.98, 123.96, 51.58, 38.21, 29.32, 26.64, 23.71, 23.02, 21.67.

CHN elemental analysis:

Calculated.: C 56.99, H 8.50, N 7.38; Found: C 56.48, H 8.56, N 7.30.

II. Prodrugs of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)

NSAIDs include a class of structurally specific drugs with a carboxylic acid moiety attached to a planar aromatic functional group, examples of which include: acetylsalicylic acid, salicylic acid, diflunisal, ibuprofen, fenoprofen, carol flurbiprofen, ketoprofen, naproxen, sulindac, indomethacin, etodolac, tolmetin, ketorolac, diclofenac, and meclofenac. NSAIDs have anti-inflammatory, analgesic, antipyretic and anticoagulant activities.

Examples of chemical structures of this class of unique compounds exhibiting a wide range of pharmacological activities are shown below.

NSAIDs are widely used to treat acute and chronic pain, regulate edema, tissue damage caused by inflammatory joint diseases, and are also effective anticoagulants in the treatment of myocardial infarction. In addition to analgesic and anti-inflammatory effects, many drugs exhibit antipyretic activity and are thus useful in reducing fever.

Some drugs in the above group are also used in the treatment of rheumatoid arthritis, osteoarthritis, acute gout, ankylosing spondylitis and dysmenorrhea.

Mechanism of action:

The main mechanism by which NSAIDs produce their therapeutic effect is through inhibition of prostaglandin synthesis. In particular NSAIDs inhibit cyclooxygenases, such as COX-1 and COX-2 enzymes, which are responsible for the synthesis of prostaglandins. COX-1 is important for regulating platelet aggregation, regulating blood flow in the kidney and stomach, and regulating gastric acid secretion, while the COX-2 enzyme plays an important role in pain and inflammatory processes. NSAIDs significantly increase clotting time and can be used to prevent thromboembolism and myocardial infarction.

All NSAIDs are relatively moderate to strong organic acids with pKa values in the range of 3-6. Most of them are carboxylic acid derivatives. Acidic groups are necessary for COX inhibitory activity, and at physiological pH, all NSAIDs are ionized. They all have quite different hydrophilic-lipophilic balance values, which are caused by aromatic groups, aromatic and aliphatic side chains, and other different heterocycles in their structures. Most NSAIDs are highly bound to plasma proteins and often compete to displace other drugs with similar affinity for plasma proteins. Therefore, co-administration of NSAIDs with other therapeutic classes of drugs must be carefully evaluated to prevent drug-drug interactions. Most of these drugs are metabolized by mammals through conjugation due to their acidic carboxyl groups. The major route of metabolic clearance of many NSAIDs is glucuronidation followed by renal elimination.

The use of acetylsalicylic acid (aspirin) to prevent coronary heart disease is well known and this drug has been shown to be life-saving in many patients with myocardial infarction. Many other uses of aspirin have also been reported, for example, the medical journal Lancet (Vol 349, p 1641) recently reported that aspirin reduced the risk of stroke in patients with early warning signs of transient ischemic heart attack. Preeclampsia and fetal growth retardation caused by blockage of placental blood vessels are two of the most common pregnancy complications, with millions of cases of preeclampsia worldwide each year. In a trial involving more than 9000 women in 16 countries, aspirin 60 mg daily reduced the risk of developing preeclampsia by 13% (Aspirin Foundation website). Aspirin has also been shown in some studies to be effective in preventing colon, lung and pancreatic cancer in postmenopausal women. Because aspirin improves blood flow, its effectiveness in the treatment of diabetes-induced dementias such as Alzheimer's disease is becoming increasingly clear.

Due to their unique drug potential, NSAIDs have attracted sufficient media attention. The main areas of clinical research on the above-mentioned drugs are as NSAIDs, especially with regard to their application in patients suffering from pain, arthritis (rheumatoid and skeletal), other inflammatory reactions, fever and the prevention of coronary heart disease. These drugs are also used to treat migraines, menstrual syndrome, back pain, and gout.

Although NSAIDs have made a very important contribution, in providing more effective and convenient methods of administration (such as galenic dosage forms, e.g., oral dosage forms, which are not only convenient, but also provide patients with suitable bioavailability and allowing administration at a suitable and controlled rate) and undesired side effects have been reported; especially severe gastric and duodenal ulcers, erythema of the mucosa, edema, erosions, perforation, Blood in the stool, ulcerative colitis, these have obviously seriously hindered its wider use or application. The dual injury theory involves direct NSAID-mediated injury followed by systemic effects of inhibition of prostaglandin synthesis. Local injury can also occur due to bile secretion by activated hepatic metabolites and subsequent duodenogastric reflux. (Arthritis and Rheumatism 1995;38(1):5-18). These effects are additive; both local and systemic mechanisms are sufficient to generate gastroduodenal mucosal injury.

Furthermore, the above-mentioned NSAIDs are characterized by being highly hydrophobic and prone to precipitation in the presence of even small amounts of water, for example when entering the body (eg, gastric juices). It is therefore particularly difficult to provide an oral dosage form which is acceptable to the patient, eg in form and taste, while being stable for storage and capable of providing a suitable controllable patient dosage when administered routinely.

Proposed liquid dosage forms, such as NSAIDs for oral administration, have hitherto been largely based on the use of natural gums such as: xanthan gum (Xanthan), cellulose, citric acid, and lime flavors (limefiavor), etc. (see U.S. Pat. No. 5,780,046). Commercially available drinking solutions of NSAIDs use incompatible orange coloring and berry flavours, citric acid, Xanthan gum (Xanthan gum), Tween 80, pregelatinized starch, glycerin, sodium benzoate and additional artificial colors and flavors . However, a number of difficulties are associated with the use of drinking solutions and similar compositions proposed in the art.

Furthermore, the palatability of known oil-based systems is problematic. In particular, the taste of drinking solutions is known to be unpleasant. Mixtures mixed with an appropriately flavored drink have been used to make conventional therapy acceptable, wherein the drink is added to pharmaceutical preparations in high dilution prior to ingestion, such as chocolate drink preparations. Employing an oil-based system also requires the use of high ethanol concentrations, so that it is inherently undesirable, especially foreseeable when administered to children. Furthermore, volatilization of ethanol, such as from capsules (which are heavily employed to address the palatability issues discussed, or other issues (eg, when opened)), will lead to the generation of NSAID precipitates. For example, when the composition is in the form of soft gelatin microcapsules, this particular difficulty necessitates the encapsulation of such microcapsule products in airtight elements, for example, airtight blisters or aluminum foil blisters. cover package. This makes the product bulkier and more expensive to produce. Furthermore, the storage properties of the aforementioned formulations are far from ideal.

Gastric irritation of NSAIDs has been a subject of major concern to practicing physicians and patients. The short-term use of aspirin, fenoprofen, flurbiprofen, indomethacin, ketorolac, meclofenamic acid, mefenamic acid, and piroxicam produces severe gastrointestinal side effects. Even ibuprofen has been shown to cause severe gastric damage when used chronically. Gastrointestinal toxicity is the most frequently encountered side effect with NSAIDs and is of great concern. About half of patients admitted with bleeding ulcers were due to the use of NSAIDs, aspirin, or both in the week prior to admission (Faulkner G, Prichard P, Somerville K et al., Aspirin and bleeding peptic ulcers in the elderly. Br Med J .1988;297:1311-1313). A survey of Tennessee Medicaid patients hospitalized for gastrointestinal complications showed that patients who used NSAJDs were four times more likely to develop gastrointestinal bleeding or peptic ulcers than those who did not (Griffin MR, Piper JM, Daugherty JR et al. Nonsteroidal anti-inflammatory drug use and increased risk for peptic ulcer disease in elderly persons. Ann Intern Med. 1991; 114:257-263). According to FDA reports, 2% to 4% of patients who continue to take NSAIDs for the treatment of rheumatoid arthritis develop severe gastrointestinal diseases every year. The relative risks of gastric ulcer (4.725), duodenal ulcer (1.1 to 1.6), bleeding (3.8), perforation, and death were all increased by NSAID use in these patients compared with patients not taking these drugs. In 1989, approximately 20,000 patients with rheumatoid arthritis were hospitalized each year at an estimated cost of $10,000 per visit. (Fries JF, Miller SR, Spitz PW et al. Toward an epidemiology of gastropathy associated with nonsteroidal anti-inflammatory drug use. J Gastroenterology. 1989; 96:647-655).

There is also a need to provide some aqueous formulations of NSAIDs for injection. It is well known that the high concentrations of ethanol and trometamol used to form the salt in the current formulation of Ketorolac are toxic. Due to the low water solubility of the drugs, there are currently no formulations that enable the required concentrations of NSAIDs to be present in aqueous solutions.

In addition to all these obvious practical difficulties, undesired side effects have also been observed with existing oral dosage forms.

In this technical field, many proposals have been made to solve the various problems encountered, including solid and liquid oral dosage forms. However, one of the most important difficulties that remains is the inherent insolubility of NSAIDs in aqueous media, thus preventing the convenient use of NSAIDs containing sufficiently high concentrations and meeting the required bioavailability criteria, for example, to allow drug release from the stomach or intestinal lumen. Efficient drug absorption and consistent and appropriately high blood/serum levels.

The NSAIDs prodrugs of the present invention overcome the problems listed above. More specifically, embodiments of the present invention relate to prodrugs of NSAIDs that significantly increase the solubility of NSAIDs in aqueous solutions, thereby avoiding the use of carriers, such as ethanol or castor oil, when administered as solutions. Furthermore, according to the present invention, the prodrugs of NSAIDs do not exhibit the side effects of prior art formulations. Furthermore, the prodrugs of the present invention almost completely avoid gastric irritation when administered orally, thereby significantly increasing the therapeutic index and potency of the tested prodrugs.

Accordingly, in one aspect, the invention relates to prodrugs of NSAIDs. Preferred prodrugs of NSAIDs are compounds of the general formula, or pharmaceutically acceptable salts thereof:

Where Y is NH-AA or O-AA, AA is an amino acid, and the amino or hydroxyl groups of AA react with the carboxylic acid groups of NSAIDs.

The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of the above various NSAIDs and their pharmaceutical carriers.

In another embodiment, the present invention is directed to a method of treatment of a patient in need of NSAID treatment, the method comprising administering to said patient an effective amount of NSAIDs.

In yet another embodiment, the present invention relates to a method of increasing the solubility of NSAIDs in aqueous solution comprising reacting the carboxyl functional group of each molecule of NSAIDs and isolating the products thereof.

In a further embodiment, the present invention relates to a method which substantially reduces or eliminates gastric mucosal injury of NSAIDs when administered to a patient substantially and in a therapeutically effective manner, said method comprising administering each NSAID The carboxyl functional group of the molecule reacts with the amino or hydroxyl groups of selected amino acids to form amide or ester covalent bonds, respectively, and the product is isolated and administered to a patient.

A. Synthesis of Ibuprofen Amino Acid Derivatives

Overview:

The procedure for the synthesis of the L-serine, L-threonine and L-hydroxyproline esters of ibuprofen is outlined in the Synthetic Sequence section. See the Experimental section for complete procedures and analyzed data. Again, these synthetic diagrams are examples. The scheme can be applied to the preparation of other amino acid prodrugs of the NSAIDs of the present invention. In general, (±)-ibuprofen (4-10 g, batchwise) was mixed with N-benzyloxy/benzyl ester protected amino acid (1 equivalent), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1 equivalent) was reacted. Once the reaction was complete, it was extracted with water to remove any excess EDC, dilute acid to remove DMAP, and sodium bicarbonate to remove ibuprofen. After drying over sodium sulfate, the crude protected amino acid ester of (±)-ibuprofen was filtered, concentrated and either used directly or purified by flash chromatography on silica gel to give protected Esters (85-95%). If a slight excess of ibuprofen and coupling reagent is used, column chromatography is usually not required, but an exhaustive extraction step is performed. The protecting group was removed by hydrogenation (25-35 psi _H2 ) in the presence of 10% palladium on carbon catalyst and hydrochloric acid. The yield of the deprotection step ranged from 70-90%. After filtration and drying, the hydrochloride salts of the serine and threonine esters of (±)-ibuprofen were purified by crystallization. L-Hydroxyproline-ibuprofen ester hydrochloride is a gel that does not solidify/crystallize. In this case, the neutral compound is purified by repeated hydrogenation without the use of acid.

Since ibuprofen starts as a mixture of enantiomers, with the exception of the threonine ester, the final products are released as a mixture of diastereomers. For the threonine ester of ibuprofen, washing with water, acetone or acetonitrile allows easy separation of the final diastereomeric salts. The insoluble isomer (SPI0016A) was determined to be the active isomer compared to an authentic standard prepared from S-(+)-ibuprofen. The serine and hydroxyproline esters of (±)-ibuprofen cannot be easily separated in this way.

Composition order:

1. SPI0015

2.SPI0016A and SPI0016B

3. SPI0017

Synthesis of L-serine ester, L-threonine ester, and L-hydroxyproline ester of (±)-ibuprofen: a) EDC, DMAP, CH ₂ Cl ₂ ; b) HCl, 10% Pd/C , EtOH c) acetone, d) 10% Pd/C, EtOH.

Experimental part:

The synthesis of SPI0015, SPI0016 and SPI0017 was carried out in two or three batches. Reagents mentioned in the experimental section were of the highest commercially available purity and were purchased from Sigma-Aldrich, Acros, or Bachem, except that solvents were purchased from Fisher Scientific or Mallinkrodt.

1) Preparation of (±)-Ibuprofen-L-serine ester hydrochloride (SPI0015).

(±)-Ibuprofen (5.04g, 24.4mmol), N-benzyloxycarbonyl-L-serine benzyl ester (8.11g, 24.6mmol), 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride (EDC, 4.87g, 25.4mmol) and 4-(N,N-dimethylamino)pyridine (DMAP, 0.40g, 3.27mmol) in an argon atmosphere at room temperature Dissolve in dichloromethane (150 mL). After stirring at room temperature under an argon atmosphere for 22 hours, water (100 mL) was added, and the layers were separated. The dichloromethane layer was washed again with water (100 mL) and dried over sodium sulfate (5 g) for 1 hour. After filtration and concentration under reduced pressure, the remaining oil was purified by flash chromatography on silica gel (250 g), eluting with hexane/ethyl acetate (3:1). Protected L-serine-(±)-ibuprofen ester (SPI001501) was produced in this step as a colorless solid (11.4 g, yield: 90%).

2(S)-Benzyloxycarbonylamino-3-[2(R,S)-(4-isobutylphenyl)propionyloxy]-propionic acid benzyl ester:

¹ H NMR (300MHz, CDCl ₃ ): δ=7.40-7.20(m, 10H), 7.14-7.01(m, 4H), 5.50(d, 1/2H, J=8.4Hz), 5.29(d, 1/ 2H, J=8.4Hz), 5.11-5.02(m, 2.5H), 4.90(d, 1/2H, J=12Hz), 4.62(m, 1H), 4.49-4.43(m, 1H), 4.36-4.32 (m, 1H), 3.59(m, 1H), 2.39-2.35(m, 2H), 1.78(m, 1H), 1.42-1.39(m, 3H), 0.85(d, 6H, J=6.6Hz).

¹³ C NMR(75MHz，CDCl ₃ )：δ＝174.05，169.19，169.07，155.68，140.73，137.20，136.12，135.05，134.91，129.44，128.67，128.65，128.60，128.41，128.33，128.30，128.19，127.19，127.16， 67.75, 67.32, 64.51, 64.32, 53.71, 45.16, 45.02, 30.35, 22.60, 18.27.

The protected ibuprofen-L-serine ester (22.50 g, 43.4 mmol) was dissolved in ethanol (200 mL) at room temperature, and it was added to a catalyst containing 10% palladium on carbon (3.86 g, 50 % wet) in the Parr bottle. Hydrochloric acid (10 mL of 37% HCl in 30 mL of water) was added, and the nitrogen atmosphere was replaced with hydrogen (25 psi). After shaking for 4 hours, the palladium catalyst was removed by filtration through celite. Ethanol/water was removed under reduced pressure. The remaining white solid was washed with water (25 mL), acetone (20 mL) and dried under high vacuum (88° C. for 4 hours). (±)-Ibuprofen-L-serine ester hydrochloride (SPI0015) was produced in this experiment as a colorless solid (11.3 g, yield: 80%).

2(S)-Amino-3-[2(R,S)-(4-isobutylphenyl)propionyloxy]propionyl hydrochloride; ((R,S)-Ibuprofen-L- Serine ester hydrochloride):

¹ H NMR (300MHz, DMSO): δ=8.92(br s, 3H), 7.22(t, 2H, J=7.5Hz), 7.10(d, 2H, J=7.5Hz), 4.56(m, 1H), 4.37-4.20(m, 2H), 3.83(q, 1H, J=6.9Hz), 2.41(d, 2H, J=6.9Hz), 1.80(m, 1H), 1.41(d, 3H, J=6.9Hz ), 0.85 (d, 6H, J=6.9Hz).

¹³ C NMR (75MHz, DMSO): δ=173.36, 173.32, 168.08, 168.04, 139.70, 128.96, 129.92, 127.20, 127.05, 62.47, 51.59, 51.49, 44.28, 44.00, 43.90, 29.68, 22.28.

HPLC analysis:

99.13% purity; rt=3.133min; Luna C18 5u column (sn 167917-13); 4.6×250mm; 254nm; 50% acrylonitrile/50% trifluoroacetic acid buffer (0.1%); 35 C; 20ul injection; 1ml /min; 1 mg/mL sample size; sample dissolved in mobile phase.

CHN elemental analysis:

Calculated: C 58.27, H 7.33, N 4.25; Measured: C 58.44, H 7.46, N 4.25.

Melting point: 169.5-170.5°C

2a) Preparation and isolation of (±)-Ibuprofen-L-threonine ester hydrochloride (SPI0016A and SPI0016B).

(±)-Ibuprofen (4.15g, 20.11mmol), N-benzyloxycarbonyl-L-threonine benzyl ester (6.90g, 20.11mmol), 1-(3-dimethylaminopropyl )-3-Ethylcarbodiimide hydrochloride (EDC, 3.95g, 20.6mmol) and 4-(N, N-dimethylamino)pyridine (DMAP, 0.25g, 2.0mmol) at room temperature argon Dissolve in dichloromethane (50 mL) in atmosphere. After stirring for 19 hours, the dichloromethane layer was washed with water (50 mL), 5% hydrochloric acid solution (2×25 mL), water (25 mL), saturated sodium bicarbonate solution (2×25 mL) and water (50 mL). After drying over sodium sulfate (5 g) for 1 hour, filtration and concentration under reduced pressure, the remaining oil was used without further purification. This step yielded protected L-threonine-(±)-ibuprofen ester (SPI001601) as a pale yellow oil (10.2 g, yield: 95.3%), which solidified upon standing.

Benzyl 2(S)-benzyloxycarbonylamino-3-[2(R,S)-(4-isobutylphenyl)-propionyloxy]butanoate:

¹ H NMR (300 MHz, CDCl ₃ ): δ=7.40-7.15 (m, 10H), 7.14-7.01 (m, 4H), 5.48-5.25 (m, 2H), 5.11-5.01 (m, 3H), 4.90 ( d, 1/2H, J=12Hz), 4.68(d, 1/2H, J=12Hz), 4.48(m, 1H), 3.60-3.48(m, 1H), 2.39(m, 2H), 1.79(m , 1H), 1.42-1.35(m, 3H), 1.27(d, 1.5H, J=6.6Hz), 1.17(d, 1.5H, J=6.6Hz), 0.85(m, 6H).

¹³ C NMR(75MHz，CDCl ₃ )：δ＝173.32，169.70，169.30，156.55，140.75，137.38，137.22，136.14，135.07，134.99，129.45，129.41，128.65，128.39，128.22，127.21，127.14，70.97，70.70， 67.81, 67.66, 67.53, 57.83, 45.19, 30.39, 22.61, 18.57, 18.30, 17.18, 16.87.

The protected ibuprofen-L-threonine ester (10.15 g, 19.0 mmol) was dissolved in hot ethanol (150 mL), and it was added to a catalyst containing 10% palladium on carbon (3.4 g, 50% wet) in a Parr bottle. Hydrochloric acid (6 mL of 37% HCl in 20 mL of water) was added, and the nitrogen atmosphere was replaced with hydrogen (30 psi). After shaking for 3 hours, the palladium catalyst was removed by filtration through celite (30 g). Ethanol/water was removed under reduced pressure. (±)-Ibuprofen-L-threonine ester hydrochloride (SPI0016A and SPI0016B, 6.4 g, crude product yield: 97%) produced in this experiment was a colorless solid. The crude mixture of diastereomers was stirred in acetone (200 mL) at room temperature under argon atmosphere for 2 hours. After 2 hours the solid (2.84 g, SPI0016A) was filtered. The filtrate (SPI0016B, 3.0 g) was concentrated under reduced pressure.

1.) Purification of SPI0016A (active isomer):

After synthesizing 3 batches of S-ibuprofen-L-threonine ester (SPI0016A), the batches were combined (total 8.78 g) and crystallized three times from DIUF water (100 mL). A small amount of zwitterions are produced each time. To recover the salt, the resulting solid (from each crystallization) was dissolved in ethanol solution containing 1% hydrochloric acid (3 mL of 37% hydrochloric acid in 100 mL of ethanol). The ethanol solution was then concentrated under reduced pressure at room temperature. After the third crystallization and recovery step, the salt (5.6 g) was stirred in acetonitrile (100 mL) at room temperature under argon atmosphere for 44 hours. It was then filtered and dried under high vacuum 50-55° until constant weight (5.5 g).

2(S)-amino-3(R)-[2(S)-(4-isobutylphenyl)propionyloxy]butanoic acid; (S-Ibuprofen-L-threonine ester hydrochloride salt, active isomer):

¹ H NMR (300MHz, DMSO): δ=8.76(br s, 3H), 7.19(d, 2H, J=8.1Hz), 7.11(d, 2H, J=8.1Hz), 5.28(dq, 1H, J =6.3, 3.6Hz), 4.14(q, 1H, J=3.6Hz), 3.80(q, 1H, J=7.2Hz), 2.41(d, 2H, J=7.2Hz), 1.80(m, 1H), 1.37 (d, 3H, J = 7.2 Hz), 1.21 (d, 3H, J = 6.3 Hz), 0.85 (d, 6H, J = 6.6 Hz).

¹³ C NMR (75 MHz, DMSO): δ=172.66, 168.24, 139.68, 137.24, 128.95, 126.97, 67.98, 55.35, 44.23, 43.83, 29.66, 22.24, 18.52, 16.47.

CHN elemental analysis:

Calculated: C 59.38, H 7.62, N 4.07; Found: C 59.17, H 7.63, N 4.04.

HPLC analysis:

98.28% purity; r.t.=6.951min.; 60% trifluoroacetic acid (0.1%)/40% acetonitrile; 1mL/min; 37.5 C; Luna C18, 3u column (SN 167917-13), 4.6×250mm;

Optical rotation: +24.5°

Melting point: 189-190°C

2) Purification of SPI0016B (inactive isomer):

After completion of 3 batches of R-Ibuprofen-L-threonine ester (SPI0016 B), the batches were combined (total 9.02 g) and crystallized from DIUF water (50 mL). The crystallization process produced small amounts of zwitterions. To recover the salt, the resulting solid was dissolved in an ethanol solution containing 1% hydrochloric acid (3 mL of 37% hydrochloric acid in 100 mL of ethanol). The ethanol solution was then concentrated under reduced pressure at room temperature. The remaining salt (5.93 g) was crystallized three times from hot toluene (100 mL) while adding a small amount of acetone (1 mL). The salt was then filtered and dried under high vacuum at room temperature until constant weight (5.1 g).

2(S)-amino-3(R)-[2(R)-(4-isobutylphenyl)propionyloxy]butyric acid; (R-Ibuprofen-L-threonine ester hydrochloride salt, inactive isomer):

¹ H NMR (300MHz, DMSO): δ=8.82(br s, 3H), 7.23(d, 2H, J=7.8Hz), 7.10(d, 2H, J=7.8Hz), 5.27(m, 1H), 4.18(m, 1H), 3.80(q, 1H, J=7.2Hz), 2.41(d, 2H, J=7.2Hz), 1.81(m, 1H), 1.41(d, 3H, J=6.9Hz), 1.34 (d, 3H, J = 6.3 Hz), 0.85 (d, 6H, J = 6.3 Hz).

¹³ C NMR (75 MHz, DMSO): δ=72.56, 168.08, 139.64, 136.98, 128.84, 127.14, 68.8, 55.29, 44.28, 29.69, 22.28, 18.24, 16.41.

CHN elemental analysis:

Calculated: C 59.38, H 7.62, N 4.07; Found: C 59.30, H 7.60, N 4.05.

HPLC analysis:

98.43% purity; r.t.=6.19min.; 60% trifluoroacetic acid (0.1%)/40% acetonitrile; 1mL/min; 37.5C; Luna C18, 3u column (SN 167917-13), 4.6×250mm; 22ul injection.

Optical rotation: +10.4°

Melting point: 176-177°C

2b) Preparation of S-(+)-Ibuprofen-L-threonine ester hydrochloride standard (SPI0016 S).

S-(+)-Ibuprofen (2.0g, 9.69mmol), N-benzyloxycarbonyl-L-threonine benzyl ester (3.25g, 9.91mmol), 1-(3-dimethylamino Propyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.90 g, 9.91 mmol) and 4-(N,N-dimethylamino)pyridine (DMAP, 0.12 g, 1.0 mmol) at room temperature Dissolve in dichloromethane (25 mL) under argon atmosphere. After stirring for 4 hours, the dichloromethane layer was washed with water (25 mL), 5% hydrochloric acid solution (25 mL), saturated sodium bicarbonate solution (2 x 25 mL) and water (25 mL). After drying over sodium sulfate (5 g) for 1 hour, filtration and concentration under reduced pressure, the remaining oil was used without further purification. This step yielded protected S-(+)-ibuprofen-L-threonine ester (SPI001601S) as a pale yellow oil (5.01 g, yield: 98%), which solidified upon standing.

Benzyl 2(S)-benzyloxycarbonylamino-3-[2(R,S)-(4-isobutylphenyl)propionyloxy]butanoate:

¹ H NMR (300MHz, CDCl ₃ ): δ=7.35-7.23(m, 10H), 7.10(d, 2H, J=7.8Hz), 7.05(d, 2H, J=7.8Hz), 5.48-5.25(m , 2H), 5.17-5.01(m, 4H), 4.50(dd, 1H, J=9.6, 1.8Hz), 3.50(q, 1H, J=7.2Hz), 2.40(d, 2H, J=7.2Hz) , 1.80(m, 1H), 1.37(d, 3H, J=7.2Hz), 1.17(d, 3H, J=6.3Hz), 0.86(d, 6H, J=6.6Hz).

¹³ C NMR (75MHz, CDCl ₃ ): δ=173.29, 169.69, 156.51, 140.68, 137.21, 136.08, 135.06, 129.40, 128.70, 128.66, 128.57, 128.38, 128.24, 127.14, 5, 70.79, 54.1, 67.7 45.11, 30.39, 22.61, 18.57, 16.87.

Protected S-(+)-ibuprofen-L-threonine ester (5.0 g, 9.40 mmol) was dissolved in hot ethanol (100 mL) and added to a solution containing 10% palladium Carbon catalyst (1.0 g, 50% wet) in a Parr bottle. Hydrochloric acid (1 mL of 37% HCl in 10 mL of water) was added and the nitrogen atmosphere was replaced with hydrogen (32 psi). After shaking for 2 hours, the palladium catalyst was removed by filtration through celite (30 g). Ethanol/water was removed under reduced pressure. S-(+)-Ibuprofen-L-threonine ester hydrochloride (SPI0016S, 2.8 g, crude product yield: 85%) produced in this experiment was a colorless solid. The salt was stirred in acetone (50 mL) at room temperature under argon atmosphere for 3 hours. After 3 hours the solid (2.24 g, 69% yield) was filtered and dried under high vacuum at room temperature until constant weight.

2(S)-amino-3(R)-[2(S)-(4-isobutylphenyl)propionyloxy]butanoic acid; (S-Ibuprofen-L-threonine ester hydrochloride salt, active isomer):

¹ H NMR (300MHz, DMSO): δ=8.76(br s, 3H), 7.19(d, 2H, J=8.1Hz), 7.11(d, 2H, J=8.1Hz), 5.28(dq, 1H, J =6.3, 3.6Hz), 4.14(q, 1H, J=3.6Hz), 3.80(q, 1H, J=7.2Hz), 2.41(d, 2H, J=7.2Hz), 1.80(m, 1H), 1.37 (d, 3H, J = 7.2 Hz), 1.21 (d, 3H, J = 6.3 Hz), 0.85 (d, 6H, J = 6.6 Hz).

¹³ C NMR (75 MHz, DMSO): δ=172.66, 168.24, 139.68, 137.24, 128.95, 126.97, 67.98, 55.35, 44.23, 43.83, 29.66, 22.24, 18.52, 16.47.

HPLC analysis:

98.28% purity; r.t.=6.951min.; 60% trifluoroacetic acid (0.1%)/40% acetonitrile; 1mL/min; 37.5 C; Luna C18, 3u column (SN 167917-13), 4.6×250mm;

Optical rotation: +26.5°

Melting point: 189-190°C

3) Preparation of (±)-Ibuprofen-L-hydroxyproline ester (SPI0017).

(±)-Ibuprofen (5.10g, 24.7mmol), N-benzyloxycarbonyl-L-hydroxyproline benzyl ester (8.80g, 24.7mmol), 1-(3-dimethylaminopropyl base)-3-ethylcarbodiimide hydrochloride (EDC, 5.10g, 26.0mmol) and 4-(N,N-dimethylamino)pyridine (DMAP, 0.30g, 2.40mmol) at room temperature Dissolve in dichloromethane (100 mL) under argon atmosphere. After stirring at room temperature under an argon atmosphere for 24 hours, water (100 mL) was added and the layers were separated. The dichloromethane layer was washed with water (100 mL), 5% sodium bicarbonate solution (2 x 50 mL) and dried over sodium sulfate (5 g) for 1 hour. After filtration and concentration under reduced pressure, the remaining oil was used without further purification. Protected (±)-Ibuprofen-L-hydroxyproline ester (SPI001701) was produced in this step as pale yellow oil (11.5 g, yield: 85%).

4(R)-[2-(4-Isobutylphenyl)propionyloxy]pyrrolidine-2(S)-carboxylic acid; ((R,S)-Ibuprofen-L-Hydroxyproline ester):

¹ H NMR (300MHz, CDCl ₃ ): δ=7.33-7.02(m, 14H), 5.25-4.95(m, 5H), 4.5 1-4.19(m, 1H), 3.75-3.50(m, 3H), 2.40 (d, 2H, J = 6.9 Hz), 2.15 (m, 1H), 1.81 (m, 1H), 1.44 (d, 3H, J = 7.0 Hz), 0.87 (d, 6H, J = 6.6 Hz).

¹³ C NMR(75 MHz，CDCl ₃ )：δ＝173.99，171.93，171.72，154.68，154.15，140.70，137.23，137.04，136.23，135.44，135.23，129.41，128.59，128.47，128.35，128.19，128.08，127.89，127.02 ,72.86,72.16,67.40,67.18,67.09,58.12,57.83,52.66,52.49,52.13,45.15,36.63,35.67,32.07,30.33,29.23,22.90,22.58,18.36.

The protected ibuprofen-L-hydroxyproline ester (11.40 g, 43.4 mmol) was dissolved in ethanol (150 mL) at room temperature, and it was added to a catalyst containing 10% palladium on carbon (2.73 g, 50% wet) in a Parr bottle. The nitrogen atmosphere was replaced with hydrogen (34 psi). After shaking for 5 hours, the palladium catalyst was removed by filtration through celite. Ethanol was removed under reduced pressure. The remaining white solid (6.60 g) was washed with DIUF water (50 mL), diethyl ether (50 mL) and dried under high vacuum until constant weight. (±)-Ibuprofen-L-hydroxyproline ester SPI0017 (5.64 g, 84% yield) was produced as a colorless solid in this experiment.

4(R)-[2-(4-Isobutylphenyl)propionyloxy]pyrrolidine-2(S)-carboxylic acid; ((R,S)-Ibuprofen-L-Hydroxyproline ester):

¹ H NMR (300MHz, CDCl ₃ ): δ=7.22(d, 2H, J=7.2Hz), 7.09(d, 2H, J=7.2Hz), 5.27(m, 1H), 4.40(t, 0.5H, J=7Hz), 4.24(t, 0.5H, J=9Hz), 3.75(m, 1H), 3.61(m, 1H), 3.28(d, 0.5H, J=13Hz), 3.15(d, 0.5H, J=13Hz), 2.42-2.10(m, 4H), 1.78(m, 1H), 1.40(br t, 3H, J=6Hz), 0.82(d, 6H, J=6Hz). (mixture of diastereomers)

¹³ C NMR (75MHz, CDCl ₃ ): δ=173.28, 173.23, 168.98, 139.88, 137.33, 137.23, 129.12, 127.26, 127.17, 72.58, 57.60, 57.50, 50.24, 50.12, 44.34, 44.15, 34 22.34, 18.43, 18.23. (mixture of diastereomers)

HPLC analysis:

100% purity; r.t.=5.35, 5.22min.; 55% trifluoroacetic acid (0.1%), 45% acrylonitrile; 1 mL/min; 32.3 C, Luna C18, serial#188255-37; 20ul injection.

CHN elemental analysis:

Calc.: C 67.69, H 7.89, N 4.39; fbund: C 67.47, H 7.87, N 4.30.

Melting point: 198-199°C

Efficacy (anti-pain potential) of (±)-Ibuprofen L-serine, L-threonine and L-hydroxyproline esters synthesized by acetylcholine-induced abdominal constriction in male albino rats:

This study was carried out to evaluate the efficacy of the L-serine, L-threonine and L-hydroxyproline esters of (±)-ibuprofen as an antagonism against acetylcholine-induced writhing in albino rats. an index. Ibuprofen (racemic mixture) and (S)-(+)-ibuprofen served as reference controls.

Different new formulations of ibuprofen and reference controls i.e. ibuprofen (racemic mixture) and (S)-(+)-ibuprofen were administered gavage to male albino mice (Swiss strain), It uses milli Q water containing 5% (v/v) Tween 80 as excipient. The study was conducted at two dose levels, 50 mg and 100 mg/kg body weight and a vehicle control group. Ten animals were used at each dose level. All doses are expressed in molar equivalents of ibuprofen. The doses and molar equivalents used are as follows.

Table 2: Formulations: Molar Equivalents:

Preparations Molar equivalent S-(+)-Ibuprofen-L-Threonine Ester 0.833 units are equivalent to 1 unit of ibuprofen (±)-Ibuprofen-L-serine ester 1.6 units is equivalent to 1 unit of ibuprofen (±)-Ibuprofen-L-Hydroxyproline Ester 1.55 units is equivalent to 1 unit of ibuprofen

Table 3: Test item: Group: Dose (mg/kg): Equivalent weight of test item:

detection item Group Dose (mg/kg) [as ibuprofen] Equivalent weight of test item [mg/kg] Excipients Excipient control group 0.0 -- S-(+)-Ibuprofen-L-threonine ester Test group 1 50.0 41.65 Test group 2 100.0 83.30   (±)-Ibuprofen-L-serine ester (Ibuprofen S) Test group 3 50.0 80.0 Test group 4 100.0 160.0 (±)-Ibuprofen-L-Hydroxyproline Ester Test group 5 50.0 77.5 Test group 6 100.0 155.0 Ibuprofen (racemic mixture) Test group 7 50.0 50.0 Test group 8 100.0 100.0 Ibuprofen S+ Test group 9 50.0 25.0 Test group 10 100.0 50.0

Efficacy in terms of the antagonism effect on acetylcholine-induced single writhing at two dose levels - 50.0 and 100.0 mg/kg - of the three formulations as well as the reference control is presented below.

Table 4: Test item: Group: Dose (mg/kg): Number of animals exhibiting a single loss of writhing (out of 10)

detection item Group Dose (mg/kg) [as ibuprofen] Number of animals exhibiting single tumbling deletion (number of animals per dose = 10) one hour after administration Three hours after administration Excipients Excipient Control 0.0 0 0 S-(+)-Ibuprofen-L-Threonine Ester low dose 50.0 1 0 high dose 100.0 3 0 (±)-Ibuprofen-L-serine ester low dose 50.0 4 2 high dose 100.0 6 4 (±)-Ibuprofen-L-Hydroxyproline Ester low dose 50.0 5 4 high dose 100.0 7 7 Ibuprofen (racemic mixture) low dose 50.0 4 2 high dose 100.0 6 6 Ibuprofen S+ low dose 50.0 5 1 high dose 100.0 6 6

Adopt Chi-square test (Chi-square test) step to carry out statistical analysis, various preparations are compared with reference controls, do not show any statistically significant difference, and compare the number of animals that do not show toss in each group, respective significant levels "p" is greater than 0.05.

Based on clinical observations of the number of animals that did not show writhing due to administration of acetylcholine, it was found that (±)-Ibuprofen-L -Hydroxyproline esters are more effective against acetylcholine-induced writhing.

Table 5: L-serine, L-threonine and L-hydroxyproline esters of (±)-Ibuprofen, Ibuprofen (racemic mixture) and Ibuprofen (S)-(+) Efficacy summary of ® based on properties against acetylcholine-induced writhing in albino mice

Dose (mg/kg) [as ibuprofen] detection item Number of animals exhibiting single tumbling deletion (number of animals per dose = 10) one hour after administration three hours after administration 50mg/kg Excipient Control 0 0 S-(+)-Ibuprofen-L-threonine ester 1 0 (±)-Ibuprofen-L-serine ester 4 2 (±)-Ibuprofen-L-Hydroxyproline Ester 5 4 Ibuprofen (racemic mixture) 4 2 Ibuprofen(S)-(+) 5 1

Table 6:

100mg/kg Excipient Control 0 0 S-(+)-Ibuprofen-L-threonine ester 3 0 (±)-Ibuprofen-L-serine ester 6 4 (±)-Ibuprofen-L-Hydroxyproline Ester 7 7 Ibuprofen (racemic mixture) 6 6 Ibuprofen(S)-(+) 6 6

Statistical analysis of the data was performed using a chi-square test procedure to evaluate the potency of the new formulation relative to the reference control. The test did not reveal any statistically significant difference between the formulations and the reference control, while comparing the number of animals in each group that did not show tumbling, each had a level of significance "p" greater than 0.05.

The data are also summarized in Figures 1 and 2. Based on the number of animals that did not show writhing due to the administration of acetylcholine, it was found from clinical observations and bar graphs (Figures 1 and 2) of efficacy comparisons that, compared with other formulations and ibuprofen (racemic mixture) and ibuprofen (S )-(+), (±)-ibuprofen-L-hydroxyproline ester was more effective against acetylcholine-induced writhing.

in conclusion

This study was conducted to evaluate the relative efficacy of new formulations of ibuprofen. The antagonism performance of the new formulations against acetylcholine churning was used as an index to determine the relative potency of the new formulations. Ibuprofen (racemic mixture) and ibuprofen (S)-(+) served as reference controls. The study was conducted at two dose levels (50.0 and 100.0 mg/kg) and a vehicle control group.

The potency in terms of antagonism effect on acetylcholine-induced single writhing at two dose levels - 50.0 and 100.0 mg/kg - of the three formulations and the reference control is shown below.

Table 7: Test item: Group: Dose (mg/kg): Number of animals exhibiting a single loss of writhing (out of 10)

detection item Group Dose (mg/kg) [as ibuprofen] Number of animals exhibiting single tumbling deletion (number of animals per dose = 10) 1 hour after administration Three hours after administration Excipients Excipient Control 0.0 0 0 S-(+)-Ibuprofen-L-Threonine Ester low dose 50.0 1 0 high dose 100.0 3 0 (±)-Ibuprofen-L-serine ester low dose 50.0 4 2 high dose 100.0 6 4 (±)-Ibuprofen-L-Hydroxyproline Ester low dose 50.0 5 4 high dose 100.0 7 7 Ibuprofen (racemic mixture) low dose 50.0 4 2 high dose 100.0 6 6 Ibuprofen (S)-(+) low dose 50.0 5 1 high dose 100.0 6 6

Statistical analysis was carried out using the chi-square test procedure. Compared with the reference control, the preparation did not show any statistically significant difference, while comparing the number of animals that did not show tumbling in each group, the respective significance level "p" was greater than 0.05.

However, based on clinical observations on the number of animals that did not show writhing due to administration of acetylcholine, it was found that (±)- Ibuprofen-L-hydroxyproline ester is more effective against acetylcholine-induced writhing.

Gastric mucosal irritant potential of the L-serine, L-threonine, and L-hydroxyproline esters of (±)-ibuprofen in fasted male albino mice

overview

This study was performed to evaluate the effect of new formulations of ibuprofen ((±)-L-serine, L-threonine and L-hydroxyproline esters of ibuprofen) on gastric Relative potential for mucosal irritation/injury. Ibuprofen (racemic mixture) and Ibuprofen (S)-(+) served as reference controls.

Different new formulations of ibuprofen and ibuprofen (racemic mixture) and ibuprofen (S)-(+) were administered by gavage to fasted male albino mice (Wistar strain) with 5 Milli Q water with % Tween 80 was used as excipient. The study was conducted at two dose levels, 200 mg and 300 mg/kg body weight, and a vehicle control group. Five animals were used at each dose level. All doses are expressed in molar equivalents of ibuprofen (racemic mixture). The doses and molar equivalents used are as follows.

Table 8: Formulations: Molar Equivalents:

Preparations Molar equivalent S-(+)-Ibuprofen-L-Threonine Ester 0.833 units are equivalent to 1 unit of ibuprofen (±)-Ibuprofen-L-serine ester 1.60 units is equivalent to 1 unit of ibuprofen (±)-Ibuprofen-L-Hydroxyproline Ester 1.55 units is equivalent to 1 unit of ibuprofen

The groups used are listed below:

Table 9: Test item: Group: Dose (mg/kg): Equivalent weight of test item:

detection item Group Dose (mg/kg) [as ibuprofen] Equivalent weight of test item [mg/kg] Excipients Excipient control group 0.0 -- S-(+)-Ibuprofen-L-Threonine Ester Test group 1 200.0 0.0 Test group 2 300.0 166.6 (±)-Ibuprofen-L-serine ester Test group 1 200.0 249.9 Test group 2 300.0 320.0 (±)-Ibuprofen-L-Hydroxyproline Ester Test group 1 200.0 480.0 Test group 2 300.0 310.0 Ibuprofen (racemic mixture) Test group 1 200.0 465.0 Test group 2 300.0 300.0 Ibuprofen (S)-(+) Test group 1 200.0 100.0 Test group 2 300.0 150.0

The mice were fasted 18 to 22 hours prior to dosing. Test items were administered as a single dose by gavage. Three hours after dosing, the animals were sacrificed by _CO2 gas inhalation. Dissect the stomach and observe:

^* Amount of mucoid exudate

^* the degree of congestion and thickening of the stomach wall

^* Bleeding point (localized or diffuse), nature of bleeding (petechiae or ecchymosis) and size and

^* Perforation or any other damage

The observations on the stimulation of gastric mucosa of each group of animals are summarized as follows

Table 10: Test items: Group: Dose (mg/kg): Observation:

detection item Group Dose (mg/kg) [as ibuprofen] observe excipient Vehicle control group 0.0 None of the animals showed any signs of gastric mucosal irritation S-(+)-Ibuprofen-L-threonine ester Test group 1 200.0 None of the dosed animals showed any signs of gastric mucosal irritation Test group 2 300.0 None of the dosed animals showed any signs of gastric mucosal irritation (±)-Ibuprofen-L-serine ester Test group 1 200.0 None of the dosed animals showed any signs of gastric mucosal irritation Test group 2 300.0 None of the dosed animals showed any signs of gastric mucosal irritation (±)-Ibuprofen-L-Hydroxyproline Ester Test group 1 200.0 None of the dosed animals showed any signs of gastric mucosal irritation Test group 2 300.0 None of the dosed animals showed any signs of gastric mucosal irritation Ibuprofen (racemic mixture) Test group 1 200.0 Signs of gastric mucosal irritation were observed in 1 of 5 animals treated Test group 2 300.0 Signs of gastric mucosal irritation were observed in 2 of 5 animals treated Ibuprofen(S)-(+) Test group 1 200.0 Signs of gastric mucosal irritation were observed in all 5 animals dosed Test group 2 300.0 Signs of gastric mucosal irritation were observed in 3 of 5 animals treated

The results of this study showed that the formulation of ibuprofen did not induce any signs of gastric mucosal irritation in fasted male albino mice at the two dose levels tested (200 mg and 300 mg/kg body weight). In contrast, both ibuprofen (racemic mixture) and ibuprofen (S)-(+) caused gastric mucosal irritation at both dose levels tested. Furthermore, ibuprofen (S)-(+) was found to be more irritating to the gastric mucosa than ibuprofen (racemic mixture).

Outline the synthesis of ketoprofen S-(+)-threonine ester:

The steps for the synthesis of the L-threonine ester of ketoprofen are outlined in the Synthetic Sequence section. This synthesis is exemplary and can be similarly applied to other amino acids. See the Experimental section for complete procedures and analyzed data. In general, (±)-ketoprofen (5 g) reacts with N-boc-L-threonine tert-butyl ester in the presence of a catalytic amount of 4-(N,N-dimethylamino)pyridine (DMAP). ¹ (1 equivalent), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1 equivalent) was reacted. Upon completion of the reaction, excess EDC was removed by water extraction, DMAP was removed by dilute acid extraction, and ketoprofen was removed by sodium bicarbonate extraction. After drying over sodium sulfate, the crude protected L-threonine-(±)-ketoprofen was filtered, concentrated, and purified by flash chromatography on silica gel to yield protected L-threonine-(±)-ketoprofen in high yield (98%). of L-threonine ester. The boc group was cleaved from ether containing 2M hydrochloric acid, followed by treatment with trifluoroacetic acid to remove the tert-butyl ester. After drying, the mixture of L-threonine-R,S(±)-ketoprofen axetil was isolated by crystallization from acetonitrile. The hydrochloride salt of L-threonine-S(+)-ketoprofen axetil was preferentially precipitated from acetonitrile. For comparison, optically pure standard samples were prepared starting from S(+)-ketoprofen. After drying and analysis, a sample of L-threonine-S(+)-ketoprofen axetil hydrochloride (1.75 g) was isolated from the mixture.

Composition order:

Synthesis of L-threonine ester of (±)-ketoprofen: a) EDC, DMAP, _CH2Cl2 ; b) HCl ( _2M ); c) TFA; d) ACN (crystalline).

Experimental part:

The synthesis of SPI0018A was performed in a single batch. Reagents mentioned in the experimental section were of the highest commercially available purity and were purchased from Sigma-Aldrieh, Acros, or Bachem, except that solvents were purchased from Fisher Scientific or Mallinkrodt.

Preparation and isolation of S(+)-ketoprofen-L-threonine ester hydrochloride (SPI0018A)

(±)-Ketoprofen (5.32 g, 20.92 mmol), N-tert-butylcarbonyl-L-threonine tert-butyl ester (Boc-Thr-OtBu, 5.17 g, 18.72 mmol) (prepared according to literature ), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 4.0g, 20.9 mmol) and 4-(N,N-dimethylamino)pyridine (DMAP , 0.22 g) was dissolved in dichloromethane (50 mL) at room temperature under argon atmosphere. After stirring for 5 hours, the dichloromethane layer was washed with water (50 mL), 5% hydrochloric acid solution (2×25 mL), water (25 mL), saturated sodium bicarbonate solution (2×25 mL) and water (50 mL). After drying over sodium sulfate (5 g) for 1 hour, filtration and concentration under reduced pressure, the remaining oil (10.3 g) was purified by column chromatography on silica gel (150 g) and washed with hexane/ethyl acetate (2:1) elute. After combining the products containing the fractions, concentration and drying under high vacuum, this step yielded protected L-threonine-(±)-ketoprofen axetil (SPI001801) as a clear oil ( 9.42 g, yield: 98%).

tert-butyl 3-[2(R,S)-(3-benzoylphenyl)propionyloxy]-2(S)-tert-butoxycarbonylaminobutyrate: (mixture of diastereomers)

¹ H NMR (300 MHz, CDCl ₃ ): δ=7.83-7.42 (m, 9H), 5.43 (dd, 1H, J=13.2, 6.9 Hz), 5.10 (dd, 1H, J=20.7, 9.3), 4.29 ( t, 1H, J=11.7Hz), 3.75(q, 1H, J=7.2Hz), 1.50-1.42(m, 19.5H), 1.30-1.18(m, 4.5H).

¹³ C NMR(75MHz，CDCl ₃ )：δ＝196.18，172.62，172.55，168.85，168.58，155.81，140.33，140.23，137.86，137.39，132.46，132.42，131.54，131.38，130.00，129.31，129.13，129.02，128.54， 128.27, 82.50, 82.37, 80.05, 71.38, 71.22, 57.59, 57.52, 45.46, 45.31, 28.40, 27.98, 27.84, 18.54, 18.48, 17.19, 16.84.

Protected (R,S)-ketoprofen-L-threonine ester (9.42 g, 18.41 mmol) was dissolved in dichloromethane (25 mL) at room temperature under argon atmosphere. Anhydrous hydrogen chloride in diethyl ether (2M, 25 mL) was added, and the mixture was stirred at room temperature for 17 hours. The mixture was concentrated under reduced pressure. The remaining foam (8.2 g) was dissolved in a mixture of dichloromethane (10 mL) and trifluoroacetic acid (20 mL). After stirring at room temperature for 6.5 hours, the solution was concentrated under reduced pressure. Toluene (25 mL) was added to the remaining oil, and the mixture was concentrated again. A mixture of ethanol (20 mL) and anhydrous hydrogen chloride (2M, 20 mL) in ether was added and the solution was concentrated for a third time. After drying at room temperature and under high vacuum for 2 hours, the (±)-ketoprofen-L-threonine ester hydrochloride (diastereomeric mixture, 7.11g, crude product yield: 98%) generated in this experiment, It is off-white solid. The crude mixture of diastereomers (7.0 g) was crystallized 3 times from acetonitrile (200 mL). After the third crystallization, the remaining white solid was dried under high vacuum at 50° C. until constant weight (4 hours). This experiment produced L-threonine-S(+)-ketoprofen axetil hydrochloride SPI0018A (2.2 g, 30% yield from SPI001801 (calculated)).

2(S)-Amino-3(R)-[2(S)-(3-benzoylphenyl)propionyloxy]butyrate hydrochloride (L-threonine-S(+)-one profen axetil hydrochloride):

¹ H NMR (300MHz, DMSO): δ=14.08(br s, 1H), 8.72(br s, 3H), 7.74-7.51(m, 9H), 5.29(t, 1H, J=4.5Hz), 4.16( m, 1H), 3.97 (q, 1H, J = 6.3 Hz), 1.42 (d, 3H, J = 6.9 Hz), 1.23 (d, 3H, J = 6.3 Hz).

¹³ C NMR (75MHz, DMSO): δ=195.34, 172.26, 168.21, 140.42, 137.05, 136.74, 132.66, 131.66, 129.48, 128.73, 128.49, 128.30, 68.23, 55.31, 44.00, 18.454, 1

CHN elemental analysis:

Calculated: C 61.30, H 5.66, N 3.57; Found: C 61.02, H 5.58, N 3.58.

HPLC analysis:

98.28% purity; r.t.=25.14min.; 55% DIUF water (0.1% trifluoroacetic acid)/45% methanol; 1mL/min; 36.4 C; Luna C18, 5u column (serial# 211739-42), 4.6×250mm; 20ul injection.

Optical rotation: +27.0°(20C, 174.4 mg/10mL ethanol, 589nm);

Melting point: 166-167°C

Preparation of S-(+)-ketoprofen-L-threonine ester hydrochloride standard substance

(+)-Ketoprofen (1.87 g, 7.74 mmol), N-tert-butylcarbonyl-L-threonine tert-butyl ester (Boc-Thr-OtBu, 2.25 g, 8.14 mmol, prepared according to literature method ), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 1.65g, 8.60mmol) and 4-(N,N-dimethylamino)pyridine (DMAP , 0.1 g) was dissolved in dichloromethane (25 mL) at room temperature under argon atmosphere. After stirring for 4 hours, the dichloromethane layer was washed with water (25 mL). After drying over sodium sulfate (5 g) for 1 hour, filtration and concentration under reduced pressure, the remaining oil was used without purification. This step yielded protected L-threonine-(+)-ketoprofen axetil as a clear oil (4.01 g, yield: ~100%).

¹ H NMR (300MHz, CDCl ₃ ): δ=7.81-7.42(m, 9H), 5.43(m, 1H), 5.10(d, 1H, J=9.3), 4.29(d, 1H, J=9.6Hz) , 3.75 (q, 1H, J=7.2Hz), 1.50-1.42(m, 21H), 1.18(d, 3H, J=6.3Hz).

¹³ C NMR (75MHz, CDCl ₃ ): δ=196.4, 172.79, 168.99, 155.94, 140.44, 137.99, 137.51, 132.59, 131.50, 130.13, 129.31, 129.25, 129.15, 128.65, 128.40, 82.82 45.43, 28.53, 28.10, 18.99, 16.96.

Protected (S)-ketoprofen-L-threonine ester (3.92 g, 7.66 mmol) was dissolved in diethyl ether (2M, 25 mL) containing anhydrous hydrogen chloride under an argon atmosphere at room temperature and stirred at room temperature 17 hours. The mixture was concentrated under reduced pressure. The remaining foam (3.4 g) was dissolved in a mixture of dichloromethane (20 mL) and trifluoroacetic acid (20 mL). After stirring at room temperature for 6.5 hours, the solution was concentrated under reduced pressure. Toluene (25 mL) was added to the remaining oil, and the mixture was concentrated again. A mixture of ethanol (20 mL) and anhydrous hydrogen chloride in ether (2M, 20 mL) was added and the solution was concentrated for a third time. The experiment yielded S(+)-ketoprofen-L-threonine ester hydrochloride (3.05 g crude) as an off-white solid after drying at room temperature under high vacuum for 2 hours. The crude was stirred with acetone (50 mL) at room temperature under argon atmosphere for 2 hours. The remaining white solid was filtered and dried under high vacuum at 50°C until constant weight (4 hours). This experiment produced L-threonine-S(+)-ketoprofen axetil hydrochloride (2.04 g, 67% yield).

¹ H NMR (300MHz, DMSO): δ=14.08(br s, 1H), 8.72(br s, 3H), 7.74-7.51(m, 9H), 5.29(t, 1H, J=4.5Hz), 4.16( m, 1H), 3.97 (q, 1H, J = 6.3 Hz), 1.42 (d, 3H, J = 6.9 Hz), 1.23 (d, 3H, J = 6.3 Hz).

¹³ C NMR (75MHz, DMSO): δ=195.34, 172.26, 168.21, 140.42, 137.05, 136.74, 132.66, 131.66, 129.48, 128.73, 128.49, 128.30, 68.23, 55.31, 44.00, 18.454, 1

HPLC analysis:

99.43% purity; r.t.=25.14min.; 55% DIUF water (0.1% trifluoroacetic acid)/45% methanol; 1mL/min; 36.4 C; Luna C18, 5u column (serial# 211739-42), 4.6×250mm; 20ul injection.

Optical rotation: +27.1°(20C, 177.8mg/10mL ethanol, 589nm);

Melting point: 166-167°C

C. Amino acid derivatives of aspirin

Overview:

The procedure for the synthesis of the L-serine, L-threonine, and L-hydroxyproline esters of acetylsalicylic acid is outlined in the Synthetic Sequences section and is exemplary for other amino acids. See the Experimental section for complete procedures and analyzed data. In general, o-acetylsalicyloyl chloride (10 g-25 g, in batches) was reacted with N-benzyloxy/benzyl ester protected amino acids under pyridine. Upon completion of the reaction (24 to 48 hours at room temperature), the mixture was poured into ice-cooled 2N hydrochloric acid. The dichloromethane portion was then washed with sodium bicarbonate, water and brine. After drying over sodium sulfate, filtration and concentration afforded the crude protected amino acid acetylsalicylate, which was purified by flash chromatography on silica gel. This step produced protected acetylsalicylic acid amino acid esters in yields ranging from 68% to 95%. Deprotection was achieved by hydrogenation (20 psi _H2 ) in the presence of 10% palladium on carbon catalyst. Amino acid acetylsalicylate was extracted from the palladium catalyst with water, concentrated and dried. The final compound was washed with solvent (water, dioxane, acetonitrile, and/or dichloromethane) until purified, and dried under high vacuum until constant weight was reached. Composition order:

1. SPIB00102

2. SPIB00101

3. SPIB00103

Synthesis of L-serine, L-threonine and L-hydroxyproline esters of acetylsalicylic acid: a) Pyridine, CH ₂ Cl ₂ ; b) 10% Pd/C, EtOH, EtOAc.

Experimental part:

Synthesis of SPIB00101, SPIB00102 and SPIB00103 was performed in one or two batches. Reagents mentioned in the experimental section were of the highest commercially available purity and were purchased from Lancaster, Sigma-Aldrich, Acros, or Bachem, except that solvents were purchased from Fisher Scientific or Mallinkrodt.

1) SPIB00102: 2-O-acetylsalicylic acid-(2S,3R)-(-)-threonine ester

A mixture of N-benzyloxycarbonyl-L-threonine benzyl ester (Z-Thr-OBzl, 21.77 g, 63.40 mmol) and anhydrous dichloromethane (500 mL) containing pyridine (25 mL) under nitrogen atmosphere Cool in an ice bath. O-acetoxybenzoyl chloride (17.63 g, 88.76 mmol) was added, and the mixture was warmed to room temperature and stirred overnight. After 24 hours, the mixture was poured into ice-cooled 2N hydrochloric acid (400 mL). After mixing the layers were separated and the dichloromethane portion was washed with water (500 mL), saturated sodium bicarbonate solution (500 mL), water (500 mL), brine (500 mL) and dried over sodium sulfate (25 g). After filtration, concentration under reduced pressure, and drying under high vacuum, the remaining yellow oil (35.43 g) was purified by flash chromatography on silica gel (300 g, 0.035-0.070 mm, 6 nm pore size) with hexane/ethyl acetate Ester (3:1) eluted. The product containing fractions was concentrated under reduced pressure, and dried under high vacuum to a constant weight. The protected acetylsalicylic acid-L-threonine ester SPIB0010201 (28.1g, yield: 88%) generated in this experiment was Colorless oil.

¹ H NMR (300MHz, CDCl ₃ ): δ = 7.74 (1H, d, J = 7.5Hz), 7.51 (1H, dt, J = 7.5, 1.5Hz), 7.34-7.17 (11H, m), 7.06 (1H , d, J=7.2Hz), 5.62(2H, m), 5.13(4H, m), 4.65(1H, dd, J=9.6, 2.4Hz), 2.29(3H, s), 1.38(3H, d, J=6.6Hz).

¹³ C NMR(75MHz，CDCl ₃ )：δ＝169.35，169.22，162.73，156.26，150.41，135.79，134.67，133.77，131.24，128.35，128.24，128.08，127.95，125.78，123.51，122.61，71.22，67.72，67.26， 57.64, 20.98, 16.88.

Protected acetylsalicylic acid-L-threonine ester SPIB0010201 (14.50 g, 28.68 mmol) was dissolved in ethanol (100 mL) and ethyl acetate (100 mL) at room temperature and added to the containing 10% bar carbon catalyst (3.0 g, 50% wet) in a Parr bottle. The nitrogen atmosphere was replaced with hydrogen (20 psi). After shaking for 20 hours, the palladium catalyst was removed by filtration through celite. The remaining solid (palladium/celite and product) was washed with water (600 x 4 mL) until the product was removed. The ethanol and water fractions were concentrated under reduced pressure at room temperature. The remaining solid was washed with water (20 mL) and dioxane (20 mL) for 48 hours. After filtration, the remaining white solid was dried at room temperature under high vacuum until the product weight was constant (16 hours). Acetylsalicylic acid-L-threonine ester SPIB00102 (4.40 g, 55% yield) was produced in this experiment as a white solid.

¹ H NMR (300MHz, D ₂ O-DCl): δ = 8.00 (1H, dd, J = 7.8, 1.5Hz), 7.74 (1H, dt, J = 7.8, 1.5Hz), 7.47 (1H, dt, J =7.8, 1.5Hz), 7.27 (1H, dd, J = 7.8, 1.5Hz), 5.76 (1H, dq, J = 6.9, 3.0Hz), 4.49 (1H, d, J = 3.0Hz), 2.39 (3H , s), 1.55 (3H, d, J = 6.9 Hz).

¹³ C NMR (75 MHz, D ₂ O-DCl): δ=173.03, 168.84, 163.97, 149.56, 135.32, 131.26, 126.85, 123.48, 121.49, 69.16, 56.36, 20.45, 15.86.

HPLC analysis:

98.7% purity; rt=6.233min; Luna C18 5u column (sn 167917-13); 4.6×250mm; 254nm; 35% methanol/65% trifluoroacetic acid (0.1%)pH=1.95; 35 C; 20ul injection; 1ml /min; the sample was dissolved in the mobile phase with 1 drop of phosphoric acid.

CHN elemental analysis:

Calculated: C 55.51, H 5.38, N 4.98; Found: C 55.37, H 5.40, N 5.03.

Melting point: 153.5°C (decomposition)

2) SPIB00101: 2-O-acetylsalicylic acid-(2S)-(+)-serine ester

Under a nitrogen atmosphere, a mixture of N-benzyloxycarbonyl-L-serine benzyl ester (Z-Ser-OBzl, 23.17 g, 70.34 mmol) and a solution of pyridine (30 mL) in anhydrous dichloromethane (500 mL) was Cool in an ice bath. o-Acetoxybenzoyl chloride (21.07 g, 106.1 mmol) was added and the mixture was allowed to warm to room temperature and stirred for two more days. After 48 hours, the mixture was poured into ice-cooled 2N hydrochloric acid (400 mL). After mixing the layers were separated and the dichloromethane portion was washed with water (500 mL), saturated sodium bicarbonate solution (500 mL), water (500 mL), brine (500 mL) and dried over sodium sulfate (25 g). Filtration and concentration under reduced pressure, after drying under high vacuum, the remaining brown oil (47.19 g) was purified by flash chromatography on silica gel (200 g, 0.035-0.070 mm, 6 nm pore size) with hexane/ethyl acetate (3:1) elution. The product containing fractions was concentrated under reduced pressure and dried under high vacuum until the weight was constant. This experiment produced protected acetylsalicylic acid-L-serine ester SPIB0010101 (32.97 g, 95% yield) as a white solid.

¹ H NMR (300MHz, CDCl ₃ ): δ = 7.74 (1H, d, J = 7.8Hz), 7.55 (1H, dt, J = 7.8, 1.5Hz), 7.33-7.21 (11H, m), 7.08 (1H , d, J = 7.5Hz), 5.68 (1H, d, J = 8.4Hz), 5.20 (2H, s), 5.12 (2H, s), 4.77 (1H, m), 4.66 (1H, dd, J = 11.4, 3.3 Hz), 4.57 (1H, dd, J = 11.4, 3.3 Hz), 2.30 (3H, s).

¹³ C NMR(75MHz，CDCl ₃ )：δ＝169.45，169.09，163.68，163.35，155.57，150.77，135.87，134.75，134.07，131.44，128.50，128.43，128.27，128.14，128.04，125.92，123.71，122.18，67.83， 67.27, 64.63, 53.55, 21.03.

Protected acetylsalicylic acid-L-serine ester SPIB0010101 (21.0 g, 42.7 mmol) was dissolved in ethanol (100 mL) and ethyl acetate (100 mL) at room temperature and added to 10% palladium carbon on Catalyst (4.20 g, 50% wet) in a Parr bottle. The nitrogen atmosphere was replaced with hydrogen (20 psi). An additional 10% palladium catalyst (4.26 g) was added after 5 hours and the hydrogen pressure (20 psi) was restored. After shaking at room temperature for 20 hours, the palladium catalyst was removed by filtration through celite. The remaining solid (palladium/celite and product) was washed with water (1500 x 2 mL) until the product was removed. The ethanol and water fractions were concentrated under reduced pressure at room temperature. The remaining solid (7.17 g) was dissolved in DIUF water (4.3 L), filtered through celite to remove insolubles, and concentrated under high vacuum at room temperature. The white solid was then washed with 1,4-dioxane (100 mL) and DIUF water (50 mL) overnight. After 24 hours the solid was filtered and dried under high vacuum until the product weight was constant (24 hours). Acetylsalicylic acid-L-serine ester SPIB00101 (6.17 g, 54% yield) produced in this experiment was a white solid.

¹ H NMR (300MHz, D ₂ O-DCl): δ = 8.05 (1H, dd, J = 7.8, 1.5Hz), 7.75 (1H, dt, J = 7.8, 1.5Hz), 7.47 (1H, dt, J = 7.8, 0.9Hz), 7.27 (1H, dd, J = 7.8, 0.9Hz), 4.87 (1H, dd, J = 12.6, 4.2Hz), 4.79 (1H, dd, J = 12.6, 3.0Hz), 4.62 (1H, dd, J = 4.2, 3.0 Hz), 2.39 (3H, s).

¹³ C NMR (75 MHz, D ₂ O-DCl): δ=173.01, 168.58, 164.54, 149.72, 135.39, 131.59, 126.87, 123.62, 121.15, 62.38, 52.05, 20.44.

HPLC analysis:

98.1% purity; r.t.=5.839min.; 65% trifluoroacetic acid (0.1%)/35% methanol; 1mL/min; 35 C; Luna C18, 3u column (SN 184225-37), 4.6×250mm; 22ul injection; DAD1B, Sig＝240,4 Ref＝550,100.

CHN elemental analysis:

Calculated: C 53.93, H 4.90, N 5.24; Found: C 54.02, H 5.00, N 5.23.

Melting point: 147.0°C (decomposition)

3) SPIB00103: 2-O-acetylsalicylic acid (2S, 4R)-4-hydroxyproline ester

Under a nitrogen atmosphere, N-benzyloxycarbonyl-L-hydroxyproline benzyl ester (Z-Ser-OBzl, 21.5 g, 60.5 mmol) 1 and a solution of pyridine (25 mL) in anhydrous dichloromethane (500 mL ) mixture was cooled in an ice bath. o-Acetoxybenzoyl chloride (13.2 g, 66.6 mmol) was added, and the mixture was warmed to room temperature and stirred overnight. After 24 hours, further o-acetoxybenzoyl chloride (5.0 g, 25.2 mmol) was added and the mixture was stirred overnight. After 48 hours, the mixture was poured into ice-cooled 1N hydrochloric acid (500 mL). After mixing the layers were separated and the dichloromethane portion was washed with water (500 mL), saturated sodium bicarbonate solution (500 mL), water (500 mL), brine (500 mL) and dried over sodium sulfate (25 g). After filtration, concentration under reduced pressure, and drying under high vacuum, the remaining yellow oil (40.7g) was purified by flash chromatography on silica gel (460g, 0.035-0.070mm, 6nm pore size) with heptane/ethyl acetate ( 3:1) elution. The product containing fractions was concentrated under reduced pressure and dried under high vacuum until the weight was constant. This experiment generated protected acetylsalicylic acid-L-hydroxyproline ester SPIB0010301 (21.31 g, 68% yield) as colorless Oil.

¹ H NMR (300MHz, CDCl ₃ ): δ = 7.92 (1H, d, J = 7.8Hz), 7.56 (1H, t, J = 7.8Hz), 7.34-7.21 (10H, m), 7.09 (1H, d , J=7.8Hz), 5.48(1H, s), 5.21(2H, m), 5.03(2H, d, J=15Hz), 4.57(1H, m), 3.85(2H, m), 2.53(1H, m), 2.28 (4H, m).

¹³ C NMR(75 MHz，CDCl ₃ )：δ＝171.72，171.49，169.25，163.47，163.30，154.52，153.93，150.54，136.05，135.94，135.21，135.00，134.17，134.12，128.43，128.32，128.28，128.20，128.05 .

Protected acetylsalicylic acid-L-hydroxyproline ester SPIB0010301 (10.6 g, 20.5 mmol) was dissolved in ethanol (75 mL) and ethyl acetate (75 mL) at room temperature and added to the containing 10% palladium on carbon catalyst (3.0 g, 50% wet) in a Parr bottle. The nitrogen atmosphere was replaced with hydrogen (20 psi). After shaking at room temperature for 17 hours, the reaction mixture was washed with water (500 mL) for 2 hours. The organic layer (top) was removed by pipette and the aqueous layer was filtered through celite. The aqueous layer portion was concentrated under reduced pressure at room temperature. The remaining solid (6.71 g) was then washed with anhydrous dichloromethane (35 mL) overnight. After 24 hours the solid was filtered and dried under high vacuum until the product weight was constant (24 hours). The acetylsalicylic acid-L-hydroxyproline ester produced in this experiment, SPIB00301 (2.87 g, 47.7% yield), was a white solid.

¹ H NMR (300MHz, D ₂ O-DCl): δ = 8.09 (1H, d, J = 7.5Hz), 7.75 (1H, t, J = 7.5Hz), 7.48 (1H, t, J = 7.5Hz) , 7.28 (1H, d, J = 7.5Hz), 5.69 (1H, m), 4.76 (1H, t, J = 7.5Hz), 3.86 (1H, dd, J = 13.5, 3.9Hz), 3.74 (1H, d, J = 13.5 Hz), 2.81 (1H, dd, J = 15.0, 7.5 Hz), 2.60 (1H, m), 2.40 (3H, s).

¹³ C NMR (75 MHz, D ₂ O-DCl): δ=173.13, 170.25, 164.31, 149.65, 135.36, 131.54, 126.87, 123.54, 121.37, 73.86, 58.34, 50.95, 34.38, 20.48.

HPLC analysis:

98.3% purity; r.t.=7.201min.; 65% trifluoroacetic acid (0.1%)/35% methanol; 1mL/min; 35C; Luna C18, 3u column (SN 184225-37), 4.6×250mm; 22ul injection; DAD1B , Sig＝240,4 Ref＝550,100.

CHN elemental analysis:

Calculated: C 57.34, H 5.16, N 4.78; Found: C 57.09, H 5.23, N 4.91.

Melting point: 162°C (decomposition)

Gastric mucosal irritating potential of the L-serine, L-threonine, and L-hydroxyproline esters of acetylsalicylic acid compared with acetylsalicylic acid

This study was performed to evaluate the effect of new formulations of aspirin (L-serine, L-threonine, and L-hydroxyproline esters of acetylsalicylic acid) on gastric mucosal irritation/injury in fasted male albino mice. relative potential. Aspirin was used as a reference control.

Different new formulations of aspirin and aspirin were administered by gavage to fasted male albino mice (Wistar strain) using a phosphate buffered saline solution containing 0.5% (w/v) carboxymethylcellulose (CMC) ( pH 2.6) as an excipient. The study was conducted at two dose levels, 100 mg and 200 mg/kg body weight and a vehicle control group. Five animals were used at each dose level. All doses are expressed in molar equivalents of aspirin. The doses and molar equivalents used are as follows.

Table 11: Formulations: Molar Equivalents

Preparations Molar equivalent L-serine ester of acetylsalicylic acid 1.483 units are equivalent to 1 unit of aspirin L-Hydroxyproline Ester of Acetylsalicylic Acid 1.628 units are equivalent to 1 unit of aspirin L-threonine ester of acetylsalicylic acid 1.561 units are equivalent to 1 unit of aspirin

Table 12: Test item: Group: Dose (mg/kg) [according to acetylsalicylic acid]: Equivalent weight of test item [mg]

detection item Group Dose (mg/kg) [as acetylsalicylic acid] The equivalent weight of the test item [mg] Excipient Control Excipient control group 0.0 -- L-Serine Ester of Acetylsalicylic Acid Test group 1 100.0 148.3 Test group 2 200.0 296.6 L-Hydroxyproline Ester of Acetylsalicylic Acid Test group 1 100.0 162.8 Test group 2 200.0 325.6 L-threonine ester of acetylsalicylic acid Test group 1 100.0 156.1 Test group 2 200.0 312.2 Acetylsalicylic acid for reference control Test group 1 100.0 100.0 Test group 2 200.0 200.0

The mice were fasted for a period of 18 to 22 hours prior to dosing. Test items were administered as a single dose by gavage. Three hours after dosing, the animals were humanely killed by _CO2 gas inhalation. Dissect the stomach and observe:

^* Amount of mucoid exudate

^* the degree of congestion and thickening of the stomach wall

^* Bleeding point (localized or diffuse), nature of bleeding (petechiae or ecchymosis) and size and

^* Piercing

The observations on the stimulation of gastric mucosa of each group of animals are summarized as follows

Table 13: Test items: Group: Dose (mg/kg) [according to acetylsalicylic acid]: Observation:

detection item Group Dosage (mg/kg) [based on acetylsalicylic acid] observe Excipient Control Vehicle control group 0.0 None of the animals showed any signs of gastric mucosal irritation L-serine ester of acetylsalicylic acid Test group 1 100.0 None of the treated animals showed any signs of gastric mucosal irritation Test group 2 200.0 None of the treated animals showed any signs of gastric mucosal irritation L-Hydroxyproline Ester of Acetylsalicylic Acid Test group 1 100.0 None of the treated animals showed any signs of gastric mucosal irritation Test group 2 200.0 None of the treated animals showed any signs of gastric mucosal irritation L-threonine ester of acetylsalicylic acid Test group 1 100.0 None of the treated animals showed any signs of gastric mucosal irritation Test group 2 200.0 None of the treated animals showed any signs of gastric mucosal irritation Reference control (acetylsalicylic acid) Test group 1 100.0 None of the treated animals showed any signs of gastric mucosal irritation Test group 2 200.0 Gastric mucosal irritation was observed in all 5 animals administered

In conclusion, it was observed that the L-serine, L-threonine and L-hydroxyproline esters of acetylsalicylic acid did not induce any signs of Irritation of the gastric mucosa. In contrast, aspirin (acetylsalicylic acid) at a dose level of 200 mg/kg caused gastric mucosal irritation in all fasted male albino mice. However, aspirin did not show any signs of gastric mucosal irritation in male rats at a dose level of 100 mg/kg.

Moreover, animals of all the different test groups did not show any clinical signs of toxicity throughout the 3-hour observation period.

Efficacy of L-serine, L-threonine and L-hydroxyproline esters of acetylsalicylic acid compared with acetylsalicylic acid on blood coagulation time in rats 1 hour after administration

Observe coagulation time

Evaluation in 1 hour after taking the medicine, the data of the mean coagulation time (MCT) of the low, middle and high dose group animals of various preparations, vehicle control and positive control group are expressed as follows (Table 14):

Table 14: Mean Clotting Time (±S.D.) Summary in Minutes - L-Serine, L-Threonine and L-Hydroxyproline Esters of Acetylsalicylic Acid and Aspirin (Positive Control): Low Dose: Medium Dosage: high dose

low dose medium dose high dose Excipient Control 4.9±1.10 L-serine ester of acetylsalicylic acid 5.7±1.34 6.8±1.48 6.9±1.37 L-Hydroxyproline Ester of Acetylsalicylic Acid 6.1±1.10 5.7±0.82 7.5±1.18 L-threonine ester of acetylsalicylic acid 5.2±1.14 5.6±0.84 7.4±0.97 Positive control (acetylsalicylic acid) 6.2±1.40 8.1±1.97 9.8±1.32

Figures 3-6 present the mean data per group for the dose relationship + mean clotting time in minutes for the aspirin L-ester series and control animals.

Statistical analysis showed that the potency of the high and medium doses was significantly improved at the 5% significance level compared to the vehicle control group (Figure 7).

Figure 4 represents group mean data for animals. It provides a dose-response relationship for L-hydroxyproline ester of aspirin and mean clotting time (MCT) minutes. Statistical analysis of Figure 4 shows a significant increase in potency at the 5% significance level for both high and low doses compared to the vehicle control group (Figure 6).

Figure 5 shows the dose response relationship for the L-threonine ester of acetylsalicylic acid versus mean clotting time (MCT) minutes. Statistical analysis showed a significant increase in potency at the 5% significance level for the high dose group compared to the vehicle control group.

Figure 6 shows the dose response relationship for acetylsalicylic acid and mean clotting time (MCT) minutes. Statistical analysis showed a significant increase in potency at the 5% significance level for the high and medium doses compared to the vehicle control group. This dose versus potency response was statistically significant and clearly evident (Figure 7).

in conclusion

In this study, the clotting time of albino mice was used as an index to evaluate the efficacy of new formulations of aspirin. Aspirin served as a positive control. The study was conducted at 3 dose levels of the new formulation and an active control group and a vehicle control group.

dose

Dose selection for most of the studies was based on dose-ranging studies of acetylsalicylic acid. All doses are expressed in molar equivalents of aspirin. The doses used for most of the experiments with different formulations and positive controls were the same and are presented below.

Table 15: Test items: Low dose (mg/kg): Medium dose (mg/kg): High dose (mg/kg)

detection item Low dose (mg/kg) Medium dose (mg/kg) High dose (mg/kg) L-Serine Ester of Acetylsalicylic Acid 1.0 4.0 10.0 L-Hydroxyproline Ester of Acetylsalicylic Acid 1.0 4.0 10.0 L-threonine ester of acetylsalicylic acid 1.0 4.0 10.0 Aspirin (positive control) 1.0 4.0 10.0

Potency (coagulation time)

The respective potencies in terms of required clotting times of the different formulations and various dose levels of acetylsalicylic acid - low, medium and high doses - are presented below.

Table 16: Low Dose: Medium Dose: High Dose

low dose medium dose high dose Excipient Control 4.9±1.10 L-serine ester of acetylsalicylic acid 5.7±1.34 6.8±1.48 6.9±1.37 L-Hydroxyproline Ester of Acetylsalicylic Acid 6.1±1.10 5.7±0.82 7.5±1.18 L-threonine ester of acetylsalicylic acid 5.2±1.14 5.6±0.84 7.4±0.97 positive control 6.2±1.40 8.1±1.97 9.8±1.32

The L-serine, L-threonine, and L-hydroxyproline esters of acetylsalicylic acid were as significant as acetylsalicylic acid in terms of clotting time observed after 1 hour, but were less effective in avoiding gastric irritation. All dosage levels were far superior to acetylsalicylic acid.

Compared with acetylsalicylic acid, the effect of L-serine ester, L-threonine ester, and L-hydroxyproline ester of acetylsalicylic acid on the coagulation time of rats after 2 hours of administration

This study was conducted to evaluate L-serine ester, L-threonine ester and Potency of L-Hydroxyproline Esters. Aspirin served as a positive control. Male albino mice were administered aspirin and its three new preparations at a dose level of 20 mg/kg body weight. No vehicle control group was used. Doses are expressed in molar equivalents of aspirin. Doses of the different formulations and positive controls used for most of the experiments are shown below.

Table 17: Test items: Dosage of acetylsalicylic acid (mg/kg)

Detection items According to the dose of acetylsalicylic acid (mg/kg) L-Serine Ester of Acetylsalicylic Acid 20.0 L-Hydroxyproline Ester of Acetylsalicylic Acid 20.0 L-threonine ester of acetylsalicylic acid 20.0 Aspirin (positive control) 20.0

Potency (coagulation time)

The corresponding potencies of the different formulations and aspirin (positive control) in terms of required clotting times at the 20 mg/kg body weight dose level are shown below.

Observation of coagulation time

The mean clotting time (MCT) data of different formulations, vehicle control and positive control were presented below for animals evaluated at 20 mg/kg body weight dose level, 2 hours (±10 minutes) after administration.

Table 18: Summary of Mean Clotting Time (±S.D.) Minutes for L-Serine, L-Threonine and L-Hydroxyproline Esters of Acetylsalicylic Acid Compared with Acetylsalicylic Acid (Positive Control)

Dose (20mg/kg) L-serine ester of acetylsalicylic acid 3.8±0.92 L-Hydroxyproline Ester of Acetylsalicylic Acid 4.2±1.32 L-threonine ester of acetylsalicylic acid 5.3±1.06 Positive control (acetylsalicylic acid) 5.4±1.17

The L-serine, L-threonine and L-hydroxyproline esters of acetylsalicylic acid were found to be effective on blood clotting time.

In conclusion, it was observed that amino acid prodrugs were effective based on the time required for blood to coagulate (coagulation time) when evaluated 2 hours after administration. However, the L-threonine ester of acetylsalicylic acid was found to have better potency than the other two formulations.

As shown in Figure 7, statistical analysis showed that the L-threonine and L-hydroxyproline esters of acetylsalicylic acid were as effective as acetylsalicylic acid, contributing to the mean clotting time observed after two hours, acetylsalicylic acid L-hydroxyproline ester and L-threonine ester of salicylic acid have no significant difference at 5% significant level relative to the positive control. However, the L-serine, L-threonine, and L-hydroxyproline esters of acetylsalicylic acid were far superior to the positive control group in terms of potential gastric irritation.

There are a number of screening assays to determine the usefulness of the prodrugs produced according to published methods. These include in vitro and in vivo screening methods.

In vitro methods include acid/base hydrolysis of the prodrug, hydrolysis in porcine pancreas, hydrolysis in rat intestinal fluid, hydrolysis in human gastric fluid, hydrolysis in human intestinal fluid, and hydrolysis in human plasma. These assays are described in the literature (Simmons, DM, Chandran, VR and Portmann, GA, Danazol Amino Acid Prodrugs: In Vitro and In Situ Biopharmaceutical Evaluation, Drug Development and Industrial Pharmacy, Vol 21, Issue 6, Page687, 1995), where All contents are incorporated by reference.

The compounds of the present invention are effective against diseases or conditions commonly treated with NSAIDs. The prodrugs disclosed herein are transformed in vivo to release the active compound and facilitate therapy by reducing or eliminating the biopharmaceutical and pharmacokinetic barriers associated with each NSAID. However, it is important to note that these prodrugs are sufficiently active on their own not to release any active drug in mammals. Because these prodrugs are more soluble in water than ibuprofen or other NSAIDs, it need not be associated with carrier excipients, such as alcohol or castor oil, which could be toxic or produce unwanted side effects. Furthermore, oral formulations containing NSAID prodrugs are absorbed into the bloodstream and are quite effective.

In this way, the prodrugs of the present invention facilitate therapy by eliminating the biopharmaceutics and pharmacokinetic barriers of existing drugs.

Furthermore, the prodrugs of the present invention can be easily synthesized in high yield by using commercially available reagents.

IV. Proline Derivatives of Paracetamol (Acetaminophen)

Overview:

The procedure for the synthesis of the L-proline ester of paracetamol is outlined in the Synthetic Sequence section. This composition is an example. See the Experimental section for complete procedures and analyzed data. Paracetamol (10 g) reacted with Boc-L-proline and EDC in the presence of catalytic amounts of DMAP. Upon completion of the reaction (3 hours at room temperature), the solution was washed with water. After drying over sodium sulfate, the crude protected paracetamol amino acid ester was filtered, concentrated and purified by flash chromatography on silica gel. This step produced the protected paracetamol L-proline ester in 72% yield. The ester is dissolved in dichloromethane and the protecting group is removed by bubbling hydrogen chloride into the solution at room temperature. After filtration, the final salt was stirred in THF until purified. The yield of the deprotection step was 91.4% after filtration and drying under high vacuum at 90°C for 4 hours.

Composition order:

Synthesis of L-proline ester of paracetamol: a) EDC, DMAP, CH ₂ Cl ₂ ; b) HCl(g), CH ₂ Cl ₂ .

Experimental part:

The synthesis of SPI0014 was performed in one batch. Reagents mentioned in the experimental section were of the highest available purity and were purchased from Lancaster, Sigma-Aldrich, or Acros, except solvents were purchased from Fisher Scientific or Mallinkrodt.

SPI0014: Pyrrolidine-2(S)-carboxylic acid-4-acetamidophenyl ester hydrochloride

Boc-L-proline (14.39 g, 68.80 mmol), paracetamol (10.02 g, 66.28 mmol), EDC (12.9 g, 67.29 mmol) and DMAP (1.10 g, 9.0 mmol) in an argon atmosphere Mix in anhydrous dichloromethane (100 mL) and stir at room temperature for 3 hours. After 3 hours, water (120 mL) was added. After mixing for 5 minutes, the layers were separated and the dichloromethane fraction was washed with water (120 mL) and dried over sodium sulfate (5 g). Filtration and concentration under reduced pressure, after drying under high vacuum, the remaining oil (24.10 g) was purified by flash chromatography on silica gel (100 g, 0.035-0.070 mm, 6 nm pore size) with hexane/ethyl acetate (1:2) elution. The product containing each fraction was concentrated under reduced pressure and dried under high vacuum until the weight was constant. This experiment produced the protected paracetamol-L-proline ester SPI001401 (16.71 g, 72.3% yield) as a white solid (foamy ).

¹ H NMR (300MHz, CDCl ₃ ): δ=8.83(1/2H, s), 8.70(1/2H, s), 7.58(1/2H, d, J=7.5Hz), 7.46(1/2H, d, J=7.5Hz), 6.96(2H,m), 4.47(1H,m), 3.59-3.45(2H,m), 2.36(1H,m), 2.17-1.90(6H,m), 1.46(9H , m).

¹³ C NMR (75MHz, CDCl ₃ ): δ=171.91, 171.75, 169.02, 154.44, 153.78, 146.36, 146.21, 121.44, 121.23, 120.82, 80.41, 80.17, 59.16, 46.78, 456, 55, 34.01, 28, 3 24.28, 23.78.

Protected paracetamol-L-proline ester SPI001401 (16.60 g, 47.64 mmol) was dissolved in dichloromethane (400 mL) at room temperature, and hydrogen chloride gas was bubbled into the solution for 2 hours. The remaining solid precipitated (1 hour). Carefully decant the dichloromethane from the white precipitate. To the precipitate was added tetrahydrofuran (200 mL), and the mixture was stirred under an argon atmosphere for 2 hr. After filtration, the remaining white solid was dried at 90°C under high vacuum until the product weight was constant (4 hours). This experiment produced paracetamol-L-proline ester hydrochloride SPI0014 (12.4 g, 91.4% yield) as a white solid.

¹ H NMR (300MHz, CDCL ₃ -DMSO): δ = 10.41 (1H, br s), 10.26 (1H, s), 9.55 (1H, br s), 7.70 (2H, d, J = 9Hz), 7.12 ( 2H, d, J=9Hz), 4.66(t, 1H, J=8.4Hz), 3.33(2H, m), 2.43(1H, m), 2.28(1H, m), 2.08(s, 3H), 2.04 (2H, m).

¹³ C NMR (75 MHz, CDCL ₃ -DMSO): δ = 168.08, 167.25, 144.55, 137.40, 121.12, 119.64, 58.53, 45.33, 27.74, 23.86, 23.08.

HPLC analysis:

99.45% purity; rt=5.733min; Luna C18 5u column (sn 167917-13); 4.6×250mm; 254nm; 15% MeOH/85% hexanesulfonate buffer (110 mmol, pH=6); 35 C ; 20ul injection; 1ml/min; 5mg/mL injection volume.

CHN elemental analysis:

Calculated: C 54.84, H 6.02, N 9.84; Found: C 54.66, H 5.98, N 9.65.

Melting point: 221-222°C

V. Amino acid derivatives of cyclosporine A

Macrocyclic immunosuppressants include a class of structurally unique, cyclic, polymeric, N-methylated undecaptides, and similar semi-synthetic macrolide structures, usually with pharmacological , especially immunosuppressive, anti-inflammatory and/or anti-parasitic activity. The first cyclosporine to be isolated was the naturally occurring fungal metabolite cyclosporine or cyclosporine also known as cyclosporin A, which has the following formula:

where MeBmt represents the N-methyl-(4R)-4-but-2E-en-1-yl-4-methyl-(L)threonyl residue of the formula

where -x-y- is CH=CH- (trans). Similar other products include, sirolimus (b), tacrolimus (c), and pimecrolimus (d), which have the following structures:

The class consisting of various cyclosporines is therefore presently very large indeed, including, for example, [Thr] ² -, [Val] ² -, [Nva] ² - and [Nva] ² -[Nva] ⁵ - cyclosporine (also known as cyclosporine C, D, G and M, respectively), [dihydro-MeBmt] ¹ -[Val] ² -cyclosporine (also known as dihydrocyclosporine D), [(D)Ser] ⁸ -cyclosporine, [MeIle] ¹¹ -cyclosporine, [(D)MeVal] ¹¹ -cyclosporine (also known as cyclosporine H), [MeAla] ⁶ - cyclosporine, [(D)Pro] ³ -cyclosporin and the like.

Throughout the specification and claims of the present invention, the various cyclosporines are defined by reference to the structure of the cyclosporine (ie, cyclosporine A) according to the conventional nomenclature for the individual cyclosporins. First point out the presence of amino acid residues that differ from existing ionic cyclosporines (e.g., "[(D)Pro] ³ " means that the cyclosporine in question has -(D)Pro- at the 3-position and not -Sar- residues), the term cyclosporine is then used to describe the remaining residues that are identical to those present in cyclosporine A.

As used herein, the term "cyclosporine" refers to the various types of cyclosporine in which x-y in the MeBmt residue has the cis or trans CH=CH, or where x-y is also included in those derivatives In said derivative, one or more amino acids at positions 2-11 of cyclosporine A are replaced by different amino acids. However, it is preferred that no more than two amino acids in the general formula of cyclosporine A are substituted, more preferably no more than one of said amino acids is substituted by an amino acid.

In addition, amino acid residues refer to, for example, the abbreviations -Ala-, -MeVal- and -αAbu-, according to conventional practice, amino acids are understood to have (L)-configuration, unless otherwise stated, such as "-(D )Ala-". Residue abbreviations preceded by "Me", such as "-MeLeu-", represent α-N-methylated residues. In the art, the individual residues of the cyclosporine molecule are numbered clockwise, starting with the -MeBmt-, dihydro-MeBmt- residue at position 1, etc. The same numerical order is used throughout the description and claims of the present invention.

Due to their unique pharmaceutical potential, macrocyclic immunosuppressants have attracted considerable attention in reports. The term "macrocyclic immunosuppressant" includes various natural and semi-synthetic derivatives of cyclosporine, and other macrolides such as sirolimus, tacrolimus and pimecrolimus. The main area of clinical research on the above drugs is their use as immunosuppressants, especially in relation to their use in organ transplant recipients, such as heart, lung, combined heart-lung, liver, kidney, pancreas, bone marrow, skin and corneal transplantation, especially allogeneic organ transplantation. These drugs are also used to treat psoriasis, atompic dermatitis, rheumatoid arthritis, and nephritic syndrome.

Macrocyclic immunosuppressants are also effective in the treatment of various autoimmune diseases and inflammatory conditions, especially inflammatory diseases with etiology that include an autoimmune component, such as arthritis (e.g., rheumatoid arthritis, chronic degenerative joint disease (arthritis chronica progredient) and joint deformation deformons) and rheumatic diseases. Specific autoimmune diseases for which cyclosporine has been proposed or treated include, autoimmune blood disorders (including, for example, hemolytic anemia, aplastic anemia, pure red blood cell anemia, and idiopathic thrombocytopenia), systemic Lupus erythematosus, polychondritis, sclerodoma, Wegener granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Jones syndrome Johnson syndrome), spontaneous diarrhea, autoimmune inflammatory bowel disease (including, for example, ulcerative colitis and Crohn's disease), endocrine opthalmopathy Graves' eye disease, sarcoidosis, Multiple sclerosis, primary biliary cirrhosis, juvenile diabetes mellitus (type I diabetes), uvetis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial Interstial lung fibrosis, psoriatic arthritis, atopic dermatitis, and glomerulonephritis (with or without nephrotic syndrome, eg, including idiopathic nephritic syndrome or minimal change nephropathy).

In addition, macrocyclic immunosuppressants also have applicability as antiparasitic agents, especially as antiprotozoal agents, and have been proposed to be effective in the treatment of malaria, coccidiomycosis and schistosomiasis. Recently, their use as agents for reversing or canceling antitumor agent-resistant contumors and the like has also been advocated.

Although macrocyclic immunosuppressants have made a very important contribution, there is still a need for more effective and convenient methods of administration (eg, galenic formulations, e.g., oral dosage forms, which are both convenient and Difficulties have been encountered in providing adequate bioavailability to patients and allowing dosing at an appropriate and controlled rate of administration), and undesired side effects have been reported; in particular, nephrotoxicity has become significantly more of a concern for it. Serious impediment to widespread use or application.

Furthermore, the macrocyclic immunosuppressants mentioned above are characterized by being highly hydrophobic and prone to precipitation in the presence of even small amounts of water, for example when entering the body (eg, gastric juices). It is therefore particularly difficult to provide oral formulations which are acceptable to the patient, eg in form and taste, and which are stable on storage and which can be administered regularly to provide a suitable and controllable dosage to the patient.

Proposed liquid formulations, eg, of macrocyclic immunosuppressants for oral administration, have hitherto mainly been based on the use of ethanol and oils or similar excipients as carrier media. Thus, commercially available macrocyclic immunosuppressant drinking solutions employ ethanol and olive oil or corn oil as the carrier medium, together with a solvent system comprising, for example, ethanol and LABRIFIL and equivalent excipients as the carrier medium. Thus, commercially available macrocyclic immunosuppressant drinking solutions employ ethanol and olive oil or corn oil as a carrier medium and Labrifil as a surfactant (see US Pat. No. 4,388,307). However, the use of drinking solutions and similar compositions proposed in the art is accompanied by a number of difficulties.

Furthermore, the palatability of known oil-based systems has proven to be problematic. In particular, the taste of known drinking solutions of various drugs is unpleasant. Mixtures mixed with a suitably flavored drink have been employed to make conventional therapy acceptable, the drink being added to the pharmaceutical preparation in high dilution prior to ingestion, eg a chocolate drink preparation. The use of oil-based systems also requires the use of high ethanol concentrations, so that it is inherently undesirable, especially when administered to children. In addition, volatilization of ethanol, such as from capsules (adopted in large numbers to address issues of palatability as discussed, or other issues (eg, when opened)), will lead to the production of macrocyclic immunosuppressant precipitates. A further set of problems arise when such compositions are in the form of, for example, soft gelatin microcapsules. This particular difficulty necessitates packaging of such microencapsulated products in airtight components, eg, airtight blisters or aluminum foil blister packages. This makes the product bulkier and more expensive to produce. Furthermore, the storage properties of the aforementioned preparations are far from ideal.

Bioavailability levels achieved with existing oral macrocyclic immunosuppressant drug delivery systems are also low and show large variability between individuals, between different patient types, and even within a single individual at different times during treatment . Bibliographical reports show that adopting the existing treatment scheme of the macrocyclic immunosuppressant drinking solution currently on the market, the average absolute bioavailability obtained is only about 30%, and there are significant differences between each group, such as in the liver (relatively low bioavailability) and bone marrow (relatively high bioavailability) transplant recipients. Interpatient variability in bioavailability has been reported from one or a few percent for some patients to 90% or more for others. As already noted, individual bioavailability is often observed to vary significantly over time. Thus, patients need more uniformity and higher bioavailability of macrocyclic immunosuppressants.

The use of such dosage forms is also characterized by wide variability in dosage to patients in need thereof. For effective immunosuppressive therapy, blood or serum levels of cyclosporine compounds must be maintained within specific ranges. This desired range can in turn vary depending on the particular disease being treated, such as whether the treatment is aimed at preventing transplant rejection or controlling an autoimmune disease or disorder, and whether the optional immunosuppressive therapy employed is accompanied by any of the general formula a-d Treatment with immunosuppressants. Since the levels of bioavailability obtained with conventional dosage forms vary widely, the daily dosage required to achieve the desired serum levels will also vary significantly between individuals and even within a single individual. Therefore, blood/serum levels must be monitored at regular and frequent intervals in patients receiving macrocyclic immunosuppressants. Monitoring of blood/serum levels is usually performed by radioimmunoassay (RIA) or equivalent immunoassay techniques such as those based on monoclonal antibodies and must be done routinely. This is inevitably time-consuming and inconvenient, and adds significantly to the overall cost of treatment.

In fact, blood/serum macrocyclic immunosuppressant levels achieved with existing drug delivery systems also exhibit wide variability between peak and trough values. For each patient, blood levels of effective macrocyclic immunosuppressants varied widely between administrations of individual doses.

For macrocyclic immunosuppressants, it is also necessary to provide water-soluble forms for injection. It is well known that for macrocyclic immunosuppressants, Cremaphore L used in current formulations is a polyoxyethylated derivative of castor oil and is a toxic excipient. There have been a large number of incidents of allergic reactions due to this castor oil component. Due to the low aqueous solubility of macrocyclic immunosuppressants, there are currently no formulations that allow them to be present in aqueous solutions at the required concentrations.

In addition to these very obvious application difficulties with existing oral dosage forms, unpleasant side effects have been observed.

Many proposals have been made in the art to solve the various problems mentioned above, including solid and liquid oral dosage forms. However, the overriding difficulty that remains is the inherent insolubility of macrocyclic immunosuppressants in aqueous media, thus preventing dosage forms containing macrocyclic immunosuppressants in sufficiently high Efficient drug absorption from the stomach or intestinal lumen with consistent and appropriately high blood/serum levels.

The particular difficulties encountered with regard to the oral administration of macrocyclic immunosuppressants will inevitably lead to limitations in the use of macrocyclic immunosuppressants in the treatment of relatively less serious or dangerous disease states. Particular areas where this has been difficult are the use of macrocyclic immunosuppressants in the treatment of autoimmune diseases and other diseases affecting the skin, such as the treatment of atopic dermatitis and psoriasis, and in hair growth which have been widely proposed in the field Stimulation, such as in the treatment of alopecia due to aging or disease.

Thus, although oral macrocyclic immunosuppressant therapy shows considerable potential benefit of the drug in patients with conditions such as psoriasis, the risk of side effects associated with oral therapy prevents its widespread use. Many different proposals have been made in the state of the art for the use of macrocyclic immunosuppressants, eg topical (administration) forms of cyclosporine and a number of topical delivery systems have been described. However, attempts at topical application have not been able to provide any definitively effective treatment.

However, the present invention overcomes the above-mentioned problems. In particular, an embodiment of the invention is a prodrug of a macrocyclic immunosuppressant that significantly increases the solubility of the prodrug in aqueous solution, thereby eliminating the need for excipients such as ethanol or castor oil when administered in solution. Forming agent. Furthermore, according to the present invention, the prodrugs of the macrocyclic immunosuppressants do not exhibit the side effects of the preparations of the prior art. Further, the inventors have discovered that when the macrocyclic immunosuppressant prodrugs of the present invention are administered to a patient as a prodrug, their absorption is increased, thereby significantly enhancing the bioavailability and potency of the drug.

Accordingly, in one aspect, the invention relates to prodrugs of macrocyclic immunosuppressants. The prodrugs comprise cyclosporine, sirolimus, tacrolimus, and pimecrolimus molecules in which any hydroxyl group is esterified with an amino acid on the side chain.

For example, one aspect of the present invention pertains to a compound having the following general formula, or a pharmaceutically acceptable salt thereof:

Wherein CYCLO represents the residue at the 2-11 position of the cyclosporine molecule, xy is CH=CH or CH ₂ CH ₂ and AA is an amino acid or a dipeptide with the formula GLY-AA. In the latter case, GLY is glycine and AA is any α-amino acid. In the dipeptide structure, AA is linked to the drug by an OH group, and glycine acts as a spacer. Glycine is esterified onto cyclosporine, followed by attachment of glycine to any AA via an amide bond using the amino group of glycine and the carboxylic acid group of AA.

The present invention also relates to a pharmaceutical composition, which comprises a therapeutically effective amount of a compound of the above formula a-d and a pharmaceutical carrier thereof.

In another embodiment, the present invention relates to a method of treatment of a patient in need of macrocyclic immunosuppressant therapy, the method comprising administering to said patient an effective amount of a compound of formula a-d above. In yet another embodiment, the present invention is directed to a method of increasing the solubility of a macrocyclic immunosuppressant in aqueous solution, said method comprising disabling the hydroxyl group of the MeBmt moiety at site 1 of the cyclosporine molecule under ester-forming conditions. The functional groups and the specific hydroxyl functional groups of the above-mentioned compounds of formula b-d react with amino acids or their acylated derivatives, or use a simple amino acid or dipeptide structure, wherein AA is linked to the drug with glycine as a spacer, and its products are isolated.

In a further embodiment, the invention relates to a method of increasing the bioavailability of a macrocyclic immunosuppressant when administered to a patient, said method comprising allowing, under ester-forming conditions, the The hydroxyl functionality of the MeBmt moiety is reacted with an amino acid or its acylated derivative, and under ester-forming conditions, the specific hydroxyl functionality of the compound of formula b-d above is reacted with an amino acid or its acylated derivative, or by using a simple amino acid or di A peptide structure in which AA is linked to a drug with glycine as a spacer, and its product is isolated and administered to a patient.

Overview:

The procedure for the synthesis of the N-(L-proline)glycine ester and N-(L-lysine)glycine ester of cyclosporine A is outlined in the Synthetic Sequence section. These examples are exemplary using amino acid synthesis schemes. See the Experimental section for complete procedures and analyzed data. Cyclosporine A (10 g) was reacted with chloroacetic anhydride (4 equiv) in anhydrous pyridine. This experiment produced the chloroacetate ester of cyclosporine A in good yield (SPI001201, 14 g, 88% yield). Chloroacetate (10.1 g) was then treated with sodium azide in DMF to give the azidoacetate ester of cyclosporine A (SPI001202, 9.9 g, 97% yield). Azidoacetate (9.8 g) was then reduced with tin chloride (9 g) to prepare the glycine ester of cyclosporine A (8.54 g, 89% yield). Using EDC as a coupling agent, the glycine ester of cyclosporine A (SPI001203) was conjugated to a two-fold excess of boc-L-proline or Boc-L-lysine. After purification by column chromatography, the boc protecting group was removed from the dipeptide ester of cyclosporine A by treatment with 2M hydrochloric acid in ether at low temperature (5°C). The L-lysine glycine ester salt of cyclosporine A was dried without further purification. The L-proline glycine ester salt of cyclosporine A required purification. The salt was converted to the free base with sodium bicarbonate and purified by filtration through silica gel eluting with acetone. It is then salted with diluted anhydrous hydrogen chloride at low temperature and dried.

Composition order:

Synthesis of N-(L-proline)glycine ester and N-(L-lysine)glycine ester of cyclosporine A: a) pyridine; b) NaN ₃ , DMF; c) SnCl ₂ , methanol; d ) boc-L-lysine, EDC; e) boc-L-proline, EDC; f) HCl, _Et2O .

Experimental part:

The synthesis of SPI0022 and SPI0023 was performed in batches. Usually small-scale experiments are performed first, followed by large-scale experiments. Reagents mentioned in the experimental section were of the highest available purity and were purchased from Aldrich, Acros or Bachem, except solvents were purchased from Fisher Scientific or Mallinkrodt. Cyclosporine A (USP grade) used in these steps was provided by Signature Pharmaceuticals, Inc.

1) SPI001201

Cyclosporine A (15.01 g, 0.0124 mol) was dissolved in anhydrous pyridine (35 mL) at room temperature under argon atmosphere. The solution was cooled to 5°C in an ice-water bath, and chloroacetic anhydride (9.10 g, 0.053 mol) was added. After stirring for 10 minutes, the ice bath was removed and the solution was stirred at room temperature under argon atmosphere for 17 hours. After 17 hours, diethyl ether (200 mL) was added. The ether layer was then washed with water (2 x 100 mL) and dried over sodium sulfate (10 g) for 1 hour. After filtration and concentration under reduced pressure, the remaining yellow foam was dried under high vacuum (1 h at room temperature) and purified by flash chromatography on silica gel (200 g) with heptane/acetone (2:1 ) elution. After combining and concentrating the product containing fractions, the remaining pale yellow foam (14.8 g) was finally purified by crystallization from hot diethyl ether (140 mL). This step yielded the chloroacetate ester of cyclosporine A, SPI001201, as a white solid (14.0 g, 88.3% yield) after cooling (-10°C, 2 hours), filtration and drying under high vacuum.

Chloroacetate of cyclosporine A:

¹ H NMR (300MHz, CDCl ₃ ):

δ=8.50(d, 1H, J=9.6Hz), 7.95(d, 1H, J=6.6Hz), 7.46(d, 1H, J=9.0Hz), 7.40(d, 1H, J=7.8Hz), 5.35-4.52(m, 15H), 4.37(t, 1H, J=7.2Hz), 4.12(d, 1H, J=14.7Hz), 3.89(d, 1H, J=14.7Hz), 3.45-3.0(m , 15H), 2.8-2.5 (m, 6H), 2.5-1.5 (m, 16H), 1.5-0.7 (m, 53H).

¹³ C NMR (75MHz, CDCl ₃ ):

δ＝173.78，173.37，172.86，172.61，171.28，171.18，170.91，170.79，168.78，167.64，167.18，128.77，126.68，75.46，65.95，58.89，57.47，55.80，55.31，54.86，54.34，50.19，48.91，48.35， 48.02，44.80，40.96，39.44，37.07，35.93，33.85，33.25，32.40，31.74，31.50，30.38，30.12，29.82，29.53，25.13，24.92，24.78，24.40，23.99，23.75，22.85，21.94，21.41，21.25， 20.84, 19.85, 18.79, 18.32, 17.89, 17.82, 15.46, 15.24, 10.08.

2) SPI001202

The chloroacetate ester of cyclosporine A SPI001201 (10.10 g, 7.89 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL) at room temperature. Sodium azide (2.15 g, 33.0 mmol) was added. The mixture was stirred at room temperature under an argon atmosphere in the dark for 24 hours. After 24 hours, diethyl ether (150 mL) was added and the precipitate was filtered. The ether layer was then washed with water (2 x 100 mL) and dried over sodium sulfate (15 g) for 30 minutes, filtered and concentrated under reduced pressure. The remaining white solid was dried at room temperature under high vacuum for 1 hour. This experiment produced the azidoacetate ester of cyclosporine A, SPI001202 (9.90 g, 97% yield) as a white solid, which was used without further purification.

Azidoacetate of cyclosporine A:

¹ H NMR (300MHz, CDCl ₃ ):

δ=8.48(d, 1H, J=9.3Hz), 7.95(d, 1H, J=6.9Hz), 7.45(d, 1H, J=9.0Hz), 7.39(d, 1H, J=7.8Hz), 5.5-4.5(m, 15H), 4.31(t, 1H, J=6.6Hz), 4.04(d, 1H, J=17.3Hz), 3.53(d, 1H, J=17.3Hz), 3.45-3.0(m , 15H), 2.8-2.5 (m, 6H), 2.5-1.5 (m, 16H), 1.5-0.7 (m, 53H).

¹³ C NMR (75MHz, CDCl ₃ ):

δ＝173.76，173.32，172.82，172.53，171.13，170.89，170.76，170.69，169.70，168.20，167.49，128.63，126.61，74.96，58.91，57.39，55.56，55.21，54.80，54.23，50.14，48.99，48.23，48.24， 47.93，44.71，40.89，39.33，39.22，37.02，35.83，33.81，32.96，32.31，31.67，31.42，30.31，30.09，29.76，29.47，25.08，24.92，24.84，24.67，24.51，24.40，23.94，23.82，23.71， 21.85, 21.33, 21.25, 20.82, 19.79, 18.71, 18.25, 17.92, 17.81, 15.17, 10.03.

3) SPI001203

The azidoacetate ester of cyclosporine A SPI001202 (9.80 g, 7.62 mmol) was dissolved in methanol (250 mL) at room temperature. Water (40 mL) was added followed by tin(II) chloride (5 g, 26.3 mmol). After the solution was stirred at room temperature for 1 hour, an additional amount of tin(II) chloride (4 g, 21.0 mmol) was added. The solution was stirred for an additional 2 hours at room temperature. A solution of water (200 mL) containing ammonia (40 mL, 29%) was added. After filtration, the solution was concentrated under reduced pressure (to 200 mL). The remaining aqueous solution was extracted with ethyl acetate (2 x 200 mL). The ethyl acetate fractions were combined, dried over sodium sulfate (20 g), filtered and concentrated under reduced pressure. The remaining clear foam was purified by filtration through silica gel (150 g), eluting with dichloromethane/methanol (20:1). This step yielded the glycine ester of cyclosporine A as a clear solid foam (8.54 g, 89% yield).

Glycine ester of cyclosporine A:

¹ H NMR (300MHz, CDCl ₃ ):

δ=8.60(d, 1H, J=9.6Hz), 8.06(d, 1H, J=6.9Hz), 7.53(d, 1H, J=8.4Hz), 7.51(d, 1H, J=6.6Hz), 5.7-4.52(m, 15H), 4.41(t, 1H, J=6.9Hz), 3.5-3.0(m, 17H), 2.82-2.5(m, 8H), 2.5-1.5(m, 16H), 1.5- 0.7 (m, 53H).

¹³ C NMR (75MHz, CDCl ₃ ):

δ＝174.10，173.67，173.23，172.72，172.55，171.18，171.10，170.73，170.61，169.68，167.77，128.82，126.42，73.83，58.57，57.32，55.99，55.20，54.74，54.31，50.08，48.82，48.28，47.90， 44.70，43.81，40.74，39.33，39.24，37.02，35.84，33.72，33.07，32.39，31.72，31.41，30.25，29.98，29.74，29.51，25.05，24.81，24.73，24.54，24.31，23.91，23.78，23.68，21.86， 21.33, 21.25, 20.68, 19.76, 18.74, 18.24, 17.94, 17.79, 15.18, 10.03.

4) SPI0022

Glycine ester of cyclosporine A (SPI001203, 2.0 g, 1.59 mmol) and boc-L-lysine (1.31 g, 3.78 mmol) and EDC (0.75 g, 3.9 mmol) at room temperature under argon atmosphere Dissolve in anhydrous dichloromethane (25mL). boc-L-lysine was prepared from dicyclohexylamine salt (2.0 g in 50 mL of diethyl ether), which was extracted sequentially with cold potassium bisulfate solution (1 g in 50 mL of water) and then cold water (2 x 50 mL). The ether layer containing boc-L-lysine was dried over sodium sulfate (5 g), filtered, concentrated, and dried at room temperature under high vacuum for 1 hour. A small amount of DMAP crystals was added to the mixture of EDC, boc-L-lysine and glycine ester of cyclosporine A, and the solution was stirred at room temperature for 4 hours. The dichloromethane solution was extracted with DIUF water (50 mL), 5% sodium bicarbonate solution (50 mL) and DIUF water (50 mL). After drying over sodium sulfate (10 g), the dichloromethane solution was filtered and concentrated under reduced pressure. The remaining white foam (3.01 g) was purified by flash column chromatography on silica gel (50 g), eluting with heptane/acetone (2:1). The product containing fractions were combined and concentrated under reduced pressure, and dried under high vacuum. The purified protected intermediate (2.34 g white solid, 92.8% yield) was placed in a flask under argon atmosphere, which was cooled in an ice-water bath. Cold anhydrous 2M hydrochloric acid in diethyl ether (20 mL) was added, and the solution was stirred for 8 hours (at 5°C). The mixture was slowly warmed to room temperature overnight. After stirring for a total of 20 hours, the flask was cooled again in an ice-water bath for 30 minutes. The product was filtered and dried at room temperature under high vacuum for 1 hour, then at 50°C for 4 hours. N-(L-lysine)-glycine ester dihydrochloride trihydrate (SPI0022, 1.59 g, 73.9% yield) of cyclosporine A was produced as a white solid in this experiment.

¹ H NMR (300 MHz, CDCl ₃ , NMR data for free base):

δ=8.58(d, 1H, J=9.3Hz), 8.04(d, 1H, J=6Hz), 7.80(d, 1H, J=6Hz), 7.49(d, 2H, J=8.4Hz), 5.70- 4.6(m, 17H), 4.41(m, 1H), 4.28(dd, 1H, J=17, 7.2Hz), 3.67(d, 1H, J=17Hz), 3.46(s 3H), 3.4-2.8(m , 16H), 2.8-2.5 (m, 8H), 2.5-1.35 (m, 24H), 1.5-0.7 (m, 50H).

¹³ C NMR (75 MHz, CDCl ₃ , NMR data for free base):

δ＝175.23，173.77，173.34，172.75，172.63，171.34，171.22，170.94，170.84，170.91，169.89，169.70，128.74，126.67，74.41，58.82，57.43，55.91，55.21，54.81，54.42，50.17，48.89，48.31， 47.98，44.78，41.92，40.82，40.69，39.44，39.32，27.19，35.91，34.88，33.71，33.25，33.12，32.44，31.83，31.50，30.38，30.06，29.81，29.55，25.14，24.90，24.52，24.43，24.00， 23.76, 21.93, 21.42, 21.29, 20.81, 19.84, 18.82, 18.32, 17.96, 17.86, 15.21, 10.10.

CHN elemental analysis:

_Calcd for _{C70H128Cl2N14O15-3H2O} : C 55.50, H 8.92 _, and _{N 12.74} ; Found: C 58.28, H _8.98 , and N 13.16.

HPLC analysis:

99.60% purity; r.t.=14.763 min.; 80% acetonitrile/20% Tris base (tromethamine) in DIUF water; 1 mL/min; 60C; Synergi Hydro RP, 4u column (serial #163383-7), 4.6 ×250mm; 20 injections; UV=210nm.

Melting point: 196.0-198°C (uncorrected)

5) SPI0023

Glycine ester of cyclosporine A (SPI001203, 7.50 g, 5.95 mmol) and boc-L-proline (2.56 g, 11.90 mmol) and EDC (2.28 g, 11.9 mmol) at room temperature under an argon atmosphere Dissolve in anhydrous dichloromethane (50mL). A small amount of DMAP crystals was added to the mixture of EDC, boc-L-proline and glycine ester of cyclosporine A, and the solution was stirred at room temperature for 3 hours. The dichloromethane solution was extracted with DIUF water (50 mL), 5% sodium bicarbonate solution (2 x 50 mL) and DIUF water (50 mL). After drying over sodium sulfate (10 g), dichloromethane was filtered and concentrated under reduced pressure. The remaining white foam (9.50 g) was purified by flash column chromatography on silica gel (150 g), eluting with heptane/acetone (2:1 followed by 1:1). The product containing fractions were combined and concentrated under reduced pressure, dried under high vacuum at room temperature (7.94 g white solid, yield: 91.7%) for 10 minutes.

The purified protected intermediate (6.46 g) was placed in a flask under argon atmosphere, which was cooled in an ice-water bath. Cold anhydrous 2M hydrochloric acid in diethyl ether (150 mL) was added and the solution was stirred for 8 hours (at 5°C). The mixture was slowly warmed to room temperature overnight. After stirring for a total of 20 hours, the flask was cooled again in an ice-water bath for 30 minutes. The product was filtered and dried at room temperature under high vacuum for 30 minutes. N-(L-proline)glycinate hydrochloride of cyclosporine A (5.17 g, yield: 84.6% , 90% purity by HPLC analysis) into the free base. The free base was extracted with dichloromethane (3 x 25 mL), dried over sodium sulfate (5 g), filtered and concentrated. The remaining off-white solid (5 g) was purified by filtration over silica gel (100 g), eluting with acetone. The product containing fractions were combined, concentrated under reduced pressure, and dried at room temperature under high vacuum for 30 minutes. The free base (3.8 g) was dissolved in ether (25 mL) and added to a solution of 2M anhydrous hydrochloric acid (5 mL) in heptane (50 mL), then cooled in an ice-water bath to regenerate the hydrochloride. After 20 minutes at 5°C, the white solid was filtered and dried at room temperature under high vacuum for 6 hours. This experiment produced cyclosporine A N-(L-proline)glycinate hydrochloride (SPI0023, 3.8 g) as a white solid.

¹ H NMR (300MHz, CDCl ₃ ):

δ=14.20(br s, 2H), 8.62(d, 1H, J=10Hz), 8.06(d, 1H, J=6.9Hz), 7.61(d, 1H, J=8.1Hz), 7.48(d, 1H , J=9Hz), 5.70-5.50(m, 3H), 5.40-4.60(m, 12H), 4.37(m, 1H), 4.20(d, 1H, J=18Hz), 3.97(d, 1H, J= 18Hz), 3.70(m, 1H), 3.45(s, 3H), 3.23-3.08(m, 12H), 2.66(s, 3H), 2.60(s, 3H), 2.50-1.80(m, 15H), 1.78 -1.20 (m, 15H), 1.15-0.66 (m, 46H).

¹³ C NMR (75 MHz, CDCl ₃ ):

δ＝174.15，173.49，172.67，172.59，171.86，171.20，171.13，171.02，170.83，169.68，168.77，167.55，128.30，127.10，80.09，75.58，62.65，59.35，57.36，55.53，55.30，54.78，54.35，53.60， 50.25，50.09，48.92，48.18，48.12，44.62，40.59，40.02，39.43，39.30，37.13，35.88，33.74，33.07，32.19，32.01，31.86，31.50，31.43，30.43，29.93，29.72，29.30，29.16，27.56， 26.04, 25.00, 24.86, 24.74, 24.39, 20.96, 19.81, 18.71, 18.26, 18.09, 17.85, 17.79, 15.09, 14.30, 10.00.

CHN elemental analysis:

Calcd _{for C69H122ClN13O14} : C 59.48, H 8.83, and N _13.07 ; Found: C 59.84 _, H 9.02, and N 12.65.

HPLC analysis:

99.59% purity; r.t.=10.613min.; 85% acetonitrile/15% Tris base in DIUF water; 1.2mL/min; 60C; Synergi Hydro RP, 4u column (serial #1633 83-7), 4.6 x 250mm; ;UV=210nm.

Melting point: 197.0-199°C (uncorrected)

These cyclosporine prodrugs of the invention are effective in the treatment of diseases or conditions for which macrocyclic immunosuppressive agents are commonly used. These prodrugs are transformed in vivo to release the active compound and alleviate or eliminate the biopharmaceutical and pharmacokinetic barriers that accompany each macrocyclic immunosuppressant, thereby increasing its therapeutic efficacy. However, it is important to note that these prodrugs are sufficiently active on their own without releasing any active drug in mammals. Because these prodrugs are more soluble in water than cyclosporine or other macrocyclic immunosuppressants, it does not require carrier excipients such as ethanol or castor oil which could be toxic or produce unwanted side effects. Furthermore, oral formulations of prodrugs containing prodrugs are absorbed into the blood and are quite effective.

Thus, the cyclosporine prodrugs of the present invention facilitate therapy by eliminating the biopharmaceutics and pharmacokinetic barriers of existing drugs.

Moreover, the prodrugs can be easily synthesized in high yields using commercially readily available reagents.

VI. Valproate

Valproic acid (2-propylpentanoic acid) is a low-molecular-weight carboxylic acid derivative widely used as an anticonvulsant, effective in the treatment of epilepsy, and also has vasodilatory activity in the brain to relieve migraine. It is given orally to control seizures in humans, while reducing the severe pain associated with migraines.

Valproic acid has been shown to have many therapeutic applications, which are quite different and somewhat surprising. For example, in addition to treating epilepsy and migraines, it is also effective in treating some psychiatric disorders such as bipolar disorder, mood stabilization, controlling aggression, impulsive behavior in personality disorders, agitation in dementia, and as a treatment for post-traumatic stress Adjunctive treatment for sexual dysfunction (PTSD).

Mechanism of action:

Although used to treat epilepsy for many years, the exact mechanism of action of valproic acid remains unknown. It has been hypothesized that it works by increasing the concentration of gamma-aminobutyric acid (GABA) in the brain. r-GABA is a neurotransmitter, the chemical substance that passes from nerve to nerve.

Valproate is the drug of choice for the treatment of myoclonic epilepsy, with or without tonic-clonic seizures, including Janz's juvenile myoclonic epilepsy, which begins in adolescence or early adulthood . Photosensitivity myoclonus is usually easily controlled. Valproate is also effective in the treatment of benign myoclonic epilepsy, posthypoxic myoclonus, and, in combination with clonazepam, in severe progressive myoclonic epilepsy, also characterized by tonic-clonic seizures . Valproate may also be preferred for the treatment of certain stimulus-sensitive (reflex, startle) epilepsy.

Although valproate is effective for infantile spasms, it is relatively contraindicated in children with spasms due to hyperglycinemia or other underlying metabolic (mitochondrial) abnormalities. Typically, the seizures of hypotonic and akinetic epilepsy in patients with Lennox-Gastaut syndrome are difficult to control, but valproate is the preferred drug for the treatment of mixed types of seizures. Because this drug is useful in certain patients refractory to various other antiepileptic agents, it justifies its trial in nearly all non-responsive patients irrespective of the type of seizure.

Despite the usefulness of valproate, hepatotoxicity can be fatal, but it is idiosyncratic and cannot be prevented by routine monitoring of liver enzymes. Hepatotoxicity occurs in very young children, who are most commonly treated with multiple anticonvulsants. Valproate-induced cytopenias may be dose-related, which requires ensuring monitoring of complete blood counts during treatment. Encephalopathy with hyperammonemia may occur without abnormal liver function tests. Pregnant women in their first month of pregnancy are at risk for neural tube defects.

Valproic acid is a low molecular weight liquid with a characteristic odor. Oral ingestion has an unpleasant taste and can severely irritate the mouth and throat. In order to convert valproic acid into a solid dosage form for oral administration, a large number of derivatives linked to carboxylic acid through covalent and ionic bonds have been prepared. A simple sodium salt of valproic acid, sodium valproate is available as a solid. However, two molecules of valproic acid are partially neutralized with one atom of sodium to form a stable coordination complex called divalproex sodium. This product is the most widely available hemi-salt of valproic acid, sold under the trade name Depakote® by Abbott Laboratories of the United States. Depakote_ is also available in an extended release formulation for oral administration.

A significant disadvantage of valproic acid is that it is difficult to administer in liquid form. Furthermore, different dosage forms of valproic acid do not uniformly produce the desired bioavailability. For example, all bioavailability of valproic acid from valproate, its sodium salt, Divalproex®, and their extended release formulations are not interchangeable at all. Because continuous monitoring of plasma valproic acid is necessary, any changes in plasma concentrations due to changes in formulation could adversely affect overall therapeutic outcome.

Prodrugs of valproic acid that overcome some of the above-mentioned difficulties are discussed in the present invention in order to improve therapeutic efficacy, uniform complete blood counts, develop pharmaceutically superior formulations, and reduce first-pass metabolism.

Until now, there has been no pharmaceutical formulation available on the market that releases valproic acid without harmful side effects. However, the present invention proposes a number of water-soluble, non-toxic valproic acid derivatives suitable for the sustained release of valproic acid in vivo without any harmful side effects and without the need for expensive additives and excipients.

Thus, in one aspect, the present invention relates to a class of prodrugs of valproic acid. This prodrug consists of the esterification of the hydroxyl group of the amino acid to the free carboxyl group present on the valproic acid molecule. In another embodiment, the amino group of the amino acid is reacted with a COOH group to form an amide bond.

More specifically, embodiments of the present invention relate to compounds of the following formula or pharmaceutically acceptable salts thereof;

Wherein R is NH-AA or O-AA, and AA is an amino acid whose amino or hydroxyl group reacts with the carboxylic acid group of valproic acid.

The present invention also relates to a pharmaceutical composition, which includes therapeutically effective doses of the above-mentioned various valproic acid prodrugs and pharmaceutical carriers thereof.

In another embodiment, the present invention relates to a method of treatment of a patient in need of treatment with valproic acid, the method comprising administering to said patient an effective amount of valproic acid.

In yet another embodiment, the present invention relates to a method of converting liquid valproic acid into a solid powder by reacting the carboxyl functional groups of valproic acid with amino or hydroxyl functional groups of amino acids and isolating the products.

In a further embodiment, the present invention relates to a method of reducing or eliminating first pass metabolism and thereby increasing the consistency of therapeutic effect by administering to a patient a prodrug in sufficient and therapeutically effective manner, said The method comprises reacting the COOH functional group of the valproic acid molecule with the _NH2 or OH functional group of a selected amino acid to form an ester or amide covalent bond, respectively, and isolating the product thereof, and administering said product to a patient.

It has been found that when an unsubstituted naturally occurring amino acid is esterified to valproic acid, the resulting prodrug is a pharmaceutically first-rate, well-flowing powder that is rapidly absorbed into the body, where it is broken down and released by Non-toxic amino acid and does not require emulsifiers, additives and other excipients.

Furthermore, it has been shown that the present invention also produces drugs which, although they are prodrugs of valproic acid; are themselves highly effective antiepileptics and exhibit this effect. The amino acid prodrugs of the present invention are thus potent antiepileptic agents and are useful in the treatment of a wide range of psychiatric disorders, whether or not the active parent drug is released exhibiting this potential.

The valproic acid prodrug has a much higher bulk density than the corresponding sodium salt and is suitable for compression into large weight tablets and capsules. Also, they do not exhibit the bitter taste and unusual odor of valproic acid. Since the acid-causing carboxylic acid group is blocked, the prodrugs of the present invention are not believed to have any acid activity, however, it has been shown that these prodrugs are effective antiepileptic agents whether or not they release valproic acid. All valproic acid prodrugs described release the active drug in vivo with all its pharmacological and psychoactive properties.

Valproic acid prodrugs clearly offer many advantages over valproic acid, for example, all side chains cleaved from these prodrugs are naturally occurring essential amino acids and are therefore non-toxic. This results in a high therapeutic index. Second, all prodrugs are readily broken down in the body to release valproic acid. Also, due to their high water solubility, they can be easily administered by using sterile lyophilized powders to form solutions in situ prior to intravenous administration, or by providing drug solutions prefilled in syringes or vials for infusion. This amino acid ester is more stable than valproic acid because the COOH group of valproic acid is blocked from reacting with base. The valproic acid prodrugs of the present invention are thus more potent than valproic acid itself, without the toxicity and other pharmaceutical problems associated with current marketed formulations.

The procedure for the synthesis of the L-serine, L-threonine, and L-hydroxyproline esters of valproic acid (2-valproic acid) is outlined in the Synthetic Sequence section and is the basis for the preparation of various prodrugs of the present invention example of . See the Experimental section for complete procedures and analyzed data. In general, valproic acid (2-8 g, in batches) was reacted with N-benzyloxy/benzyl ester protected amino acids using EDC in the presence of a catalytic amount of DMAP. Upon completion of the reaction (20 h at room temperature), the mixture was extracted with DIUF water, dried over sodium sulfate, and concentrated under reduced pressure. The crude material was either used directly in the deprotection step or purified by column chromatography. This step produced protected amino acid esters of valproate in yields ranging from 72% to 92%. Deprotection was achieved by hydrogenation (30 psi _H2 ) in the presence of 10% palladium on carbon catalyst. Amino acid esters of valproic acid were extracted from the palladium catalyst with ethanol, concentrated and dried. The final salt is formed by acidification with hydrochloric acid. The crude salt was then purified by the method described in the experimental section (yields ranging from 57% to 92%).

Composition order:

1. SPIC001

2. SPIC002

3. SPIC003

Synthesis of L-serine, L-threonine and L-hydroxyproline esters of valproic acid: a) EDC, DMAP, CH ₂ Cl ₂ ; b) H ₂ , 10% Pd/C, EtOH, EtOAc ; c) HCl.

Experimental part:

The synthesis of SPIC001, SPIC002 and SPIC003 was carried out in one or two batches. Reagents mentioned in the experimental section were commercially available in the highest purity and were purchased from Lancaster, Sigma-Aldrich, Acros or Bachem, except solvents were purchased from Fisher Scientific or Mallinkrodt.

1) SPIC001: 2-Propylvaleric acid-2(S)-amino-2-carboxyethyl ester hydrochloride

  (L-serine valproate hydrochloride)

2-Propylvaleric acid (valproic acid, 6.48 g, 44.93 mmol), N-benzyloxycarbonyl-L-serine benzyl ester (Z-Ser-OBzl, 14.80 g, 44.93 mmol) , EDC (8.61 g, 44.91 mmol) and DMAP (549 mg, 4.49 mmol) in anhydrous dichloromethane (50 mL) was stirred at room temperature for 20 hours. After 20 hours, the dichloromethane was washed with water (3 x 50 mL) and dried over magnesium sulfate (5 g), filtered and concentrated under reduced pressure. The remaining colorless oil (20.87g) was purified by column chromatography on silica gel (150g, 0.035-0.070mm, 6nm pore size), eluting with hexane/ethyl acetate (3:1). After the product containing the fractions was concentrated under reduced pressure and dried under high vacuum until the weight was constant, this experiment produced the protected L-serine valproate SPIC00101 as a colorless oil (18.9 g, 92% yield ).

¹ H NMR (300MHz, DMSO): δ = 7.96 (1H, d, J = 8.1Hz), 7.35 (10H, m), 5.14 (2H, s), 5.05 (2H, s), 4.5 1 (1H, m ), 4.29 (2H, m), 2.29 (1H, m), 1.50-1.25 (4H, m), 1.25-1.10 (4H, m), 0.80 (6H, t, J=6.6 Hz).

¹³ C NMR (75MHz, DMSO): δ=174.88, 169.15, 155.85, 136.58, 135.45, 128.26, 128.18, 127.47, 127.71, 127.57, 66.32, 65.66, 62.47, 53.09, 44.20, 33.95, 33.97

Protected L-serine valproate SPIC00101 (18.9 g, 41.48 mmol) was dissolved in ethanol (60 mL) and ethyl acetate (60 mL) at room temperature and added to a solution containing 10% palladium Carbon catalyst (3.0 g, 50% wet) in a Parr bottle (500 mL). The nitrogen atmosphere was replaced with hydrogen (30 psi). After shaking for 4 hours, additional palladium catalyst (1.0 g) in ethanol/ethyl acetate (1:1, 100 mL) was added and the reaction mixture was shaken overnight at room temperature under hydrogen (30 psi). After 24 hours the catalyst was removed by filtration through a thin layer of charcoal. Ethanol and ethyl acetate were concentrated under reduced pressure at room temperature. After drying under high vacuum, the remaining solid was acidified with hydrochloric acid in ether (2M, 24.6 mL). After the mixture was stored in the refrigerator for 2 hours, it was filtered and the mixture was washed with additional cold diethyl ether (10 mL). After filtration, the remaining white solid was dried at room temperature under high vacuum until the product weight was constant (24 hours). This experiment produced L-serine valproate hydrochloride SPIC001 (6.34 g, 57% yield) as a white solid.

¹ H NMR (300MHz, DMSO): δ=8.73(br s, 3H), 4.47(dd, 1H, J=12.9, 4.5Hz), 4.31(dd, 2H, J=12.9, 3.6Hz), 2.36(m , 1H), 1.50(m, 2H), 1.39(m, 2H), 1.20(m, 4H), 0.84(t, 6H, J=7Hz).

¹³ C NMR (75 MHz, DMSO): δ = 174.67, 168.19, 61.84, 51.16, 44.12, 33.76, 33.58, 20.07, 19.92, 13.97, 13.89.

HPLC analysis:

98.49% purity; rt=4.767min; Luna C18 5u column (sn 167917-13); 4.6×250mm; 254nm; 33% acrylonitrile/66% DIUF water; 35C; 20ul injection; 1ml/min; 20mg/mL injection amount; the sample is dissolved in the mobile phase.

CHN elemental analysis:

Calculated: C 49.34, H 8.28, N 5.23; Found: C 49.22, H 8.35, N 5.24.

Melting point: 159-160°C

2) SPIC002: 4(R)-(2-Propylpentanoyloxy)pyrrolidine-2(S)-carboxylic acid

   (L-Hydroxyproline Valproate)

In an argon atmosphere, 2-propylvaleric acid (valproic acid, 4.32 g, 30 mmol), N-benzyloxycarbonyl-L-hydroxyproline benzyl ester (Z-Hyp-OBzl, 10.66 g, 30 A mixture of mmol) ¹ , EDC (5.74 g, 30 mmol) and DMAP (366 mg, 3 mmol) in anhydrous dichloromethane (30 mL) was stirred at room temperature for 20 hours. After 20 hours, the dichloromethane was washed with water (3 x 30 mL) and dried over magnesium sulfate (5 g), filtered and concentrated under reduced pressure. The remaining colorless oil SPIC00201 (11.95 g, 24.7 mmol, 82.4% yield) was used without purification.

¹ H NMR (300MHz, CDCl ₃ ): δ=7.29(10H, m), 5.28-5.00(5H, m), 4.55(1/2H, t, J=8Hz), 4.46(1/2H, t, J =8Hz), 3.80-3.60(2H, m), 2.43-2.16(3H, m), 1.60-1.45(2H, m), 1.40-1.32(2H, m), 1.28-1.20(4H, m), 0.86 (6H, m).

¹³ C NMR(75MHz，DMSO)：δ＝174.74，171.40，171.05，153.79，153.31，136.34，136.20，135.57，135.38，128.24，128.13，127.95，127.87，127.67，127.52，127.28，127.10，72.29，71.53，66.34 , 66.10, 57.66, 57.19, 52.27, 51.89, 44.13, 40.33, 35.78, 34.79, 34.04, 33.92, 33.35, 20.00, 19.91, 13.79, 13.73.

Protected L-hydroxyproline valproate SPIC00201 (17.24 g, 35.79 mmol) was dissolved in ethanol (50 mL) and ethyl acetate (100 mL) at room temperature and added to the 10% palladium on carbon catalyst (3.5 g, 50% wet) in a Parr bottle (500 mL). The nitrogen atmosphere was replaced with hydrogen (30 psi). After shaking for 15 hours, the catalyst was removed by filtration through a thin layer of celite and charcoal. The ethanol and ethyl acetate mixture was concentrated under reduced pressure at room temperature. After drying overnight at room temperature under high vacuum, this experiment resulted in L-hydroxyproline valproate hydrochloride SPIC002 (9.2 g, yield: 99.8%) as a white solid. To remove trace impurities, zwitterions were purified by reverse-phase column chromatography (50 g ODS silica gel) in two batches. The zwitterions were placed on a column of DIUF water and eluted with a mixture of DIUF water/methanol (2:1, 1:1, 1:2, 100% methanol).

The product containing fractions were combined, concentrated under reduced pressure at 20 °C (or less), and dried at room temperature under high vacuum until constant weight (24 hours, 6.4 g of white solid recovered).

¹ H NMR (300MHz, CDCl ₃ ): δ=12.40(br s, 1H), 8.32(br s, 1H), 5.28(m, 1H), 4.11(t, 1H, J=7.2Hz), 3.59(m , 1H), 3.34(br d, 1H, J=10.5Hz), 2.50-2.22(m, 3H), 1.62-1.50(m, 2H), 1.50-1.32(m, 2H), 1.32-1.19(m, 4H), 0.88 (t, 6H, J = 7.2 Hz).

¹³ C NMR (75 MHz, CDCl ₃ ): δ=175.99, 173.35, 71.83, 59.56, 49.77, 45.08, 36.19, 34.51, 20.87, 14.31.

HPLC analysis:

99.20% purity; r.t.=7.228min.; 70% DIUF water/30% acetonitrile; 1mL/min; 36.8C; Luna C18, 5u column (serial#167917-13), 4.6×250mm; Mutually.

CHN elemental analysis:

Calculated: C 60.68, H 9.01, N 5.44; Found: C 60.58, H 9.12, N 5.48.

Melting point: 179.0-180.0°C

3) SPIC003: 2-Propylvalproic acid-2(S)-amino-2-carboxy-1(R)-methylethyl ester hydrochloride (L-threonine valproate hydrochloride)

In an argon atmosphere, 2-propylpentanoic acid (valproic acid, 4.32 g, 30 mmol), N-benzyloxycarbonyl-L-threonine benzyl ester (Z-Thr-OBzl, 10.30 g, 30 mmol mol), EDC (5.74 g, 30 mmol) and DMAP (366 mg, 3.0 mmol) in anhydrous dichloromethane (30 mL) was stirred at room temperature for 20 hours. After 20 hours, the dichloromethane was washed with water (3 x 30 mL) and dried over magnesium sulfate (5 g), filtered and concentrated under reduced pressure. The remaining colorless oil (13.44g) was purified by column chromatography on silica gel (100g, 0.035-0.070mm, 6nm pore size), eluting with hexane/ethyl acetate (4:1).

The product containing the fractions was concentrated under reduced pressure and dried under high vacuum until the weight was constant. This experiment produced the protected L-threonine valproate SPIC00301 (12.65 g, 89.8% yield) as a colorless oil things.

¹ H NMR (300MHz, CDCl ₃ ): δ=7.40-7.05 (11H, m), 5.45 (1H, m), 5.17-5.02 (4H, m), 4.53 (1H, d, J=9.6Hz), 2.24 (1H, m), 1.58-1.40 (2H, m), 1.40-1.15 (9H, m), 0.86 (6H, m).

¹³ C NMR (75MHz, DMSO): δ=174.24, 169.29, 156.48, 136.61, 135.34, 128.26, 128.20, 127.74, 127.67, 127.58, 69.04, 66.33, 65.78, 57.62, 44.50, 33.80, 30.9 , 13.87.

Protected L-threonine valproate SPIC00301 (12.65 g, 26.9 mmol) was dissolved in ethanol (50 mL) and ethyl acetate (50 mL) at room temperature and added to a solution containing 10 % palladium on carbon catalyst (2.53 g, 50% wet) in a Parr bottle (500 mL). The nitrogen atmosphere was replaced with hydrogen (30 psi). After 20 hours the catalyst was removed by filtration through a thin layer of charcoal and washed with ethanol (25 mL). Ethanol and ethyl acetate were concentrated at room temperature under reduced pressure. After drying under high vacuum, the remaining solid (6.13 g) was acidified with hydrochloric acid (3.1 mL conc.) in DIUF water (50 mL). The solution was filtered a second time with charcoal and dried overnight in a lyophilizer. This experiment produced L-threonine valproate hydrochloride SPIC003 (6.52 g, 86.0% yield) as a white solid.

Batches of L-threonine valproate hydrochloride SPIC003 (8.8 g) were combined and purified by crystallization from acetonitrile. After dissolving the salt in hot acetonitrile (225 mL), the material was treated with charcoal, filtered, and left in a 5°C refrigerator overnight. After 18 hours the white solid was filtered, washed with cold acetonitrile (10 mL), and dried under high vacuum at room temperature until the product weight was constant (24 hours). L-threonine valproate hydrochloride SPIC003 (6.82 g, 77.5% recovery rate) recovered in this step was a white solid.

¹ H NMR (300MHz, DMSO): δ=8.71(br s, 3H), 5.28(m, 1H), 4.16(d, 1H, J=2.7Hz), 2.33(m, 1H), 1.56-1.40(m , 2 H), 1.37-1.27 (m, 5H), 1.21-1.13 (m, 4H), 0.84 (t, 6H, J=6.6Hz).

¹³ C NMR (75 MHz, DMSO): δ = 173.97, 168.19, 67.69, 55.42, 44.43, 33.95, 33.78, 20.07, 19.95, 16.54, 13.94.

HPLC analysis:

98.88% purity; r.t.=4.864min.; 70% DIUF water/30% acetonitrile; 1mL/min; 40C; Luna C18, 5u column (serial#211739-42), 4.6×250mm; 20ul injection; middle.

CHN elemental analysis:

Calculated: C 51.15, H 8.59, N 4.97; Found: C 51.29, H 8.59, N 4.98.

Melting point: 144°C

The room temperature solubility of each of the above esters in water was determined by dissolving an excess of each drug and allowing it to stand for several hours. The resulting solution was centrifuged at 1500 revolutions per minute (rpm) for 3 minutes, and the supernatant was taken for analysis. The results showed that the solubility of these esters in water exceeded 50 mg/mL.

There are a number of screening assays to determine the utility of the resulting prodrugs according to published methods. These assays include in vitro and in vivo screening methods.

In vitro methods include acid/base hydrolysis of the prodrug, hydrolysis in porcine pancreas, hydrolysis in rat intestinal fluid, hydrolysis in human gastric fluid, hydrolysis in human intestinal fluid, and hydrolysis in human plasma. These assays are described in the literature (Simmons, DM, Chandran, VR and Portmann, GA, Danazol Amino Acid Prodrugs: In Vitro and In Situ Biopharmaceutical Evaluation, Drug Development and Industrial Pharmacy, Vol 21, Issue 6, Page687, 1995), where All contents are incorporated by reference.

The valproic acid prodrugs of the present invention are effective for the treatment of diseases or conditions for which valproic acid is commonly used. The prodrugs disclosed herein are transformed in vivo to release the active compound and facilitate therapy by reducing or eliminating the biopharmaceutics and pharmacokinetic barriers of each valproate prodrug. However, it is important to note that these prodrugs are sufficiently active on their own not to release any active drug in mammals.

Thus, the prodrugs of the present invention facilitate therapy by removing the biopharmaceutical and pharmacokinetic barriers of existing drugs.

Furthermore, these prodrugs can be easily synthesized in high yields using commercially readily available reagents.

VII. Water-Soluble Prodrugs of Fibric Acid Derivatives

Fenoxyacid derivatives are useful antihyperlipidemic agents for the treatment of hyperlipidemia in mammals, the symptoms of which are high triglycerides, low HDL (high density lipoprotein or "good" cholesterol), and high cholesterol. Fenoxylic acid derivatives are also used to lower LDL (low-density lipoprotein or "bad" cholesterol). The general structure of phenoxyacid analogs is shown in the formula below, where X is various mixed aliphatic and aromatic functional groups. Specific derivatives included in this general formula are clofibric acid, fenofibric acid, ciprfibrate and gemfibrozil, among others.

Fenoxy acid analogs

Typical examples of the chemical groups of the X moiety in the above structures are shown below.

The analogs of firic acid shown in the above structure have shown a number of therapeutic applications which are quite different and somewhat surprising. In summary, these derivatives are useful in the treatment of dyslipidemia and dyslipoproteinemia. Dyslipidemia and dyslipoproteinemia as defined herein include hypercholesterolemia, abnormal and elevated cholesterol levels, abnormal and elevated LDL cholesterol levels, abnormal and elevated total cholesterol levels, abnormal and elevated plasma cholesterol levels, triglycerides Abnormal and high levels of esters, hypertriglyceridemia, abnormal levels of lipoproteins, abnormal and high levels of low-density lipoproteins (LDLs), abnormal and high levels of very low-density lipoproteins, and very low levels of intermediate-density lipoproteins Abnormal and elevated, abnormal high-density lipoprotein levels, hyperlipidemia, hyperchylomicronemia, abnormal chylomicron levels, and associated dysfunctions and combinations thereof, as described in the literature (The ILIB Lipid Handbook for Clinical Practice , Blood Lipids and Coronary Heart Disease, Second Edition, A.M.Gotto et al, International Lipid Information Bureau, New York, N.Y., 2000), which is incorporated herein by reference.

Mechanism of action:

The mechanism of action of phenoxyacid derivatives in clinical practice has been elucidated by activation of peroxisome proliferator-activated receptor alpha (PPAR-α) in transgenic mice in vivo and in human hepatocyte cultures in vitro. By this mechanism, phenoxyacid derivatives increase lipolysis by activating lipoprotein lipase, excrete triglyceride-rich particles from plasma, and reduce apolipoprotein C-III (inhibition of lipoprotein lipase activity). agent) production.

The resulting triglycerides produce a change in LDL size and composition, from densely packed small particles (thought to be atherogenic due to their susceptibility to oxidation) to large light particles. These larger particles have a higher affinity for cholesterol receptors and are rapidly metabolically broken down. Activation of PPAR-α also induces increased synthesis of apolipoproteins A-I, A-II and HDL cholesterol. Fenoxyacid derivatives are also effective in the treatment of gout because they reduce serum uric acid levels in hyperuricemic patients.

Types of hyperlipidemia include type I, type IIa, type IIb, type III, type IV and type V. The levels on which these types of profiles are based are relative to the normal lipids (cholesterol and triglycerides) and lipoproteins described above. The different classifications are derived from Drug Facts and Comparisons, 52nd Edition (1998) page 1066, which is not incorporated herein by reference.

Many phenoxyacid derivatives do not have sufficient bioavailability when administered orally, and absorption is variable, unstable, and food-dependent. In fact, it is impossible for many phenoxyacid derivatives to have absolute bioavailability, because the phenoxyacid prodrugs currently on the market are insoluble in water, so parenteral injection forms are difficult to provide. Moreover, because these drugs are usually administered as esters, they are in fact prodrugs. These prodrugs must be metabolized in the body to release the active drug, phenoxyacid. However, since these drugs are ester formulations, they are rather insoluble in water, making them difficult to formulate and not easily broken down in the body to release the active drug.

Many phenoxyacid derivatives are low to moderate molecular weight solids with a characteristic odour. Oral use has an unpleasant taste and can severely irritate the mouth and throat. Taking the drug with food provides higher blood levels than fasting. The fed/fasted difference in bioavailability was more pronounced when phenoxyacid derivatives were compared to their corresponding prodrug derivatives. All bioavailability has been reported to be between 40-60 and vary widely between patients.

A significant problem with currently marketed phenoxyacid derivatives is that when these prodrugs are cleaved in vivo, they release prodrug moieties which are themselves highly toxic. For example, in the case of fenofibrate and gemfibrozil, isopropanol is released when esterases break down from the promoiety of fenofibric acid. It is well known that isopropanol is highly toxic when released into any mammalian tissue.

To improve therapeutic efficacy, uniform complete blood counts, develop pharmaceutically superior formulations, and improve drug solubility in water, the present invention details alternative prodrugs of phenoxyacid derivatives that overcome many of the above-mentioned difficulties.

Accordingly, in one aspect, the invention relates to alternative classes of phenoxyacid derivative prodrugs. The prodrug consists of the hydroxyl group of an amino acid esterified to the free carboxyl group present on the phenoxyacid derivative molecule. In another embodiment, the amino group of the amino acid reacts with the COOH of the phenoxy acid to form an amide bond.

More specifically, one aspect of the invention relates to compounds of the formula, or pharmaceutically acceptable salts thereof, wherein X is as defined above,

Fenoxy acid analogs

Wherein R is NH-AA or O-AA, and AA is an amino acid, and the amino group or hydroxyl group in the amino acid reacts with the carboxylic acid group of the phenoxyacid derivative.

In one embodiment, the present invention also relates to a pharmaceutical composition, which includes a therapeutically effective amount of the various prodrugs of the above-mentioned phenoxyacid derivatives and their pharmaceutical carriers.

In another embodiment, the present invention relates to a method of treatment of a patient in need of treatment with a phenoxyacid derivative, the method comprising administering to said patient an effective amount of a phenoxyacid derivative.

In yet another embodiment, the present invention relates to a method for converting liquid phenoxyacid derivatives into solid powders by reacting the carboxyl functional groups of the phenoxyacid derivatives with the amino or hydroxyl groups of amino acids and isolating their product.

In a further embodiment, the present invention relates to a method by administering to a patient a prodrug in sufficient and therapeutically effective manner to allow for easy absorption of the derivative upon oral administration and thereby enhance the consistency of the therapeutic effect. The prodrug comprises reacting the COOH functional group of the phenoxyacid derivative molecule with the _NH2 or OH functional group of the selected amino acid to form an ester or amide covalent bond respectively, and isolating the product thereof, and administering the product.

It has been determined that when an unsubstituted naturally occurring amino acid is esterified to a phenoxyacid derivative, the resulting prodrug is a pharmaceutically class-leading, well-flowing powder that is rapidly absorbed into the body, where it is Breaks down and releases non-toxic amino acids and does not require emulsifiers, additives and other excipients.

Furthermore, it has been found that the present invention also produces drugs which, although they are prodrugs of phenoxyacid derivatives; are themselves highly effective antihyperlipidemics and exhibit this effect. Therefore, the amino acid prodrugs of the present invention are effective antihyperlipidemic drugs and are useful for treating a large number of hypercholesterolemia-related diseases, and exhibit this potential whether or not the active parent drug is released.

Since the acidic acid-causing carboxylic acid group is blocked, the prodrugs of the present invention are not considered to possess any acidity, however, it has been shown that these prodrugs are effective antihyperlipidemic agents whether or not they release phenoxyacid derivatives. All of the phenoxyacid derivative prodrugs described release the active drug in vivo with all its pharmacological and cholesterol-lowering properties.

The present invention clearly offers many advantages over phenoxyacid derivatives, for example, all side chains cleaved from these prodrugs are naturally occurring essential amino acids and are therefore non-toxic. This results in a high therapeutic index. Second, all of these prodrugs are readily broken down in vivo to release phenoxyacid derivatives. Also, due to their high water solubility, they are easy to administer by using sterile lyophilized powders to form solutions in situ prior to intravenous administration, or by providing drug solutions prefilled in syringes or vials for infusion. Amino acid esters are more stable than phenoxyacid derivatives because the COOH groups of phenoxyacid derivatives are blocked from reacting with bases. The phenoxyacid derivative prodrugs described herein are therefore more potent than the phenoxyacid derivatives themselves, without the toxicity and other pharmaceutical problems associated with currently marketed formulations.

The prodrugs of the present invention are antihyperlipidemic drugs effective in the treatment of hyperlipidemia in mammals, the symptoms of which are high triglycerides, low HDL (high density lipoprotein or "good" cholesterol) and high cholesterol. Fenoxylic acid derivatives are also used to lower LDL (low-density lipoprotein or "bad" cholesterol).

Typical examples of synthesizing L-threonine esters, L-hydroxyproline esters and L-serine esters of phenoxy acid derivatives are shown in the following synthetic methods. These steps can also be used for the synthesis of all other compounds that are derivatives of phenoxyacid.

Synthesis of prodrugs of phenoxyacid derivatives

The procedure for the synthesis of the L-serine, L-threonine, and L-hydroxyproline esters of fenofibric acid is outlined in the Synthetic Sequence section and serves as an example. The complete procedure and analyzed data can be found in the experimental section. Generally, fenofibric acid (100 g batches) was prepared from 4-chloro-4'-hydroxybezophenone according to literature procedures. Fenofibric acid was reacted with tert-butyl esters of N-Boc protected amino acids (L-serine, L-threonine and L-hydroxyproline) using EDC as a coupling agent and a catalytic amount of DMAP. The protecting group was removed at low temperature (5°C, 3-6 days) with a mixture of hydrochloric acid (1M) in acetic acid and dichloromethane. The amino acid ester salt of fenofibric acid was purified by crystallization from ethyl acetate and dried under high vacuum.

Composition order:

Synthesis of L-serine ester, L-threonine ester and L-hydroxyproline ester of fenofibric acid: a) Boc-Ser-OtBu, EDC, DMAP, CH ₂ Cl ₂ ; b) Boc-Thr-OtBu , EDC, DMAP _{, CH2Cl2} ; c) Boc-Hyp-OtBu, _EDC , DMAP, _CH2Cl2 ; d) HCl, AcOH, _{CH2Cl2 .}

Experimental part:

Synthesis of SPIB00201, SPIB00202 and SPIB00203 was performed in one or two batches. Reagents mentioned in the experimental section were commercially available in the highest purity available from Lancaster, Sigma-Aldrich, Acros, or Bachem, except solvents were purchased from Fisher Scientific or Mallinkrodt.

1) Synthesis of fenofibric acid:

A mixture of 4-chloro-4'-hydroxybenzophenone (116 g, 0.500 mol) and sodium hydroxide (120 g, 3.00 mol) was heated to reflux in acetone (1 L) for 2 hours. Turn off heat and remove heat source. A mixture of chloroform (179 g, 1.50 mol) in acetone (300 mL) was added dropwise. The reaction mixture was stirred overnight without heating. The mixture was heated to reflux for 8 hours, then cooled to room temperature. The precipitate was removed by filtration and washed with acetone (100 mL). The filtrate was concentrated under reduced pressure to give a brown oil. Water (200 mL) was added to the brown oil and acidified (to pH=1) with 1N hydrochloric acid. The precipitate formed was filtered and dried under high vacuum. The remaining yellow solid (268 g) was recrystallized from toluene in 4 batches (400 mL of toluene each). After filtration and drying under high vacuum, this experiment produced fenofibric acid (116 g, 73% yield) as a pale yellow solid.

¹ H NMR (300MHz, DMSO-d ₆ ): δ = 13.22 (1H, s, br), 7.72 (4H, d, J = 8.4Hz), 7.61 (2H, d, J = 7.8Hz), 6.93 (2H , d, J=7.8Hz), 1.60 (6H, s).

¹³ C NMR (75 MHz, DMSO-d ₆ ): δ=192.96, 174.18, 159.35, 136.84, 136.12, 131.67, 131.02, 129.12, 128.43, 116.91, 78.87, 25.13.

2) SPIB00201: L-serine fenofibrate

To fenofibric acid (11.6 g, 36.3 mmol), N-benzyloxycarbonyl-L-serine tert-butyl ester (Boc-Ser-OtBu, 8.62 g, 33.0 mmol), EDC (7.59 g, 39.6 mmol) and DMAP (484 mg, 3.96 mmol) was added dropwise with anhydrous dichloromethane (150 mL). After the addition was complete, the ice bath was removed, and the reaction mixture was stirred at room temperature under argon atmosphere for 20 hours. After 20 hours, additional dichloromethane (200 mL) was added and the solution was washed with water (2 x 200 mL) and brine (200 mL). After drying over sodium sulfate and filtering, the solution was concentrated under reduced pressure. The remaining yellow oil (21.2 g) was purified by column chromatography on silica gel (400 g, 0.035-0.070 mm, 6 nm pore size), eluting with heptane/ethyl acetate (3:1). After the product containing each fraction was concentrated under reduced pressure, it was dried under high vacuum until the weight was constant. This experiment generated protected L-serine fenofibrate SPIB0020101 (16.2 g, 87% yield), which was a shallow Yellow oil.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.75 (2H, d, J = 9.0 Hz), 7.72 (2H, d, J = 9.0 Hz), 7.45 (2H, d, J = 8.7 Hz), 6.86 ( 2H, d, J = 8.7Hz), 5.04 (1H, d, J = 6.9Hz), 4.55-4.42 (3H, m), 1.66 (3H, s), 1.65 (3H, s), 1.43 (9H, s ), 1.39 (9H, s).

¹³ C NMR (75MHz, CDCl ₃ ): δ=193.92, 172.99, 168.07, 159.24, 154.87, 138.24, 136.19, 131.94, 131.06, 130.40, 128.41, 117.26, 82.88, 80.13, 758, 24, 24, 63.97 25.70, 25.30.

To a solution of the protected L-serine fenofibrate SPIB0020101 (16.2 g, 28.8 mmol) in anhydrous dichloromethane (100 mL), cooled to 5 °C, was added dropwise hydrochloric acid in acetic acid under an atmosphere of argon. (400 mL, 1 M, 400 mmol) solution. The reaction mixture was stirred at 5°C for 3 days. After 3 days the mixture was concentrated under reduced pressure and dried under high vacuum to remove acetic acid. Ethyl acetate (100 mL) was added to the remaining pale yellow oil (24.7 g). The solution was concentrated and dried again. Ethyl acetate (65 mL) was added to the remaining pale yellow oil (17.0 g). The mixture was heated to reflux for 5 minutes and cooled to room temperature. The precipitate was removed by filtration and dried overnight at room temperature under high vacuum, then at 43°C for 1 hour. This experiment produced L-serine fenofibrate hydrochloride SPIB00201 (7.66 g, 60% yield) as a white solid.

¹ H NMR (300MHz, DMSO-d ₆ ): δ = 14.12 (1H, s, br), 8.77 (3H, s, br), 7.72 (4H, m), 7.62 (2H, d, J = 8.4Hz) , 6.92 (2H, d, J = 9.0Hz), 4.62 (1H, dd, J = 12.0, 4.2Hz), 4.50 (1H, dd, J = 12.0, 2.4Hz), 4.41 (1H, m), 1.64 ( 3H, s), 1.63 (3H, s).

¹³ C NMR (75 MHz, DMSO-d ₆ ): δ=193.06, 171.70, 168.06, 158.72, 136.93, 136.06, 131.73, 131.09, 129.62, 128.49, 117.64, 79.02, 62.99, 51.11, 25.044, 24.

HPLC analysis:

100% purity; r.t.=4.361min.; 55% trifluoroacetic acid (0.1%), 45% acrylonitrile; 1mL/min; 32.3 C, Luna C18, serial#167917-13; 20ul injection., NB275-49.

CHN elemental analysis:

Calculated: C 54.31, H 4.79, N 3.17; Found: C 54.37, H 4.78, N 3.12.

Melting point: 151°C (decomposition)

3) SPIB00202: L-threonine fenofibrate

To fenofibric acid (25.5 g, 79.9 mmol), N-benzyloxycarbonyl-L-threonine tert-butyl ester (Boc-Thr-OtBu, 20.0 g, 72.6 mmol) cooled in an ice-water bath, To a mixture of EDC (16.7 g, 87.1 mmol), EDC (16.7 g, 87.1 mmol) and DMAP (1.06 g, 8.71 mmol) was added dropwise anhydrous dichloromethane (200 mL). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature under argon atmosphere for 20 hours. After 20 hours, additional EDC (1.39 g, 7.26 mmol) was added and the experiment was allowed to stir at room temperature under argon over a weekend. After 4 days, additional dichloromethane (300 mL) was added and the solution was washed with water (300 mL) and brine (300 mL). After drying over sodium sulfate and filtering, the solution was concentrated under reduced pressure. The remaining yellow oil (53.5 g) was purified by column chromatography on silica gel (500 g, 0.035-0.070 mm, 6 nm pore size), eluting with heptane/ethyl acetate (3:1). The product containing each fraction was concentrated under reduced pressure and dried under high vacuum until the weight was constant. This experiment generated protected L-threonine fenofibrate SPIB0020201 (34.1 g, 82% yield) as a white foam shape.

¹ H NMR (300 MHz, CDCl ₃ ): δ = 7.74 (2H, d, J = 8.4 Hz), 7.72 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.4 Hz), 6.87 ( 2H, d, J = 8.4Hz), 5.47 (1H, m), 4.98 (1H, d, J = 9.9Hz), 4, 31 (1H, d, J = 9.9Hz), 1.65 (3H, s), 1.64 (3H, s), 1.45 (9H, s), 1.42 (9H, s), 1.22 (3H, d, J=6.3Hz).

¹³ C NMR (75MHz, CDCl ₃ ): δ=193.94, 172.14, 168.70, 159.26, 155.62, 138.28, 136.18, 131.90, 131.08, 130.37, 128.43, 117.40, 82.70, 80.17, 79.38, 27.96, 72.02 26.44, 24.79, 16.90.

To a solution of protected L-threonine fenofibrate SPIB0020201 (34.1 g, 59.2 mmol) in anhydrous dichloromethane (100 mL) cooled to 5° C. was added dropwise under argon atmosphere with stirring A solution of hydrochloric acid in acetic acid (600 mL, 1 M, 600 mmol). The reaction mixture was kept at 5°C for 6 days. The mixture was concentrated under reduced pressure and dried under high vacuum to remove acetic acid. Ethyl acetate (500 mL) was added to the remaining white solid (45.8 g). The mixture was heated to reflux for 10 minutes and cooled to room temperature. The precipitate was removed by filtration and dried overnight at room temperature under high vacuum. The L-threonine fenofibrate hydrochloride SPIB00202 (26.3 g, 97% yield) produced in this experiment was a white solid.

¹ H NMR (300MHz, DMSO-d ₆ ): δ=14.10 (1H, s, br), 8.84 (3H, s, br), 7.73 (4H, m), 7.63 (2H, d, J=8.1Hz) , 6.89(2H, d, J=8.7Hz), 5.44(1H, m), 4.31(1H, s), 1.64(3H, s), 1.62(3H, s), 1.38(3H, d, J=6.3 Hz).

¹³ C NMR (75 MHz, DMSO-d ₆ ): δ=193.04, 171.00, 168.13, 158.76, 136.90, 136.08, 131.70, 131.06, 129.49, 128.48, 117.41, 78.99, 69.40, 55.21, 25.529, 26.0 HPLC analysis:

98.59% purity; r.t.=4.687min.; 55% trifluoroacetic acid (0.1%), 45% acrylonitrile; 1mL/min; 32.3 C, Luna C18, serial#167917-13; 20ul injection, NB275-49, DAD1B, Sig=210.4, Ref=550,100.

CHN elemental analysis:

Calculated: C 55.27, H 5.08, N 3.07; Found: C 54.98, H 5.13, N 3.03.

Melting point: 160.5°C (decomposition)

4) SPIB00203: L-hydroxyproline fenofibrate

To fenofibric acid (24.9 g, 78.1 mmol), N-benzyloxycarbonyl-L-hydroxyproline tert-butyl ester (Boc-Hyp-OtBu, 20.4 g, 71.0 mmol) cooled in an ice-water bath, according to To a mixture of EDC (16.3 g, 85.2 mmol) and DMAP (1.04 g, 8.52 mmol) was added dropwise anhydrous dichloromethane (200 mL). After the addition was complete, the ice bath was removed and the reaction mixture was stirred at room temperature under argon atmosphere for 20 hours. After 20 hours, additional EDC (1.63 g, 8.52 mmol) was added and the experiment was allowed to stir at room temperature under argon over a weekend. After 4 days, the solution was washed with water (200 mL) and brine (200 mL). After drying over sodium sulfate and filtering, the solution was concentrated under reduced pressure. The remaining yellow oil (49.4 g) was purified by column chromatography on silica gel (500 g, 0.035-0.070 mm, 6 nm pore size), eluting with heptane/ethyl acetate (2:1). After the product containing each fraction was concentrated under reduced pressure, it was dried under high vacuum until the weight was constant. This experiment generated protected L-hydroxyproline fenofibrate SPIB0020301 (26.4g, 63% yield), which It is a colorless oil.

¹ H NMR (300MHz, CDCl ₃ ): δ = 7.76 (2H, d, J = 8.1 Hz), 7.73 (2H, d, J = 8.1 Hz), 7.46 (2H, d, J = 8.1 Hz), 6.84 ( 2H, d, J=8.1Hz), 5.32(1H, m), 4.13(0.38H, t, J=7.8Hz), 4.00(0.62H, t, J=7.8Hz), 3.67(1.62H, m) , 3.46(0.38H, d, J=12.6Hz), 2.29(1H, m), 2.15(1H, m), 1.68(3H, s), 1.66(3H, s), 1.44-1.38(18H, m) .

¹³ C NMR (75 MHz, CDCl ₃ ): δ=193.88, 172.98, 171.14, 159.25, 153.48, 138.23, 136.16, 131.99, 131.08, 130.36, 128.44, 117.03, 116.91, 81.478, 80.33, 2.73, 890 , 58.23, 51.88, 51.58, 36.33, 35.31, 31.92, 28.29, 28.00, 25.89, 24.95.

To a solution of the protected L-hydroxyproline fenofibrate SPIB0020301 (26.0 g, 44.2 mmol) in anhydrous dichloromethane (100 mL) cooled to 5 °C was stirred dropwise under an argon atmosphere. A solution of hydrochloric acid in acetic acid (450 mL, 1 M, 450 mmol) was added. The reaction mixture was stirred at 5°C for 4 days. After 4 days, the mixture was concentrated under reduced pressure and dried under high vacuum to remove acetic acid. Ethyl acetate (200 mL) was added to the remaining yellow oil (31.5 g). The mixture was sonicated, concentrated under reduced pressure, and dried under high vacuum. Ethyl acetate (300 mL) was added to the remaining white solid (23.2 g). The ethyl acetate mixture was heated to reflux for 10 minutes and cooled to room temperature. The precipitate was removed by filtration and dried overnight at room temperature under high vacuum. This experiment produced L-hydroxyproline fenofibrate hydrochloride SPIB00203 (15.8 g, 76% yield) as a white solid.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ=14.07 (1H, s, br), 10.75 (1H, s, br), 9.40 (1H, s, br), 7.71 (4H, d, J=8.1 Hz), 7.60(2H, d, J=8.1Hz), 6.96(2H, d, J=8.1Hz), 5.42(1H, m), 4.24(1H, t, J=9.0Hz), 3.61(1H, dd, J = 13.2, 4.2 Hz), 3.28 (1H, d, J = 13.2 Hz), 2.35 (2H, m), 1.66 (3H, s), 1.64 (3H, s).

¹³ C NMR (75MHz, DMSO-d ₆ ): δ=193.00, 171.52, 169.14, 158.81, 136.87, 136.09, 131.81, 131.05, 129.48, 128.46, 117.28, 78.99, 73.79, 57.54, 50.23, 25.34.6

HPLC analysis:

100% purity; r.t.=8.369min.; 60% DIUF water (0.1% trifluoroacetic acid)/40% acetonitrile; 1mL/min; 36.4 C; Luna C18, 5u column (serial# 191070-3), 4.6×250mm; 20ul injection; DAD1A, Sig=210.4, Ref=550,100.

HPLC-MS (ESI): Calculated: M ⁺ = 431; Found: M+H = 432.3

Melting point: 187.5°C (decomposition)

The solubility of each of the above esters in water at room temperature was determined by dissolving an excess of each drug and allowing it to stand for several hours. The resulting solution was centrifuged at 1500 revolutions per minute (rpm) for 3 minutes and the supernatant analyzed. It shows that the solubility of these esters in water exceeds 50 mg/mL.

experiment

The level of triglycerides in the blood of the mice was checked at the beginning of the timing. Then, the mice were fed a high-sugar diet, such as 30% sucrose in water, for 1 week. Mice were then measured for triglycerides at the end of 1 week and fed a normal diet. From days 7-14, the mice were given the drugs of the test group or the control group. Triglycerides in rat blood were measured again on day 14.

In the comparison of fenofibrate (control) with L-serine ester of fenofibric acid (test drug), each drug and control were tested with 3 rats each at the same doses of 50, 100 and 200 mg/kg.

The result is shown below.

Summary - Dose Ranging Study - Serum Lipid Reducing Properties - Fenofibrate and Its Formulations Test Sample: L-Serine Ester of Fenofibric Acid

Excipient: milli Q water with 1% Tween 80

Test items Dose (Mg/kg) animal number Triglycerides (mg/dl) start day Day 7 Day 14 excipient 0 1 81 168 121 2 88 171 222 3 114 133 162 Reference control fenofibrate 50 4 95 157 101 5 92 228 76 6 80 150 73 100 7 110 204 62 8 115 195 69 9 96 167 93 200 10 144 90 48 11 56 106 51 12 58 125 38 L-serine ester of fenofibric acid 50 13 88 148 86 14 94 145 86 15 100 127 73 100 16 109 - 46 17 129 100 69 18 71 183 47 200 19 74 240 83 20 81 158 61 twenty one 42 77 46

From the above results, it can be concluded that the use of highly water-soluble serine esters is effective.

There are a number of screening assays to determine the utility of the prodrugs produced according to published methods. These include in vitro and in vivo screening methods.

In vitro methods include acid/base hydrolysis of the prodrug, hydrolysis in porcine pancreas, hydrolysis in rat intestinal fluid, hydrolysis in human gastric fluid, hydrolysis in human intestinal fluid, and hydrolysis in human plasma. These assays are described in Simmons, DM, Chandran, VR and Portmann, GA, Danazol Amino Acid Prodrugs: In Vitro and In Situ Biopharmaceutical Evaluation, Drug Development and Industrial Pharmacy, Vol 21, Issue 6, Page 687, 1995, all of which are cited in refer to.

These phenoxyacid prodrugs of the present invention are effective for the treatment of diseases or conditions that are generally treated with phenoxyacid derivatives. The prodrugs disclosed herein are transformed in vivo to release the active compound and facilitate therapy by alleviating or eliminating the biopharmaceutical and pharmacokinetic barriers associated with various phenoxyacid derivatives. However, it is important to note that these prodrugs are sufficiently active on their own not to release any active drug in mammals.

In this way, the prodrugs of the present invention facilitate therapy by eliminating the biopharmaceutics and pharmacokinetic barriers of existing drugs.

Moreover, the prodrugs can be easily synthesized in high yields by using commercially readily available reagents.

The phenoxyacid prodrugs of the present invention are effective for the treatment of diseases or conditions commonly treated with phenoxyacid derivatives. The prodrugs disclosed herein are transformed in vivo to release the active compound and facilitate therapy by alleviating or eliminating the biopharmaceutical and pharmacokinetic barriers associated with various phenoxyacid derivatives. However, it is important to note that these prodrugs are sufficiently active on their own not to release any active drug in mammals.

Thus, the phenoxyacid prodrugs of the present invention facilitate therapy by eliminating the biopharmaceutical and pharmacokinetic barriers of existing drugs. Moreover, the prodrugs can be easily synthesized in high yields by using commercially available reagents.

In the above general formula and in the claims, it is to be understood that AA has the following definitions in

In this definition, AA refers to an amino acid residue having no amino groups in the main chain or side chains.

In this definition, AA refers to an amino acid residue having less hydroxyl groups on the side chain.

AA refers to an amino acid group without a carboxyl group on the main chain or side chain.

4) OAA - This is an ester bond between the hydroxyl group of the drug and the carboxyl group on the amino acid backbone or side chain. Thus, as written, the OAA is

wherein R _O is a side chain amino acid as defined above.

In other words, OAA- may refer to an ester bond between the carboxyl group of the drug and the hydroxyl group on the side chain of those amino acids having hydroxyl groups such as threonine, serine, hydroxyproline, tyrosine, and the like. The hydroxy group forms part of the ester bond, described above with O. Thus, as written, AA refers to an amino acid with a hydroxyl group on the side chain, but when expressed as OAA, AA does not have a hydroxyl group because the oxygen atom is represented in the general formula.

It should be understood that, although the present invention has been described in detail in conjunction with its description, the above description is to illustrate the present invention, rather than to limit the scope of the present invention, the scope of the present invention is determined by the appended claims limited in scope. Other aspects, advantages and modifications are within the scope of the following claims.

Claims (563)

1. method that strengthens at least two kinds of therapeutic properties of medicine, described medicine has the functional group of the acylated derivatives that is selected from hydroxyl, amino, carboxyl or described carboxyl, and the therapeutic properties of described enhancing is selected from as follows:

(a) taste of Gai Shaning or smell

(b) Qi Wang octanol/water distribution coefficient

(c) stability of Gai Shaning

(d) permeability of enhancing blood brain barrier

(e) eliminate the interior first pass effect of liver

(f) minimizing of intestines liver recycle

(g) painless injection of parenteral formulation

(h) bioavilability of Gai Shaning

(i) variation of raising absorption ratio

(j) reduce side effect (k) dosage proportionality

(1) selective hydrolysis of prodrug on site of action

(m) controllable release performance

(n) medicine of target transmits

(o) reduce toxicity (p) and reduce dosage

(q) change metabolic pathway on site of action, to discharge more multiple medicines thing

(r) be increased in solvability in the aqueous solution

(s) strengthen effectiveness,

Described method comprises that (a) effectively forming between described medicine and the described amino under the condition of covalent bond, with described medicine and amino acid reaction and (b) to its patient who needs to the product of (a).

2. according to the process of claim 1 wherein that described amino acid is naturally occurring amino acid.

3. according to the process of claim 1 wherein that described amino acid is α-L-amino acid.

4. according to the process of claim 1 wherein that described amino acid is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

5. according to the process of claim 1 wherein that AA is proline, glycine, lysine, hydroxyproline or alanine.

6. according to the method for claim 5, wherein AA is Lys or hydroxyproline.

7. according to the method for claim 6, wherein AA is Lys.

8. according to the process of claim 1 wherein that described medicine is a cyclosporin, Lopinavir, Ritonavir, Cefdinir, Zileuton, viracept see nelfinaivr, flavoxate, Candesartan, Propofol, Nisoldipine, Amlodipine, Ciprofloxacin, Ofloxacin, fosinopril, enalapril, Ramipril, benazepil, Moexipril, Trandolapril, nasmil, the Amoxicillin, cefuroxime, cefotaxime, Cefpodoxime, Atovaquone, Ganciclovir, Penciclovir, famciclovir, aciclovir, nicotinic acid, retinene, the third oxygen sweet smell, salsalate, paracetamol, brufen, Lovastatin, simvastatin, Atorvastatin, Pravastatin, Fluvastatin, Nadolol, Valsartan, methylphenidate, sulfonamide, Sulfasalazine, methylprednisolone, Medroxyprogesterone, Estramustine, Miglitol, Mefloquine, capecitabine, reach that azoles, eprosartan, divalproex sodium, fenofibrate, Gabapentin, Omeprazole, Lansoprazole, megestrol acetate, melbine, tazarotene, sumatriptan, naratriptan, Zomitriptan, aspirin, Olmesartan, sirolimus, tacrolimus, clopidogrel, anphotericin, tenofovir, Unoprostone, fulvestrant, Cefditoren, efavirenz, eplerenone, the treprostinil that, or adefovirdipivoxil.

9. the compound of a following formula, or its pharmaceutically acceptable salt:

Or

Or

Or

Or

Wherein CYCLO represents the residue on the 2-11 site of cyclosporin molecule; X-y is CH=CH or CH ₂=CH ₂, and R ²Be OAA or OGly-AA, AA is the amino acid residue that does not have the OH base on the carboxyl, and wherein Gly is a glycine residue, and is the interval group that is connected to the oxygen atom of cyclosporin, sirolimus, tacrolimus or Elidel.

10. according to the compound of claim 9, wherein AA is a kind of naturally occurring α-L-amino acid.

11. according to the compound of claim 9, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

12. according to the compound of claim 9, wherein AA is proline, glycine, lysine or ornithine.

13. according to the compound of claim 9, wherein AA is Lys or ornithine.

14. according to the compound of claim 9, wherein said compound has following formula

15. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 9-14 and its pharmaceutically acceptable carrier.

16. a treatment needs the patient's of cyclosporin treatment method, it comprise to described patient give with treatment go up effective dose according to each described compound of claim 9-14.

17. method that strengthens the cyclosporin dose ratio; it comprises the hydroxy functional group of the MeBmt part that is positioned at site 1 on the cyclosporin molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to the patient.

18. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is the amino acid residue of the hydroxyl of carboxyl.

19. according to the compound of claim 18, wherein AA is naturally occurring α-L-amino acid.

20. according to the compound of claim 18, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

21. according to the compound of claim 18, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

22. according to the compound of claim 18, wherein AA is Lys or hydroxyproline.

23. according to the compound of claim 18, wherein AA is Lys.

24. a pharmaceutical composition, it comprise treatment go up effective dose according to each described compound of claim 18-23 or its pharmaceutically acceptable carrier.

25. a treatment needs a kind of method of the patient of Lopinavir treatment, it comprise to described patient give with treatment go up effective dose according to each described compound of claim 18-23.

26. a method that increases Lopinavir solvability in the aqueous solution, it comprises the hydroxy functional group of Lopinavir molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

27. a method that increases the bioavilability of Lopinavir when patient's administration comprises the hydroxy functional group of Lopinavir molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separate its product, to the described product of described patient's administration.

28. a method for the treatment of mammal AIDS, it comprise to described mammal give with the treatment effective dose according to each described compound of claim 18-23, to suppress hiv protease.

29. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁AA ₁Be not have the OH group and the amino acid that on its side chain, has OH; And AA removes NH ₂The amino acid of group.

30. according to the compound of claim 29, wherein AA and AA ₁Be L-α-naturally occurring amino acid.

31. compound according to claim 29, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, and AA ₁Be Ser, Thr, Tyr or hydroxyproline.

32. according to the compound of claim 29, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine, perhaps AA ₁Be Tyr, hydroxyproline or serine.

33. according to the compound of claim 29, wherein AA or AA ₁Be serine or hydroxyproline.

34. according to the compound of claim 29, wherein AA or AA ₁It is hydroxyproline.

35. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 29-34, or its pharmaceutically acceptable carrier.

36. a treatment needs the patient's of Cefdinir treatment method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 29-34.

37. a method that increases Cefdinir solvability in the aqueous solution, it comprises that the carboxylic acid functional that makes the Cefdinir molecule and amino acid or its acylated derivatives react under ester or acid amides formation condition, and separates its product.

38. method that to patient's administration the time, increases the bioavilability of Cefdinir; it comprises that the carboxylic acid functional that makes the Cefdinir molecule and amino acid or its acylated derivatives react under ester or acid amides formation condition; and separate its product and give and described product to described patient.

39. a method for the treatment of the infectious disease that mammal causes by pathogenic microorganisms, it comprise to described mammal give with the treatment effective dose according to each described compound of claim 29-34.

40. a following formula: compound, or its pharmaceutically acceptable salt:

Zileuton

Wherein AA is the amino acid that does not have OH on carboxyl.

41. according to the compound of claim 40, wherein AA is L-α-naturally occurring amino acid.

42. according to the compound of claim 40, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

43. according to the compound of claim 40, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

44. according to the compound of claim 40, wherein AA is Lys or hydroxyproline.

45. according to the compound of claim 40, wherein AA is Lys.

46. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 40-45, or its pharmaceutically acceptable carrier.

47. a treatment needs the patient's of Zileuton treatment method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 40-45.

48. a method that increases Zileuton solvability in the aqueous solution comprises that the hydroxy functional group that makes the Zileuton molecule and an amino acid or its acylated derivatives react, and separates its product under the ester formation condition.

49. a method for the treatment of mammal asthma, it comprise to described mammal give with the treatment effective dose according to each described compound of claim 40-45.

50. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is the amino acid that does not have hydroxyl on its carboxyl.

51. according to the compound of claim 50, wherein AA is the naturally occurring a-amino acid of L-.

52. according to the compound of claim 50, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

53. according to the compound of claim 50, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

54. according to the compound of claim 50, wherein AA is Lys or hydroxyproline.

55. according to the compound of claim 50, wherein AA is Lys.

56. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 50-55 and its pharmaceutically acceptable carrier.

57. a treatment needs the patient's of viracept see nelfinaivr treatment method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 50-55.

58. a method that increases viracept see nelfinaivr solvability in the aqueous solution, it comprises that the hydroxy functional group that makes the viracept see nelfinaivr molecule and amino acid or its acylated derivatives react under the ester formation condition, and separates its product.

59. method that to patient's administration the time, increases the bioavilability of viracept see nelfinaivr; it comprises that the hydroxy functional group that makes the viracept see nelfinaivr molecule and amino acid or its acylated derivatives react under the ester formation condition; and separate its product, give and described product to described patient.

60. a method for the treatment of the AIDS that mammal causes by HIV, it comprise to the described mammal of this treatment of needs give with treatment go up effective dose according to each described compound of claim 50-55.

61. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA ₁Connect by ester bond, and do not have the amino acid residue of hydroxyl, and have only hydroxyl on its side chain, be connected by amido link with AA, and be not have amino amino acid residue.

62. according to the compound of claim 61, wherein AA and AA ₁It is naturally occurring L-a-amino acid alone.

63. compound according to claim 61, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Thr, Ser, Tyr or hydroxyproline.

64. according to the compound of claim 61, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine, and AA ₁Be Thr, Ser or hydroxyproline.

65. according to the compound of claim 61, wherein AA or AA ₁Be serine or hydroxyproline.

66. according to the compound of claim 61, wherein AA or AA ₁It is hydroxyproline.

67. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 61-66 and its a kind of pharmaceutically acceptable carrier.

68. a treatment needs a kind of method of the patient of flavoxate treatment, it comprise to described patient give with the treatment effective dose according to each described compound of claim 61-66.

69. a method that increases flavoxate solvability in the aqueous solution, it comprises that the carboxylic acid functional that makes the flavoxate molecule and amino acid or its acylated derivatives react under ester or acid amides formation condition, and separates its product.

70. method that to patient's administration the time, increases the bioavilability of flavoxate; it comprises that the carboxylic acid functional that makes the flavoxate molecule and amino acid or its acylated derivatives react under ester or acid amides formation condition; and separate its product and give and described product to described patient.

71. a method for the treatment of mammal uropoiesis spasm, it comprise to the described mammal of needs treatments give with the treatment effective dose according to each described compound of claim 61-66.

72. a following formula: compound, or its pharmaceutically acceptable salt:

Candesartan Cilexetil

Wherein R is NH-AA ₁Or O-AA, be connected by amido link with AA, and be not have amino amino acid residue on main chain or the side chain, and AA ₁Be the amino acid residue that does not have hydroxyl, and on its side chain, have hydroxyl.

73. according to the compound of claim 72, wherein AA ₁Be Ser, Try or Tyr or hydroxyproline.

74. according to the compound of claim 72, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

75. according to the compound of claim 72, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine, or AA ₁Be serine, threonine or hydroxyproline.

76. according to the compound of claim 72, wherein AA or AA ₁Or serine or hydroxyproline.

77. according to the compound of claim 72, wherein AA or AA ₁It is hydroxyproline.

78. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 72-77 and its pharmaceutically acceptable carrier.

79. a treatment needs a kind of method of the patient of Candesartan treatment, the method comprise on described patient's drug treatment effective dose according to each described compound of claim 72-77.

80. a method that increases Candesartan solvability in the aqueous solution, it comprises the carboxylic acid functional of Candesartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

81. method that to patient's administration the time, increases the bioavilability of Candesartan; it comprises the carboxylic acid functional of Candesartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product, give and described product to described patient.

82. a treatment mammal hypertensive method, it comprise to the described mammal of needs treatment give with the treatment effective dose according to each described compound of claim 72-77.

83. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is the amino acid that does not have hydroxyl on its carboxyl.

84. 3 compound according to Claim 8, wherein AA is a kind of naturally occurring L-amino acid.

85. 3 compound according to Claim 8, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

86. 3 compound according to Claim 8, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

87. 3 compound according to Claim 8, wherein AA is Lys, Gly or proline.

88. 3 compound according to Claim 8, wherein AA is a proline.

89. a pharmaceutical composition, it comprises each described compound of 3-88 according to Claim 8 and its pharmaceutically acceptable carrier for the treatment of effective dose.

90. a treatment needs the patient's of Propofol treatment method, the method comprises each described compound of 3-88 according to Claim 8 of effective dose on described patient's drug treatment.

91. the method that the safety that increases the long anaesthetic effect of Propofol in the aqueous solution distributes, it comprises the hydroxy functional group of Propofol molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

92. a method that increases the bioavilability of Propofol to patient's administration the time, it comprises the hydroxy functional group of Propofol molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product, to described patient to and described product.

93. a method that provides central nervous system to anaesthetize to the patient, it comprises each described compound of 3-88 according to Claim 8 of giving and treating effective dose to the patient of this anesthesia of needs.

94. a following formula: compound, or its pharmaceutically acceptable salt:

The Amlodipine Nisoldipine

R ₂Be

R ₄Be NH-AA ₁Or O-AA,

R ₅Be AA ₂,

Wherein AA is the amino acid residue that does not have hydroxyl that is connected by ester bond, and it has hydroxyl on side chain,

AA ₁Be not have amino amino acid residue,

AA ₂Be the amino acid residue that on carboxyl, does not have hydroxyl,

AA ₃It is the amino acid residue that on amino, does not have hydrogen atom.

95. according to the compound of claim 94, wherein AA, AA ₁, AA ₂And AA ₃It is naturally occurring L-a-amino acid alone.

96. according to the compound of claim 94, wherein AA ₁, AA ₂And AA ₃Be alone the residue of Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, and AA is Ser, Thr, hydroxyproline or Tyr.

97. according to the compound of claim 94, wherein AA ₁, AA ₂And AA ₃It is alone the residue of proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

98. according to the compound of claim 94, wherein AA, AA ₁, AA ₂And AA ₃It is alone the amino acid residue of serine or hydroxyproline.

99. according to the compound of claim 94, wherein AA, AA ₁, AA ₂And AA ₃It is alone the amino acid residue of hydroxyproline.

100. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 94-99 and its pharmaceutically acceptable carrier.

101. a treatment needs the patient's of calcium channel blocker treatment method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 94-100.

102. method that increases calcium channel blocker solvability in the aqueous solution; described calcium channel blocker is selected from Amlodipine or Nisoldipine; described method comprises reacts the carboxylic acid functional of calcium channel blocking agent molecule and amino acid or its acylated derivatives under ester or acid amides formation condition, and separates its product.

103. method that to patient's administration the time, increases the bioavilability of calcium channel blocker; described calcium channel blocker is selected from Amlodipine or Nisoldipine; described method comprises reacts the carboxylic acid functional of calcium ion channel blocker molecule and amino acid or its acylated derivatives under ester or acid amides formation condition; and separate its product and give and described product to described patient.

104. a treatment mammal hypertensive method, comprise to the mammal of the described treatment of needs give with the treatment effective dose according to each described compound of claim 94-100.

105. a following formula: compound, or its pharmaceutically acceptable salt:

The Ofloxacin Ciprofloxacin

Wherein R is NH-AA or O-AA ₁, wherein AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have hydroxyl, but have hydroxyl on its side chain.

106. according to the compound of claim 105, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

107. compound according to claim 105, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

108. according to the compound of claim 105, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

109. according to the compound of claim 105, wherein AA or AA ₁Be serine or hydroxyproline.

110. according to the compound of claim 105, wherein AA or AA ₁It is hydroxyproline.

111. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 105-109 and its pharmaceutically acceptable carrier.

112. a treatment is by the patient's of infected by microbes infectious disease method, and xacin-series (oxacin) and Ciprofloxacin are poisonous treatments to this microorganism, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 105-109.

113. method that increases quinolone antibiotic solvability in the aqueous solution; described quinolone antibiotic has carboxylic group or acidylate group; described method comprises reacts the carboxylic acid functional of quinolone antibiotic molecule and amino acid or its acylated derivatives under ester or acid amides formation condition, and separates its product.

114. method that to patient's administration the time, increases the antibiotic bioavilability of quinolone; described quinolone antibiotic has carboxylic group or acidylate group; described method comprises reacts the carboxylic acid functional of quinolone antibiotic molecule and amino acid or its acylated derivatives under ester or acid amides formation condition; and separate its product, give and described product to described patient.

115. method for the treatment of the infectious disease that mammal causes by pathogenic microorganisms, and Ofloxacin and Ciprofloxacin are poisonous to described pathogenic microorganisms, and described method comprises to described mammal gives various preparations according to each described use quinolone Antibiotique composition of claim 105-109 with antimicrobial effective amount.

116. a following formula: compound, perhaps pharmaceutically acceptable salt:

Enalapril

Ramipril

Fosinopril Na

Benazepil

Perindopril

Moexipril

Trandolapril

Wherein R is NH-AA or O-AA ₁, and AA do not have amino amino acid residue, and AA ₁Be not have the amino acid residue of OH group and on its side chain, have the OH group.

117. according to the compound of claim 116, wherein AA and AA ₁It is alone naturally occurring L-a-amino acid.

118. compound according to claim 116, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be hydroxyproline, Tyr or Ser or Thr.

119. according to the compound of claim 116, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine, or AA ₁Be serine, hydroxyproline or Thr.

120. according to the compound of claim 116, wherein AA or AA ₁Be alone serine or hydroxyproline.

121. according to the compound of claim 116, wherein AA or AA ₁It is hydroxyproline.

122. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 116-121 and its pharmaceutically acceptable carrier.

123. a method for the treatment of the hyperpietic, it comprise to described patient give with the treatment effective dose according to each described compound of claim 116-121.

124. method that increases ace inhibitor solvability in the aqueous solution; described ace inhibitor has carboxyl or acidylate group; described method comprises reacts the carboxylic acid functional of ace inhibitor molecules and amino acid or its acylated derivatives under ester or acid amides formation condition, and separates its product.

125. method that to patient's administration the time, increases the bioavilability of ace inhibitor; described ace inhibitor has carboxyl or acidylate group; described method comprises reacts the carboxylic acid functional of ace inhibitor molecules and amino acid or its acylated derivatives under ester or acid amides formation condition; and separate its product and give and described product to described patient.

126. a following formula: compound, or its pharmaceutically acceptable salt:

Nasmil

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on its carboxyl, and R is an ethyl.

127. according to the compound of claim 126, wherein AA is naturally occurring L-a-amino acid.

128. according to the compound of claim 126, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

129. according to the compound of claim 126, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

130. according to the compound of claim 126, wherein AA is Lys or hydroxyproline.

131. according to the compound of claim 126, wherein AA is Lys.

132. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 126-131 and its pharmaceutically acceptable carrier.

133. a treatment needs the patient's of nasmil treatment method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 126-131.

134. a method that increases nasmil solvability in the aqueous solution, it comprises the hydroxy functional group of nasmil molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

135. method that to patient's administration the time, increases the bioavilability of nasmil; it comprises the hydroxy functional group of nasmil molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product, to the described product of described patient's administration.

136. a following formula: compound, or its pharmaceutically acceptable salt:

The Amoxicillin

Cefuroxime

Cefotaxime

Cefpodoxime

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described OH group, and on its side chain, have the OH group.

137. according to the compound of claim 136, wherein AA and AA ₁It is alone naturally occurring L-a-amino acid.

138. compound according to claim 136, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Ser, Thr, Tyr or hydroxyproline.

139. according to the compound of claim 136, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

140. according to the compound of claim 136, wherein AA or AA ₁Be serine or hydroxyproline.

141. according to the compound of claim 136, wherein AA or AA ₁It is hydroxyproline.

142. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 136-141 and its pharmaceutically acceptable carrier.

143. a treatment is by the patient's of infected by microbes method, and Amoxicillin, cefuroxime, cefotaxime and Cefpodoxime (ceftazidime) are poisonous to this microorganism, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 136-141.

144. method that increases cephalosporin antibiotics solvability in the aqueous solution; described cephalosporin antibiotics has carboxylic acid functional; described method comprises reacts the carboxylic acid functional of cynnematin antibiotic molecule and amino acid or its acylated derivatives under ester or acid amides formation condition, and separates its product.

145. method that to patient's administration the time, increases the bioavilability of cephalosporin antibiotics; described cephalosporin antibiotics has a carboxylic acid functional; described method comprises that the carboxylic acid functional that makes the cephalosporin antibiotics molecule and amino acid or its acylated derivatives react under ester or acid amides formation condition; and separate its product, give and described product to described patient.

146. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

147. according to the compound of claim 146, wherein AA is naturally occurring L-a-amino acid.

148. according to the compound of claim 146, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

149. according to the compound of claim 146, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

150. according to the compound of claim 146, wherein AA is Lys or hydroxyproline.

151. according to the compound of claim 146, wherein AA is Lys.

152. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 146-151 and its pharmaceutically acceptable carrier.

153. the method for the mammiferous malaria that causes by the plasmodium parasite of treatment, it comprise to described patient give with the treatment effective dose according to each described compound of claim 146-151.

154. a method that increases Atovaquone solvability in the aqueous solution, it comprises the hydroxy functional group of Atovaquone molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

155. method that to patient's administration the time, increases the bioavilability of Atovaquone; it comprises the hydroxy functional group of Atovaquone molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product, give and described product to described patient.

156. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

157. according to the compound of claim 156, wherein AA is the naturally occurring a-amino acid of L-.

158. compound according to claim 156, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, condition is for when described medicine is aciclovir, and AA is not Ala or Gly so.

159. according to the compound of claim 156, wherein AA is proline, lysine, hydroxyproline or alanine.

160. according to the compound of claim 156, wherein AA is Lys or proline.

161. according to the compound of claim 156, wherein AA is Lys.

162. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 156-161 and its pharmaceutically acceptable carrier.

163. a treatment suffers from the patient's of human cytomegalovirus method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 156-161.

164. an increase has the method for nucleoside analog solvability in the aqueous solution of OH functional group, it comprises the hydroxy functional group of nucleoside analog molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

165. method that to patient's administration the time, increases the bioavilability of nucleoside analog with OH functional group; it comprises the hydroxy functional group of nucleoside analog molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

166. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described OH group, and on its side chain, have the OH group.

167. according to the compound of claim 166, wherein AA and AA ₁It is alone naturally occurring L-a-amino acid.

168. compound according to claim 166, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Thr, Ser or hydroxyproline.

169. according to the compound of claim 166, wherein AA is alanine, proline, glycine, lysine, serine, threonine or hydroxyproline.

170. according to the compound of claim 166, wherein AA or AA ₁Or serine or hydroxyproline.

171. according to the compound of claim 166, wherein AA or AA ₁It is hydroxyproline.

172. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 166-171, and pharmaceutically acceptable carrier.

173. a method that reduces mammal body lipid concentration, it comprise to described patient give with the treatment effective dose according to each described compound of claim 166-171.

174. a method that increases nicotinic acid solvability in the aqueous solution, it comprises the carboxylic acid functional of nicotinic acid molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

175. method that to patient's administration the time, increases the bioavilability of nicotinic acid; it comprises the carboxylic acid functional of nicotinic acid molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product, give and described product to described patient.

176. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described OH group, and on its side chain, have the OH group.

177. according to the compound of claim 176, wherein AA and AA ₁It is alone naturally occurring L-a-amino acid.

178. compound according to claim 176, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

179. according to the compound of claim 176, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

180. according to the compound of claim 176, wherein AA or AA ₁Be serine or hydroxyproline.

181. according to the compound of claim 176, wherein AA or AA ₁It is hydroxyproline.

182. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 176-181 and its pharmaceutically acceptable carrier.

183. an a kind of method for the treatment of the dermatosis patient that need to activate retinoid X acceptor, the method comprise to described patient give with the treatment effective dose according to each described compound of claim 176-181.

184. a method that increases retinene solvability in the aqueous solution, it comprises the carboxylic acid functional of retinene molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

185. method that to patient's administration the time, increases the bioavilability of retinene; it comprises the carboxylic acid functional of retinene molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product, give and described product to described patient.

186. a following formula: compound, or its pharmaceutically acceptable salt:

The third oxygen sweet smell

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

187. according to the compound of claim 186, wherein AA is naturally occurring L-a-amino acid.

188. according to the compound of claim 186, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

189. according to the compound of claim 186, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

190. according to the compound of claim 186, wherein AA is Lys or hydroxyproline.

191. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 186-190 and its pharmaceutically acceptable carrier.

192. a method for the treatment of mammal pain, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 186-190.

193. a method that increases by third oxygen sweet smell solvability in the aqueous solution, it comprises the hydroxy functional group of the fragrant molecule of third oxygen and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

194. method that to patient's administration the time, increases the bioavilability of the third oxygen sweet smell; it comprises the hydroxy functional group of the fragrant molecule of third oxygen and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

195. a following formula: compound, or its pharmaceutically acceptable salt:

Salsalate

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have hydroxyl, and on its side chain, have hydroxyl.

196. according to the compound of claim 195, wherein AA and AA ₁It is alone naturally occurring L-a-amino acid.

197. compound according to claim 195, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

198. according to the compound of claim 195, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

199. according to the compound of claim 195, wherein AA is Lys or hydroxyproline.

200. according to the compound of claim 195, wherein AA is Lys.

201. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 195-200 and its pharmaceutically acceptable carrier.

202. a method for the treatment of patient's inflammation, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 195-200.

203. a method that increases salsalate solvability in the aqueous solution, it comprises the hydroxy functional group of salsalate molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

204. method that to patient's administration the time, increases the bioavilability of salsalate; it comprises the hydroxy functional group of salsalate molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

205. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is the amino acid residue that does not have hydroxyl on carboxyl.

206. according to the compound of claim 205, wherein AA is naturally occurring L-a-amino acid.

207. according to the compound of claim 205, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

208. according to the compound of claim 205, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

209. according to the compound of claim 205, wherein AA is Lys or proline.

210. according to the compound of claim 205, wherein AA is a proline.

211. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 205-209 and its pharmaceutically acceptable carrier.

212. a treatment suffers from the method for pain or fever, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 205-209.

213. a method that increases paracetamol solvability in the aqueous solution, it comprises the hydroxy functional group of paracetamol molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

214. method that to patient's administration the time, increases the bioavilability of paracetamol; it comprises the hydroxy functional group of paracetamol molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

215. a following formula: compound, or its pharmaceutically acceptable salt:

Brufen

Wherein R is NH-AA or O-AA ₁, AA does not have an amino amino acid residue on it, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

216. according to the compound of claim 215, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

217. compound according to claim 215, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA1 is Thr, Ser, Tyr or hydroxyproline.

218. according to the compound of claim 215, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

219. according to the compound of claim 215, wherein AA or AA ₁Be serine or hydroxyproline.

220. according to the compound of claim 215, wherein AA or AA ₁It is hydroxyproline.

221. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 215-220 and its pharmaceutically acceptable carrier.

222. a method for the treatment of patient's pain, fever or inflammation, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 215-220.

223. a method that increases brufen solvability in the aqueous solution, it comprises the carboxylic acid functional of brufen molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

224. method that to patient's administration the time, increases the bioavilability of brufen; it comprises the carboxylic acid functional of brufen molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

225. method that reduces the brufen gastric irritation; it comprises the carboxylic acid functional of brufen molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product; with give and described product to patient that it is needed, described product to the stimulation of stomach less than brufen.

226. a following formula: compound, or its pharmaceutically acceptable salt:

Simvastatin

Pravastatin

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

227. according to the compound of claim 226, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

228. compound according to claim 226, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA1 is Tyr, Ser, Thr or hydroxyproline.

229. according to the compound of claim 226, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

230. according to the compound of claim 226, wherein AA or AA ₁Be serine or hydroxyproline.

231. according to the compound of claim 226, wherein AA or AA ₁It is hydroxyproline.

232. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 226-231 and its pharmaceutically acceptable carrier.

233. one kind is reduced the method for cholesterol concentration that the mammal that needs treatment needs the patient of Si Dating class pharmacotherapy, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 226-231.

234. a following formula: compound, or its pharmaceutically acceptable salt:

Nadolol

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

235. according to the compound of claim 234, wherein AA is naturally occurring L-a-amino acid.

236. according to the compound of claim 234, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

237. according to the compound of claim 234, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

238. according to the compound of claim 234, wherein AA is Lys or hydroxyproline.

239. according to the compound of claim 234, wherein AA is Lys.

240. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 234-239 and pharmaceutically acceptable carrier thereof.

241. a treatment suffers from the patient's of angina pectoris of being selected from and high blood pressure disease method, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 234-239.

242. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

243. according to the compound of claim 242, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

244. compound according to claim 242, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Ser, Thr, Tyr or hydroxyproline.

245. according to the compound of claim 242, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

246. according to the compound of claim 242, wherein AA or AA ₁Be serine or hydroxyproline.

247. according to the compound of claim 242, wherein AA or AA ₁It is hydroxyproline.

248. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 242-247 and its pharmaceutically acceptable carrier.

249. a method for the treatment of the hyperpietic, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 242-247.

250. a method that increases Valsartan solvability in the aqueous solution, it comprises the carboxylic acid functional of Valsartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

251. method that to patient's administration the time, increases the bioavilability of Valsartan; it comprises the carboxylic acid functional of Valsartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product, give and described product to described patient.

252. a following formula: compound, or its pharmaceutically acceptable salt:

Methylphenidate

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have a hydroxyl.

253. according to the compound of claim 252, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

254. compound according to claim 252, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

255. according to the compound of claim 252, wherein AA is proline, glycine, bad ammonia, serine, threonine, hydroxyproline or alanine.

256. according to the compound of claim 252, wherein AA or AA ₁Be serine or hydroxyproline.

257. according to the compound of claim 252, wherein AA or AA ₁It is hydroxyproline.

258. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 252-257 and its pharmaceutically acceptable carrier.

259. a treatment suffers from the method for attention deficit disorder and hypnolepsy disease, described method comprise to the described patient of this treatment of needs give with the treatment effective dose according to each described compound of claim 252-257.

260. a method that increases methylphenidate solvability in the aqueous solution, it comprises that the carboxylic acid functional that makes the methylphenidate molecule and amino acid or its acylated derivatives react under ester or acid amides formation condition, and separates its product.

261. method that to patient's administration the time, increases the bioavilability of methylphenidate; it comprises the carboxylic acid functional of methylphenidate molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product, give and described product to described patient.

262. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

263. according to the compound of claim 262, wherein AA is naturally occurring L-a-amino acid.

264. according to the compound of claim 262, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

265. according to the compound of claim 262, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

266. according to the compound of claim 262, wherein AA is Lys or hydroxyproline.

267. according to the compound of claim 262, wherein AA is Lys.

268. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 262-267 and its pharmaceutically acceptable carrier.

269. a treatment is by the method for tissue damage, infection, allergy or self-inflammation that immunological diseases cause, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 262-267.

270. a method that increases methylprednisolone solvability in the aqueous solution, it comprises that the hydroxy functional group that makes the methylprednisolone molecule and amino acid or its acylated derivatives react under the ester formation condition, and separates its product.

271. method that to patient's administration the time, increases the bioavilability of methylprednisolone; it comprises that the hydroxy functional group that makes the methylprednisolone molecule and amino acid or its acylated derivatives react under the ester formation condition; and separate its product, give and described product to described patient.

272. a compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

273. according to the compound of claim 272, wherein AA is naturally occurring L-a-amino acid.

274. according to the compound of claim 272, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

275. according to the compound of claim 272, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

276. according to the compound of claim 272, wherein AA is Lys or hydroxyproline.

277. according to the compound of claim 272, wherein AA is Lys.

278. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 272-277 and its pharmaceutically acceptable carrier.

279. one kind makes patient's method of contraception, this method comprise to described patient give with treatment go up effective dose according to each described compound of claim 272-277.

280. a method that increases Medroxyprogesterone solvability in the aqueous solution, it comprises the hydroxy functional group of Medroxyprogesterone molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

281. method that to patient's administration the time, increases the bioavilability of Medroxyprogesterone; it comprises the hydroxy functional group of Medroxyprogesterone molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

282. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that removes the OH group on carboxyl.

283. according to the compound of claim 282, wherein AA is a kind of a-amino acid.

284. according to the compound of claim 282, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

285. according to the compound of claim 282, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

286. according to the compound of claim 282, wherein AA is Lys or hydroxyproline.

287. according to the compound of claim 282, wherein AA is Lys.

288. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 282-287 and its pharmaceutically acceptable carrier.

289. a treatment needs the patient's of Estramustine treatment method, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 282-287.

290. a method that increases Estramustine solvability in the aqueous solution, it comprises the hydroxy functional group of Estramustine molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

291. a following formula: compound, or its pharmaceutically acceptable salt:

Miglitol

Wherein AA is connected by ester bond and is the amino acid residue that does not have the OH group on carboxyl.

292. according to the compound of claim 291, wherein AA is naturally occurring L-a-amino acid.

293. according to the compound of claim 291, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

294. according to the compound of claim 291, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

295. according to the compound of claim 291, wherein AA is Lys or hydroxyproline.

296. according to the compound of claim 291, wherein AA is Lys.

297. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 291-296 and its pharmaceutically acceptable carrier.

298. a method for the treatment of the type ii diabetes patient, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 291-296.

299. a method that increases Miglitol solvability in the aqueous solution, it comprises the hydroxy functional group of Miglitol molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

300. method that to patient's administration the time, increases the bioavilability of Miglitol; it comprises the hydroxy functional group of Miglitol molecule and amino acid or its acylated derivatives is reacted in the ester formation condition; and separate its product and give and described product to described patient.

301. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have the OH group on carboxyl.

302. according to the compound of claim 301, wherein AA is a kind of naturally occurring L-a-amino acid.

303. according to the compound of claim 301, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

304. according to the compound of claim 301, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

305. according to the compound of claim 301, wherein AA is Lys or hydroxyproline.

306. according to the compound of claim 301, wherein AA is Lys.

307. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 301-306 and its pharmaceutically acceptable carrier.

308. a method for the treatment of malaria patients, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 301-306.

309. a method that increases Mefloquine solvability in the aqueous solution, it comprises the hydroxy functional group of Mefloquine molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

310. method that to patient's administration the time, increases the bioavilability of Mefloquine; it comprises the hydroxy functional group of Mefloquine molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

311. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA forms ester bond and is the amino acid residue that does not have the OH group on carboxyl.

312. according to the compound of claim 311, wherein AA is a kind of naturally occurring L-a-amino acid.

313. according to the compound of claim 311, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

314. according to the compound of claim 311, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

315. according to the compound of claim 311, wherein AA is Lys or hydroxyproline.

316. according to the compound of claim 311, wherein AA is Lys.

317. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 311-315 and its pharmaceutically acceptable carrier.

318. a treatment suffers from endometriosis patient's method, this method comprise to described patient give with the treatment effective dose according to each described compound of claim 311-315.

319. an increase reaches the method for that azoles solvability in the aqueous solution, it comprises and reacting under the ester formation condition reaching the hydroxy functional group of that azoles molecule and amino acid or its acylated derivatives, and separates its product.

320. method that to patient's administration the time, increases the bioavilability that reaches that azoles; it comprises and reacting under the ester formation condition reaching the hydroxy functional group of that azoles molecule and amino acid or its acylated derivatives; and separate its product and give and described product to described patient.

321. a following formula: compound, or its pharmaceutically acceptable salt:

Eprosartan

Wherein R or NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

322. according to the compound of claim 321, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

323. compound according to claim 321, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

324. according to the compound of claim 321, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

325. according to the compound of claim 321, wherein AA or AA ₁Be serine or hydroxyproline.

326. according to the compound of claim 321, wherein AA or AA ₁It is hydroxyproline.

327. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 321-326 and its pharmaceutically acceptable carrier.

328. a treatment needs the patient's of Eprosartan treatment method, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 321-326.

329. a method that increases Eprosartan solvability in the aqueous solution, it comprises the carboxylic acid functional of Eprosartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

330. method that to patient's administration the time, increases the bioavilability of Eprosartan; it comprises the carboxylic acid functional of Eprosartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

331. a following formula: compound, or its pharmaceutically acceptable salt:

Valproic acid

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

332. according to the compound of claim 331, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

333. compound according to claim 331, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Thr, Ser, Tyr or hydroxyproline.

334. according to the compound of claim 331, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

335. according to the compound of claim 331, wherein AA or AA ₁Be serine or hydroxyproline.

336. according to the compound of claim 331, wherein AA or AA ₁It is hydroxyproline.

337. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 331-336 and its pharmaceutically acceptable carrier.

338. a treatment suffers from the patient's of epilepsy method, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 331-336.

339. a method that increases divalproex sodium solvability in the aqueous solution, it comprises the carboxylic acid functional of divalproex sodium molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

340. method that to patient's administration the time, increases the bioavilability of divalproex sodium; it comprises the carboxylic acid functional of divalproex sodium molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

341. a following formula: compound, or its pharmaceutically acceptable salt:

Fenofibrate

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

342. according to the compound of claim 341, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

343. compound according to claim 341, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Thr, Ser, Tyr or hydroxyproline.

344. according to the compound of claim 341, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

345. according to the compound of claim 341, wherein AA or AA ₁Be serine or hydroxyproline.

346. according to the compound of claim 341, wherein AA or AA ₁It is hydroxyproline.

347. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 341-346 and its pharmaceutically acceptable carrier.

348. a treatment needs the patient's of fenofibrate treatment method, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 341-346.

349. a method that increases fenofibrate solvability in the aqueous solution, it comprises the carboxylic acid functional of fenofibrate molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

350. method that to patient's administration the time, increases the bioavilability of fenofibrate; it comprises the carboxylic acid functional of fenofibrate molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

351. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

352. according to the compound of claim 351, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

353. compound according to claim 351, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Thr, Ser, Tyr or hydroxyproline.

354. according to the compound of claim 351, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

355. according to the compound of claim 351, wherein AA or AA ₁Be serine or hydroxyproline.

356. according to the compound of claim 351, wherein AA or AA ₁Be hydroxyproline or tyrosine.

357. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 351-356 and its pharmaceutically acceptable carrier.

358. a treatment needs the patient's of Gabapentin treatment method, described method comprise to described patient treat effective dose according to each described compound of claim 351-356.

359. a method that increases Gabapentin solvability in the aqueous solution, it comprises the carboxylic acid functional of Gabapentin molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

360. method that to patient's administration the time, increases the bioavilability of Gabapentin; it comprises the carboxylic acid functional of Gabapentin molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give described product to described patient.

361. a following formula: compound, or its pharmaceutically acceptable salt:

Omeprazole

Lansoprazole

Wherein AA is connected by amino key and is the amino acid residue that does not have hydroxyl on carboxyl.

362. according to the compound of claim 361, wherein AA is naturally occurring L-a-amino acid.

363. according to the compound of claim 361, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

364. according to the compound of claim 361, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

365. according to the compound of claim 361, wherein AA is serine or hydroxyproline.

366. according to the compound of claim 361, wherein AA is a hydroxyproline.

367. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 361-366 and pharmaceutically acceptable carrier.

368. a method for the treatment of the hyperhydrochloria patient, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 361-366.

369. a method that increases proton pump inhibitor solvability in the aqueous solution, it comprises the amido functional group of proton pump inhibitor molecule carboxylic moiety amino acid whose with it is reacted under the acid amides formation condition, and separates its product.

370. method that to patient's administration the time, increases the bioavilability of proton pump inhibitor, it comprises the amido functional group of proton pump inhibitor molecule carboxylic moiety amino acid whose with it is reacted under the acid amides formation condition, and separate its product and give and described product to described patient.

371. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

372. according to the compound of claim 371, wherein AA is a kind of naturally occurring L-a-amino acid.

373. according to the compound of claim 371, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

374. according to the compound of claim 371, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

375. according to the compound of claim 371, wherein AA is Lys or hydroxyproline.

376. according to the compound of claim 371, wherein AA is Lys.

377. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 371-376 and its pharmaceutically acceptable carrier.

378. a method that needs the treatment apositia patient of megestrol acetate treatment, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 371-376.

379. a method that increases megestrol acetate solvability in the aqueous solution, it comprises the hydroxy functional group of megestrol acetate molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

380. method that to patient's administration the time, increases the bioavilability of megestrol acetate; it comprises the hydroxy functional group of megestrol acetate molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

381. a following formula: compound, or its pharmaceutically acceptable salt:

Melbine

Wherein R is CO-AA, and AA is connected by amido link and is the amino acid residue that does not have carboxyl.

382. according to the compound of claim 381, wherein AA is naturally occurring L-a-amino acid.

383. according to the compound of claim 381, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

384. according to the compound of claim 381, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

385. according to the compound of claim 381, wherein AA is serine or hydroxyproline.

386. according to the compound of claim 381, wherein AA is a hydroxyproline.

387. a pharmaceutical composition, comprise the treatment effective dose according to each described compound of claim 381-386 and its pharmaceutically acceptable carrier.

388. a method for the treatment of the hyperglycemia patient, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 381-386.

389. a method that increases melbine solvability in the aqueous solution, it comprises the amido functional group of melbine molecule carboxylic moiety amino acid whose with it is reacted under the acid amides formation condition, and separates its product.

390. method that to patient's administration the time, increases the bioavilability of melbine, it comprises the amido functional group of melbine molecule carboxylic moiety amino acid whose with it is reacted under the acid amides formation condition, and separate its product and give and described product to described patient.

391. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

392. according to the compound of claim 391, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

393. compound according to claim 391, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

394. according to the compound of claim 391, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

395. according to the compound of claim 391, wherein AA or AA ₁Be serine or hydroxyproline.

396. according to the compound of claim 391, wherein AA or AA ₁It is hydroxyproline.

397. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 391-396 and its pharmaceutically acceptable carrier.

398. a method for the treatment of psoriasis and patients with acne, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 391-396.

399. a method that increases tazarotene solvability in the aqueous solution, it comprises the carboxylic acid functional of tazarotene molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

400. method that to patient's administration the time, increases the bioavilability of tazarotene; it comprises the carboxylic acid functional of tazarotene molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

401. a following formula: compound, or its pharmaceutically acceptable salt:

Sumatriptan

Zomitriptan

Wherein R is CO-AA, and AA is connected by amido link and is the amino acid residue that does not have carboxyl.

402. according to the compound of claim 401, wherein AA is naturally occurring L-a-amino acid.

403. according to the compound of claim 401, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

404. according to the compound of claim 401, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

405. according to the compound of claim 401, wherein AA is serine or hydroxyproline.

406. according to the compound of claim 401, wherein AA is a hydroxyproline.

407. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 401-406 and its pharmaceutically acceptable carrier.

408. the treatment migraineur's of needs treatment method, described method comprise to described patient treatment treatment effective dose according to each described compound of claim 401-406.

409. one kind increases the optionally method of 5-HT receptor potentiators solvability in the aqueous solution, it comprises the amido functional group carboxylic moiety amino acid whose with it of 5-HT receptor potentiators molecule is optionally reacted under the acid amides formation condition, and separates its product.

410. one kind increases the optionally method of the bioavilability of 5-HT receptor potentiators to patient's administration the time, it comprises the amido functional group carboxylic moiety amino acid whose with it of 5-HT receptor potentiators molecule is optionally reacted under the acid amides formation condition, and separate its product and give and described product to described patient.

411. a following formula: compound, or its pharmaceutically acceptable salt:

Aspirin

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be not have described hydroxyl and the amino acid residue that on side chain, has hydroxyl.

412. according to the compound of claim 411, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

413. compound according to claim 411, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

414. according to the compound of claim 411, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

415. according to the compound of claim 411, wherein AA or AA ₁Be serine or hydroxyproline.

416. according to the compound of claim 411, wherein AA or AA ₁It is hydroxyproline.

417. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 411-416 and its pharmaceutically acceptable carrier.

418. a method that increases aspirin solvability in the aqueous solution, it comprises the carboxylic acid functional of aspirin molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

419. method that to patient's administration the time, increases the bioavilability of aspirin; it comprises the carboxylic acid functional of aspirin molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

420. a minimizing is by the method for the gastrointestinal stimulation that causes to the administration aspirin; it comprises the carboxylic acid functional of aspirin molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; give and formed product to described mammal, wherein said product is littler to gastric irritation with respect to aspirin.

421. a following formula: compound, or its pharmaceutically acceptable salt:

Olmesartan

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

422. according to the compound of claim 421, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

423. compound according to claim 421, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

424. according to the compound of claim 421, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

425. according to the compound of claim 421, wherein AA or AA ₁Be serine or hydroxyproline.

426. according to the compound of claim 421, wherein AA or AA ₁It is hydroxyproline.

427. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 421-426 and its pharmaceutically acceptable carrier.

428. the treatment hyperpietic's of the described treatment of needs method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 421-426.

429. a method that increases Olmesartan solvability in the aqueous solution, it comprises the carboxylic acid functional of Olmesartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

430. method that to patient's administration the time, increases the bioavilability of Olmesartan; it comprises the carboxylic acid functional of Olmesartan molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

431. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is connected by ester bond and is the amino acid residue that does not have hydroxyl on carboxyl.

432. according to the compound of claim 431, wherein AA is a kind of naturally occurring L-a-amino acid.

433. according to the compound of claim 431, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

434. according to the compound of claim 431, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

435. according to the compound of claim 431, wherein AA is Lys or hydroxyproline.

436. according to the compound of claim 431, wherein AA is Lys.

437. a pharmaceutical composition, it comprise the treatment effective dose according to the described compound of claim 431 and its pharmaceutically acceptable carrier.

438. a treatment needs the patient's of immunosuppressant treatment method, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 431-436.

439. a method that increases immunodepressant solvability in the aqueous solution, it comprises the hydroxy functional group of immunosupress agent molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

440. method that to patient's administration the time, increases the bioavilability of immunodepressant; it comprises the hydroxy functional group of immunosupress agent molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

441. a following formula: compound, or its pharmaceutically acceptable salt:

Clopidogrel

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

442. according to the compound of claim 441, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

443. compound according to claim 441, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

444. according to the compound of claim 441, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

445. according to the compound of claim 441, wherein AA or AA ₁Be serine or hydroxyproline.

446. according to the compound of claim 441, wherein AA or AA ₁It is hydroxyproline.

447. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 441-446 and its pharmaceutically acceptable carrier.

448. a method for the treatment of cardiac muscle of mammal infraction, it comprise to the mammal of its needs is given with treatment on effective dose according to each described compound of claim 441-446.

449. a method that increases clopidogrel solvability in the aqueous solution, it comprises the carboxylic acid functional of clopidogrel molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

450. method that to patient's administration the time, increases the bioavilability of clopidogrel; it comprises the carboxylic acid functional of clopidogrel molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

451. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

452. according to the compound of claim 451, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

453. compound according to claim 451, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

454. according to the compound of claim 451, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

455. according to the compound of claim 451, wherein AA or AA ₁Be serine or hydroxyproline.

456. according to the compound of claim 451, wherein AA or AA ₁It is hydroxyproline.

457. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 451-456 and its pharmaceutically acceptable carrier.

458. a treatment needs the patient's of amphotericin B treatment method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 451-456.

459. a method that increases amphotericin B solvability in the aqueous solution, it comprises the carboxylic acid functional of amphotericin B molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

460. method that to patient's administration the time, increases the bioavilability of amphotericin B; it comprises the carboxylic acid functional of amphotericin B molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

461. a following formula: compound and its pharmaceutically acceptable salt

Wherein R is O-AA, and AA is connected by ester bond and is the amino acid residue that does not have the OH group on carboxyl.

462. according to the compound of claim 461, wherein AA is naturally occurring L-a-amino acid.

463. according to the compound of claim 461, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

464. according to the compound of claim 461, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

465. according to the compound of claim 461, wherein AA is serine or hydroxyproline.

466. according to the compound of claim 461, wherein AA is a hydroxyproline.

467. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 461-466 and its pharmaceutically acceptable carrier.

468. a treatment needs the patient's of tenofovir treatment method, described method comprise to described patient's administering therapeutic effective dose according to each described compound of claim 461-466.

469. a method that increases tenofovir solvability in the aqueous solution, it comprises the phosphoric acid functional group of tenofovir molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

470. method that to patient's administration the time, increases the bioavilability of tenofovir; comprise the phosphoric acid functional group of tenofovir molecule and amino acid or its acylated derivatives are reacted under the ester formation condition; and separate its product and give and described product to described patient.

471. a following formula: compound, or its pharmaceutically acceptable salt:

Unoprostone

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

472. according to the compound of claim 471, wherein AA and AA ₁It is alone naturally occurring L-a-amino acid.

473. compound according to claim 471, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

474. according to the compound of claim 471, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

475. according to the compound of claim 471, wherein AA or AA ₁Be serine or hydroxyproline.

476. according to the compound of claim 471, wherein AA or AA ₁It is hydroxyproline.

477. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 471-476 and its pharmaceutically acceptable carrier.

478. a method for the treatment of glaucoma patient, it comprise to described patient give with the treatment effective dose according to each described compound of claim 471-476.

479. a method that increases Unoprostone solvability in the aqueous solution, it comprises the carboxylic acid functional of Unoprostone molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

480. method that to patient's administration the time, increases the bioavilability of Unoprostone; it comprises the carboxylic acid functional of Unoprostone molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

481. a following formula: compound, or its pharmaceutically acceptable salt

Wherein AA is connected by ester bond and is the amino acid that does not have OH on carboxyl.

482. according to the compound of claim 481, wherein AA is naturally occurring L-a-amino acid.

483. according to the compound of claim 481, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

484. according to the compound of claim 481, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

485. according to the compound of claim 481, wherein AA is Lys or hydroxyproline.

486. according to the compound of claim 481, wherein AA is Lys.

487. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 481-486 and its pharmaceutically acceptable carrier.

488. a method for the treatment of breast cancer, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 481-486.

489. a method that increases fulvestrant solvability in the aqueous solution, it comprises the hydroxy functional group of fulvestrant molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

490. method that to patient's administration the time, increases the bioavilability of fulvestrant; it comprises the hydroxy functional group of fulvestrant molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

491. a following formula: compound and its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁Be the amino acid residue that does not have described hydroxyl, and on its side chain, have hydroxyl.

492. according to the compound of claim 491, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

493. compound according to claim 491, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Ser, Thr or hydroxyproline.

494. according to the compound of claim 491, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

495. according to the compound of claim 491, wherein AA or AA ₁Be serine or hydroxyproline.

496. according to the compound of claim 491, wherein AA or AA ₁It is hydroxyproline.

497. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 491-496 and its pharmaceutically acceptable carrier.

498. a treatment is subjected to the patient's of infected by microbes method, it comprise to described patient give with the treatment effective dose according to each described compound of claim 491-496.

499. a method that increases Cefditoren solvability in the aqueous solution, it comprises the carboxylic acid functional of Cefditoren molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

500. method that to patient's administration the time, increases the bioavilability of Cefditoren; it comprises the carboxylic acid functional of Cefditoren molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

501. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is CO-AA, and AA is connected by amido link and is the amino acid residue that does not have the OH group on carboxyl.

502. according to the compound of claim 501, wherein AA is naturally occurring L-a-amino acid.

503. according to the compound of claim 501, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

504. according to the compound of claim 501, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

505. according to the compound of claim 501, wherein AA is serine or hydroxyproline.

506. according to the compound of claim 501, wherein AA is a hydroxyproline.

507. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 501-505 and its pharmaceutically acceptable carrier.

508. a method for the treatment of the patient who infects AIDS, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 501-505.

509. a method that increases efavirenz solvability in the aqueous solution, it comprises the amine functional group of efavirenz molecule carboxylic moiety amino acid whose with it is reacted under the acid amides formation condition, and separates its product.

510. method that to patient's administration the time, increases the bioavilability of efavirenz, it comprises the amido functional group of efavirenz molecule carboxylic moiety amino acid whose with it is reacted under the acid amides formation condition, and separate its product and give and described product to described patient.

511. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is NH-AA or O-AA ₁, AA does not have amino amino acid residue, and AA ₁It is the amino acid residue that does not have described hydroxyl and on its side chain, have hydroxyl.

512. according to the compound of claim 511, wherein AA and AA ₁It is naturally occurring L-a-amino acid.

513. compound according to claim 511, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy, or AA ₁Be Tyr, Thr, Ser or hydroxyproline.

514. according to the compound of claim 511, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

515. according to the compound of claim 511, wherein AA or AA ₁Be serine or hydroxyproline.

516. according to the compound of claim 511, wherein AA or AA ₁It is hydroxyproline.

517. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 511-516 and its pharmaceutically acceptable carrier.

518. the hypertensive method of treatment, it comprise to the patient of required treatment give with the treatment effective dose according to each described compound of claim 511-516.

519. a method that increases eplerenone solvability in the aqueous solution, it comprises the carboxylic acid functional of eplerenone molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition, and separates its product.

520. method that to patient's administration the time, increases the bioavilability of eplerenone; it comprises the carboxylic acid functional of eplerenone molecule and amino acid or its acylated derivatives is reacted under ester or acid amides formation condition; and separate its product and give and described product to described patient.

521. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein AA is an amino acid residue that is connected by ester bond.

522. according to the compound of claim 521, wherein AA is naturally occurring L-a-amino acid.

523. according to the compound of claim 521, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

524. according to the compound of claim 521, wherein AA is proline, glycine, lysine, hydroxyproline or alanine.

525. according to the compound of claim 521, wherein AA is Lys or hydroxyproline.

526. according to the compound of claim 521, wherein AA is Lys.

527. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 521-526 and its pharmaceutically acceptable carrier.

528. a treatment needs the cardiovascular related diseases patient's of your treatment of treprostinil method, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 521-526.

529. one kind increases your method of solvability in the aqueous solution of treprostinil, it comprises the hydroxy functional group of your molecule of treprostinil and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

530. method that to patient's administration the time, increases your bioavilability of treprostinil; it comprises the hydroxy functional group of your molecule of treprostinil and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

531. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein R is O-AA, and AA is connected by ester bond and is the amino acid residue that does not have the OH group on carboxyl.

532. according to the compound of claim 531, wherein AA is naturally occurring L-a-amino acid.

533. according to the compound of claim 531, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

534. according to the compound of claim 531, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

535. according to the compound of claim 531, wherein AA is serine or hydroxyproline.

536. according to the compound of claim 531, wherein AA is a hydroxyproline.

537. a pharmaceutical composition, it comprise the treatment effective dose according to each described a kind of compound of claim 531-536 and its pharmaceutically acceptable carrier.

538. a method for the treatment of AIDS patient, described method comprise to described patient give with the treatment effective dose according to each described compound of claim 531-536.

539. a method that increases adefovirdipivoxil solvability in the aqueous solution, it comprises the phosphoric acid functional group of adefovirdipivoxil molecule and amino acid or its acylated derivatives is reacted under the ester formation condition, and separates its product.

540. method that to patient's administration the time, increases the bioavilability of adefovirdipivoxil; it comprises the phosphoric acid functional group of adefovirdipivoxil molecule and amino acid or its acylated derivatives is reacted under the ester formation condition; and separate its product and give and described product to described patient.

541. a following formula: compound, or its pharmaceutically acceptable salt:

R-N＝N-AA ₁-COOH

Sulfo-medicine azo derivative or

R-NH CO-AA-NH ₂

The sulfa drugs amide derivatives

Wherein R is the sulfanilamide (SN) part of general category sulfonamide, AA ₁Be not have amino, also do not have an amino acid residue of carboxyl.

542. according to the compound of claim 541, wherein AA is naturally occurring L-a-amino acid.

543. according to the compound of claim 541, wherein AA is the L-isomer.

544. according to the compound of claim 541, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

545. according to the compound of claim 541, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

546. according to the compound of claim 541, wherein AA is serine or hydroxyproline.

547. according to the compound of claim 541, wherein AA is a hydroxyproline.

548. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 541-547 and its pharmaceutically acceptable carrier.

549. a method that increases sulfa drugs solvability in the aqueous solution, it comprises the amine of sulfa drugs molecule and amino acid or its acylated derivatives is reacted under azo or acid amides formation condition, and separates its product.

550. method that to patient's administration the time, increases the bioavilability of sulfa drugs; it comprises the amido functional group of sulfa drugs molecule and amino acid or its acylated derivatives is reacted under azo or acid amides formation condition; and separate its product and give and described product to described patient.

551. method that the limpid water-soluble intravenous formulations of sulfa drugs is provided to patient's administration the time; it comprises the amine of sulfa drugs molecule and amino acid or its acylated derivatives is reacted under azo or acid amides formation condition; and separate its product and to described patient to give and described product without the enteron aisle mode.

552. method that the appropriate formulation of sulfa drugs is provided to patient's administration the time; it comprises the amido functional group of sulfa drugs molecule and amino acid or its acylated derivatives is reacted under azo or acid amides formation condition; and separate its product and to described patient with per rectum, through skin, contain clothes, transvaginal or give and described product through the mode of nose.

553. a following formula: compound, or its pharmaceutically acceptable salt:

Wherein the chemical constitution of salazine is a 5-aminosalicylic acid, and R ₁Be not have carboxyl and amino amino acid residue.

554. according to the compound of claim 553, wherein AA is an a-amino acid.

555. according to the compound of claim 553, wherein AA is Lys, Leu, Ile, Gly, Asp, Glu, Met, Ala, Val, Pro, His, Tyr, Ser, Nor, Thr, Arg, Phe, Trp, Hyp, Hsr, Car, Ort, Cys, Sar or Dcy.

556. according to the compound of claim 553, wherein AA is proline, glycine, lysine, serine, threonine, hydroxyproline or alanine.

557. according to the compound of claim 553, wherein AA is serine or hydroxyproline.

558. according to the compound of claim 553, wherein AA is a hydroxyproline.

559. a pharmaceutical composition, it comprise the treatment effective dose according to each described compound of claim 553-558 and its pharmaceutically acceptable carrier.

560. a method that increases salazine solvability in the aqueous solution, it comprises the amido functional group of salazine molecule and amino acid or its acylated derivatives is reacted under the azo bond formation condition, and separates its product.

561. a kind of method that to patient's administration the time, increases the bioavilability of salazine; it comprises the amido functional group of salazine molecule and amino acid or its acylated derivatives is reacted under the azo bond formation condition; and separate its product and to the described product of described patient's administration.

562. method that the limpid water-soluble intravenous formulations of salazine is provided to patient's administration the time; it comprises the amido functional group of salazine molecule and amino acid or its acylated derivatives is reacted under the azo bond formation condition; and separate its product and give and described product in the parenteral mode to described patient.

563. a method for the treatment of other inflammation communicate illness of mammal ulcerative colitis, Crohn's disease and colon and rectum, this method comprise to the described mammal of its needs is given with medicine treatment effective dose according to each described compound of claim 553-558.

Images