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WO2012046062A1 - Utilisation de promédicaments pour éviter les événements indésirables à médiation gi - Google Patents

Utilisation de promédicaments pour éviter les événements indésirables à médiation gi Download PDF

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Publication number
WO2012046062A1
WO2012046062A1 PCT/GB2011/051911 GB2011051911W WO2012046062A1 WO 2012046062 A1 WO2012046062 A1 WO 2012046062A1 GB 2011051911 W GB2011051911 W GB 2011051911W WO 2012046062 A1 WO2012046062 A1 WO 2012046062A1
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Prior art keywords
prodrug
group
acid
ester
drug
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Inventor
Richard Franklin
Martin Quibell
Robert Tyson
Bernard Golding
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Shire LLC
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Shire LLC
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Priority claimed from GBGB1016752.6A external-priority patent/GB201016752D0/en
Priority claimed from GBGB1111382.6A external-priority patent/GB201111382D0/en
Priority claimed from GBGB1111378.4A external-priority patent/GB201111378D0/en
Application filed by Shire LLC filed Critical Shire LLC
Publication of WO2012046062A1 publication Critical patent/WO2012046062A1/fr
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    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3839—Polyphosphonic acids
    • C07F9/3873—Polyphosphonic acids containing nitrogen substituent, e.g. N.....H or N-hydrocarbon group which can be substituted by halogen or nitro(so), N.....O, N.....S, N.....C(=X)- (X =O, S), N.....N, N...C(=X)...N (X =O, S)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
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    • A61P19/00—Drugs for skeletal disorders
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    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/91—Nitro radicals
    • C07D233/92—Nitro radicals attached in position 4 or 5
    • C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/28—Oxygen atom
    • C07D473/30—Oxygen atom attached in position 6, e.g. hypoxanthine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/59—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3 with hetero atoms directly attached in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to the use of prodrugs of a wide diversity of drugs (other than opioids) to transiently inactivate them and so reduce directly, locally mediated adverse gastrointestinal (Gl) side-effects normally evident after administration of the parent compound. Additionally, such prodrugs may confer improved pharmacokinetics.
  • these adverse Gl effects are the result, in part or wholly, of direct drug action from within the Gl tract i.e. they are locally mediated from within the gut lumen.
  • the systemic pharmacological target receptor may also be present in the gut and interactions at this level may cause unwanted local effects.
  • Antibiotic associated diarrhoea occurs in about 5-30% of patients either during early antibiotic therapy or up to 2 months after the end of treatment. While almost all antibiotics, particularly those that acting on anaerobes, can cause diarrhoea, this is higher with aminopenicillins, cephalosporins and clindamycin and lincomycin. A prominent influencing factor in such effects is the extent of absorption and also entero hepatic circulation which may lead to drug reaching the lower gut whereupon it can act locally on the gut microflora in the large bowel.
  • ceftobiprole and ceftaroline which are effective against methicillin resistant Staphylococcus aureus (MRSA) are poorly orally absorbed whether free or as their respective prodrugs, ceftobiprole medocaril and ceftaroline fosamil (El Sohl AA (2009) Expert Opinion Pharmacother.10 1675-1686).
  • MRSA methicillin resistant Staphylococcus aureus
  • Another class of drugs blighted by significant Gl side effects are the sodium channel blocking class 1 anti-arrhythmics.
  • Compounds such as propafenone are associated with marked nausea and vomiting which may be ascribed to their direct local anaesthetic activity in inhibiting slow wave movement of the stomach which may lead to gastric stasis and emesis.
  • Acetyl choline esterase inhibitors such as donepezil used in the treatment of Alzheimer's disease are associated with marked nausea, vomiting and diarrhoea.
  • the incidence of nausea after a daily dose of 10mg was -24% while diarrhoea was seen in some 17% of patients after the same dosage (Geldmecher DS (2004) 4, 5-16).
  • Both donepezil and rivastigmine are renowned to be better tolerated when given by the transdermal route avoiding direct instillation into the gut (Terahara T et al (2007) WO2007/129712, Sadowsky CH (2010) Int J Clin Pract. 64,188-93).
  • Non-steroidal anti- inflammatory drugs may lead to stomach ulcers and other serious complications such as Gl bleeding or perforation.
  • Gl bleeding or perforation One study estimates that these complications cause >100,000 hospital admissions and 16,500 deaths each year in the United States (Wolf M M et al (1999) N Engl J Med 340-1888-89). While these effects are generally thought to be, in large part, the result of systemic inhibition of prostaglandin synthetase, there is also considered to be an importantcontribution from direct local irritancy of these acidic molecules within the stomach and upper Gl tract (Fiorucci S et al (2001 ) Digest Liver Dis 33 (Suppl 2) S35-43).
  • enteric coated formulations in an attempt to mitigate this upper Gl irritant effect.
  • patients may be given either H2 antagonists or proton pump inhibitors or misoprostol in an attempt to ameliorate the effects of gastric acid production on the ulceration.
  • H2 antagonists or proton pump inhibitors or misoprostol in an attempt to ameliorate the effects of gastric acid production on the ulceration.
  • these measures are not always effective.
  • serotonin re-uptake inhibitors for the treatment of depression, is associated with marked gastrointestinal side effects such as nausea, diarrhoea and constipation. Up to 25% of treated patients may be so affected which can limit the use of these compounds.
  • SERT serotonin re-uptake transporter
  • the expression of the serotonin re-uptake transporter (SERT) in the gastrointestinal mucosa and the known role of serotonin in the propulsive actions of the gut suggests that these effects are the result of a direct action of these compounds within the lumen (Gerson MD( 2000) Gastroenterol 16 113-120).
  • Bisphosphonates used in the treatment of osteoporosis, represent another class of drug associated with unwanted Gl effects. Between 25 and 50% of patients experience serious gastrointestinal side-effects including ulceration of the oesophagus. To minimize the risk of upper Gl irritation patients are instructed to ensure tablets are taken on arising (not at bedtime), that they should not be taken with liquids other than water, and that patients should wait at least 30 minutes after dosing before eating, drinking, or taking any other medbations. The action of this class of compounds on the gut, including the oesophagus, has been unequivocally proven to be due to a direct irritant action on the mucosa.
  • enteric coated capsules of didanosine are associated with an improved Gl tolerability (Moreno S et al (2007) Drugs 67 1441 -1462) implying these Gl adverse events are effected by direct local drug action within the stomach.
  • Another class of therapeutic agent associated with marked Gl side effects include the biguanide anti-diabetic agents typified by metformin.
  • metformin biguanide anti-diabetic agents
  • the incidence of diarrhoea was 53% compared to 1 1.7 % in those receiving placebo
  • vomiting was recorded in 25.5% of patients on therapy compared to 8.3% receiving placebo.
  • Diarrhoea led to a discontinuation of the medication in 6% of these patients (Prescribing information on Glucophage® and Glucophage XR ® Bristol-Myers Squibb).
  • no detailed pharmacology studies have been reported investigating the mechanism of metformin induced adverse Gl effects but much circumstantial evidence, including the lesser Gl effects associated a sustained release formulation, suggest a role for direct action from within the lumen.
  • acetazolamide Another compound with which Gl side-effects are evident is acetazolamide. These can include taste alteration and gastrointestinal disturbances such as nausea, vomiting and diarrhoea and may be the result of locally mediated inhibition of carbonic anhydrase in the gut mucosa.
  • a prodrug for treating a systemic disorder having a structure of Formula (I) or a pharmaceutically acceptable salt thereof:
  • D- is a non-opioid drug having a free hydroxyl group, a free amine group or an enolisable carbonyl group, the drug being for use in treating said systemic disorder;
  • -R is an amino acid residue containing from 2 to 20 carbon atoms or a peptide formed from 2 to 10 independently selected amino acids each containing from 2 to 20 carbon atoms; or -R is an amino amide residue containing from 2 to 20 carbon atoms and terminating with a -CONR a R group, or -R is a peptide formed from 2 to 9 independently selected amino acids each containing from 2 to 20 carbon atoms and terminating with an amino amide residue containing from 2 to 20 carbon atoms, the amino amide residue terminating with a -CONR a R group;
  • R a and R when present are each independently selected from the group consisting of: H, C 1-6 alkyl, -(CH 2 )
  • R and R 2 are each independently selected at each occurrence from the group comprising:
  • R and R 2 may form a carbonyl, an ethylene or a C 3 . 6 cycloalkyl;
  • R 3 and R 4 are each independently selected at each occurrence from the group comprising:
  • R 5 and R 6 are each independently selected from the group consisting of: H, C 1-6 alkyl, Ci_ 6 haloalkyl, C 3 . 8 cycloalkyl and phenyl;
  • R 7 is selected from the group consisting of: hydro xyl, Ci_ 6 alkyl, Ci_ 6 alkoxy, C 3 . 8 cycloalkyl and phenyl;
  • X is selected from the group consisting of: a bond, -0-, -NH-, and a saturated or unsaturated ring having from 3 to 6 carbon atoms in the ring;
  • M is selected from the group consisting of:
  • n and p are each independently an integer of 0 - 16, provided that the sum of n and p is an integer of 0 - 16;
  • n is an integer of 0 - 2;
  • q is an integer of 0 - 3.
  • the terminal portion of the amino acid residue or peptide (-R) may be in the form of the free acid i.e. terminating in a -COOH group or may be in a masked (protected) form such as in the form of a carboxylate ester or carboxamide. Sometimes, the amino acid or peptide residue terminates with an amino group.
  • the amino acid residue or peptide (-R) terminates with a carboxylic acid group -COOH or an amino group -NH 2 .
  • the residue terminates with a carboxamide group CONR a R .
  • the residue terminates with a carboxylate ester COOR a .
  • a prodrug for treating a systemic disorder having a structure of Formula (II) or a pharmaceutically acceptable salt thereof:
  • D- is a non-opioid drug having a free hydroxyl group, a free amine group or an enolisable carbonyl group, the drug being for use in treating said systemic disorder;
  • -R is -OR a or -NR a R ;
  • R a and R are each independently selected from the group consisting of: H, Ci_ 6 alkyl, -(CH 2 ) r -C 3 . 6 cycloalkyl, phenyl and benzyl, or wherein R a and R together with the nitrogen atom to which they are attached form a ring containing 3, 4, 5 or 6 carbon atoms; wherein each of the R a and R groups may be unsubstituted or substituted with 1 or 2 substituent groups independently selected at each occurrence from the group consisting of: F, CI, CN and OH; r is an integer of 0 or 1 ;
  • R and R 2 are each independently selected at each occurrence from the group comprising:
  • R and R 2 may form a carbonyl, an ethylene or a C 3 . 6 cycloalkyl;
  • R 3 and R 4 are each independently selected at each occurrence from the group comprising:
  • R 5 and R 6 are each independently selected from the group consisting of: H, C 1-6 alkyl, Ci_ 6 haloalkyl, C 3 _8 cycloalkyl and phenyl;
  • R 7 is selected from the group consisting of: hydro xyl, Ci_ 6 alkyl, Ci_ 6 alkoxy, C 3 . 8 cycloalkyl and phenyl;
  • X is selected from the group consisting of: a bond, -0-, -NH-, and a saturated or unsaturated ring having from 3 to 6 carbon atoms in the ring;
  • M is selected from the group consisting of:
  • n and p are each independently an integer of 0 - 16, provided that the sum of n and p is an integer of 0 - 16;
  • n is an integer of 0 - 2;
  • q is an integer of 0 - 3.
  • the non-opioid drug normally exhibit adverse gastrointestinal effects when administered alone (i.e. without being covalently bonded to -L-R).
  • the prodrug of Formula I exhibits reduced adverse gastrointestinal effects compared to the adverse gastrointestinal effects of the non-opioid drug when administered alone (i.e. without being covalently bound to -L-R).
  • a prodrug having a structure of Formula (I) or Formula (II) as defined above or a pharmaceutically acceptable salt thereof wherein D- is a drug selected from the group consisting of:- metronidazole, 2-, 3- or 4- clindamycin, lincamycin, ampbillin, amoxicillin, clinafloxacin, delafloxacin, gemifloxacin, nadifloxacin, pazufloxacin, sitafloxacin, sparfloxacin, trovafloxacin, tosufloxacin, ceftabiprole (active metabolite of ceftabiprole medocaril), ceftaroline (active metabolite of ceftaroline fosamil) cefixime, ceftriaxone, cefoperazone, cefotaxime, cefadroxil, donepezil, memantine, miglustat, e
  • D- is a drug selected from the group consisting of:-
  • the terminal portion of the amino acid residue or peptide (-R) may be in the form of the free acid i.e. terminating in a -COOH group or may be in a masked (protected) form such as in the form of a carboxylate ester or carboxamide. Sometimes, the amino acid or peptide residue terminates with an amino group.
  • the amino acid residue or peptide (-R) terminates with a carboxylic acid group -COOH or an amino group -NH 2 .
  • the residue terminates with a carboxamide group CONR a R .
  • the residue terminates with a carboxylate ester COOR a .
  • the disorder may be one of a diverse collection of diseases treatable with a relevant drug or drugs amenable to this pro-drugging strategy.
  • Some examples include metronidazole or clindamycin for bacterial infections, propafenone for the treatment of arrhythmias, miglustat or eliglustat for Gauchers disease, donepezil for Alzheimer's disease, piroxicam for rheumatoid arthritis, venlefaxine or fluvoxamine for depression, pazopanib, and melphalan for cancer, alendronate for osteoporosis, amprenavir for viral infections and metformin for diabetes.
  • the present invention is directed to a method for minimizing the gastrointestinal side effects normally associated with administration of a parent drug possessing a derivatisable group (e.g., a hydroxyl, amine or an enolisable carbonyl group).
  • the method comprises orally administering a prodrug or a pharmaceutically acceptable salt thereof to a subject in need thereofwherein upon oral administration the prodrug or pharmaceutically acceptable salt minimizes, if not completely avoids, the gastrointestinal side effects usually seen after oral administration of the unbound drug.
  • the prodrug may have the structure of Formula I, or be a pharmaceutically acceptable salt thereof.
  • the amount of the drug is preferably a therapeutically effective amount.
  • the present invention is directed to a method for extending the sustainment of plasma drug concentrations of a drug having a derivatisable group (e.g., a hydroxyl, amine or an enolisable carbonyl group).
  • a drug having a derivatisable group e.g., a hydroxyl, amine or an enolisable carbonyl group.
  • the presence of quantities of unhydrolyzed prodrug in plasma provides a reservoir for continued generation of the active drug. Maintenance of plasma drug levels reduces the frequency of drug dosage, and so improves patient compliance.
  • the method comprises administering to a subject in need thereof a prodrug or a pharmaceutically acceptable salt thereof, wherein upon oral administration the extended duration of sustainment is at least 20% greater than that of the drug when administered alone.
  • the prodrug may have the structure of Formula I or be a pharmaceutically acceptable salt thereof.
  • the amount of the prodrug is preferably a therapeutically effective amount.
  • the present invention is directed to a method for increasing the oral bioavailability of a parent drug having a derivatisable group (e.g., a hydroxyl, amine, or an enolisable carbonyl group).
  • the method comprises administering to a subject in need thereof, a prodrug or a pharmaceutically acceptable salt thereof, wherein upon oral administration the bioavailablity is increased at least 20% above that of the drug when administered alone.
  • the prodrug may have the structure of Formula I or be a pharmaceutically acceptable salt thereof.
  • the amount of the prodrug is preferably a therapeutically effective amount.
  • the present invention is directed to a method for reducing the intersubject variability in attained plasma levels of a parent drug having a derivatisable group (e.g., a hydroxyl, amine or an enolisable carbonyl group).
  • the method comprises administering to a subject in need thereof a prodrug or a pharmaceutically acceptable salt thereof, wherein upon oral administration the variability is reduced by at least 20% of that seen when the drug is administered alone.
  • the prodrug may have the structure of Formula I or be a pharmaceutically acceptable salt thereof.
  • the amount of the prodrug is preferably a therapeutically effective amount.
  • Figure 1 shows the plasma clindmaycin concentrations after giving either the parent drug or clindamycin succinyl valine ester prodrug.
  • Figure 2 shows the plasma clindmaycin concentrations after giving either the parent drug or clindamycin glutaryl PABA ester prodrug.
  • combinations of the L and R groups contemplated within the scope of the present invention include those in which combinations of variables (and substituents) of the L and R groups are permissible so that such combinations result in stable compounds of Formula (I).
  • combinations of the variables can be selected by one of ordinary skill in the art to provide compounds of Formula (I) that are chembally stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth in the example section and figures.
  • the invention encompasses tautomeric forms of the compounds specifically disclosed, as well as geometrical and optical isomers.
  • the compounds specifically disclosed include an alkene
  • the illustrated structures are intended to include both the E- and Z- geometrical isomers.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 may independently be optionally substituted, where chemically possible, with at each occurrence between 1 and 5 substituents independently selected from the group comprising, F, CI, Br, NH 2 , Me, Et, N0 2 , OH and COOH.
  • M is [038] In an alternative embodiment, M is
  • X is a bond
  • X is -O-
  • X is -NH-.
  • X is aryl, preferably phenyl.
  • R and R 2 are each independently selected from the group consisting of: hydrogen and Ci_ 4 alkyl.
  • R 5 is H.
  • R 6 is H.
  • R 7 is selected from the group consisting of: hydro xyl and Ci_ 6 alkyl.
  • R 7 is hydroxyl
  • n 2 or 3.
  • m is 0.
  • p is 0.
  • n is an integer of from 0 to 16
  • m is 0,
  • p is 0 and
  • X is a bond.
  • n is an integer of from 2 to 3
  • m is 0,
  • p is 0 and
  • X is a bond.
  • n and p are each independently an integer of from 0 to 1 , provided that the sum of n and p is an integer of from 0 to 1 , p is 1 and X is a bond.
  • n, m and p are all 0 and X is aryl, preferably X is phenyl.
  • n is an integer of from 1 to 3
  • m and p are both 0
  • X is selected from the group consisting of: -O- and -NH-.
  • M is , n is an integer of from 0 to 16, m is 0, p is 0 and X is a bond.
  • M is , n is an integer of from 2 to 3, m is 0, p is 0 and X is a bond.
  • R and R 2 are each independently selected from the group consisting of: H and C 1- alkyl , and further preferably R and R 2 are each independently selected from the group consisting of: H and methyl.
  • M is ,, nn aanndd pp ; are each independently an integer of from 0 to 1 , provided that the sum of n and p is an integer of from 0 to 1 , p is 1 and X is a bond.
  • M is , m and p are all 0 and X is aryl, preferably X is phenyl.
  • M is is an integer of from 1 to 3, m and p are both 0 and X is selected from the group consisting of: -O- and -NH-. [066] In an embodiment, M is
  • L is
  • L is
  • L is
  • L is a residue including a dicarboxylic acid moiety selected from those recited in table 1a. It is noted that the actual carboxylic acid (i.e. prior to its attachment between the non-opioid drug and R 3 ) is recited in table 1 :
  • Adipic Acid Hexanedioic Acid HOOC-(CH 2 ) 4 -COOH
  • Sebacic Acid Decanedioic Acid HOOC-(CH 2 ) 8 -COOH
  • Undecanedioic Acid Undecanedioic Acid HOOC-(CH 2 ) 9 -COOH
  • Dodecanedioic Acid Dodecanedioic Acid HOOC-(CH 2 ) 10 -COOH
  • Tetradecanedioic Acid 1 12-Dodecanedicarboxylic Acid HOOC-(CH 2 ) 12 -COOH
  • Pentadecanedioic Acid 1 15-Pentadecanedioic Acid HOOC-(CH 2 ) 13 -COOH
  • L is a residue selected from those recited in table 1 b. Table 1 b.
  • -R is an amino acid residue containing from 2 to 20 carbon atoms or a peptide formed from 2 to 10 independently selected amino acids each containing from 2 to 20 carbon atoms. In an embodimentof the first and third aspects, R is an amino acid residue containing from 2 to 20 carbon atoms.
  • R is -OR a .
  • R is -NR a R .
  • R a is selected from the group consisting of: H, Me, Et and cyclopropyl.
  • R a is H.
  • R is selected from the group consisting of: H, Me, Et and cyclopropyl. Preferably, R is H. [081] In an embodiment of any of the aspects, r is 0. In an embodiment, r is 1 .
  • amino acid residue is (S) valine.
  • the amino acid residue is para amino benzoic acid (PABA).
  • -L-R has a structure selected from the group consisting of:
  • the amino acid residue is wherein R a is other than H.
  • amino acid residue is N-[086]
  • -L-R has a structure selected from the group consisting of: wherein R a is other than H; is other than H; is other than H;
  • rein R is other than H
  • -L-R has the structure selected from the group consisting of:
  • -L-R has the structure selected from the group consisting of:
  • -L-R has the structure selected from the group consisting of:
  • the prodrugs of the first and third aspects may metabolise to the prodrugs of the second and third aspects (i.e. prodrugs having the parent drug compound conjugated only to the linking group and no longer having the terminal amino acid or peptide present).
  • the prodrugs of the first and third aspects may therefore generate the prodrugs of the second and third aspects after administration to a subject.
  • D is selected from the group consisting of: metronidazole, 2-, 3- or 4- clindamycin, lincomycin, ampicillin, amoxicillin, clinafloxacin, delafloxacin, gemifloxacin, nadifloxacin, pazufloxacin, sitafloxacin, sparfloxacin, trovafloxacin, tosufloxacin, ceftobiprole (active metabolite of ceftobiprole medocaril), ceftaroline (active metabolite of ceftaroline fosamil) cefixime, ceftriaxone, cefoperazone, cefotaxime, cefadroxil, donepezil, memantine, miglustat, eliglustat, venlafaxine, desvenlafaxine, fluvoxamine, milnacipran, alendronate, etidronate, pamidronate, neridronate
  • D is selected from the group consisting of: metronidazole, 2-, 3- or 4- clindamycin, lincomycin, ampicillin, amoxicillin, clinafloxacin, delafloxacin, gemifloxacin, nadifloxacin, pazufloxacin, sitafloxacin, sparfloxacin, trovafloxacin, tosufloxacin, ceftobiprole (active metabolite of ceftobiprole medocaril), ceftaroline (active metabolite of ceftaroline fosamil) cefixime, ceftriaxone, cefoperazone, cefotaxime, cefadroxil, donepezil, memantine, miglustat, eliglustat, venlafaxine, desvenlafaxine, fluvoxamine, milnacipran, alendronate, etidronate, pamidronate, neridronate
  • D is selected from the group consisting of: metronidazole, 2-, 3- or 4- clindamycin, lincomycin, ampicillin, amoxicillin, clinafloxacin, delafloxacin, gemifloxacin, nadifloxacin, pazufloxacin, sitafloxacin, sparfloxacin, trovafloxacin, tosufloxacin, ceftobiprole (active metabolite of ceftobiprole medocaril), ceftaroline (active metabolite of ceftaroline fosamil) cefixime, ceftriaxone, cefoperazone, cefotaxime, cefadroxil, donepezil and memantine.
  • metronidazole 2-, 3- or 4- clindamycin, lincomycin, ampicillin, amoxicillin, clinafloxacin, delafloxacin, gemifloxacin, nadifloxacin, pazu
  • the drug is derivatised by attaching the linker to a hydroxyl group and is selected from the group consisting of: metronidazole, 2-, 3- or 4- clindamycin, lincomycin, delafloxacin, nadifloxacin, ceftobiprole (active metabolite of ceftobiprole medocaril), cefoperazone, cefadroxil, miglustat, eliglustat, venlafaxine, desvenlafaxine, alendronate, etidronate, pamidronate, neridronate, olpadronate, ibandronate, zoledronate, hydroxyurea, amprenavir, saquinavir, ritonavir, indinavir, nelfinavir, lopinavir, atazanavir, tipranavir, darunavir, didanosine, propafenone, piroxicam,
  • the drug is derivatised by attaching the linker to a hydroxyl group and is selected from the group consisting of: metronidazole, 2-, 3- or 4- clindamycin, lincomycin, delafloxacin, nadifloxacin, ceftobiprole (active metabolite of ceftobiprole medocaril), cefoperazone and cefadroxil.
  • the drug is derivatised by attaching the linker to an amine (1 ° or 2°) and is selected from the group consisting of: ampicillin, amoxicillin, clinafloxacin, delafloxacin, gemifloxacin, pazufloxacin, sitafloxacin, sparfloxacin, trovafloxacin, tosufloxacin, ceftobiprole (active metabolite of ceftobiprole medocaril), ceftaroline (active metabolite of ceftaroline fosamil) cefixime, ceftriaxone, cefotaxime, cefadroxil, memantine, fluvoxamine, milnacipran, alendronate, pamidronate, neridronate, pazopanib, thioguanine, melphelan, hydroxyurea, temozolomide, metformin, amprenavir, saquinavir
  • the drug is derivatised by attaching the linker to an amine (1 ° or 2°) and is selected from the group consisting of: ampicillin, amoxicillin, clinafloxacin, delafloxacin, gemifloxacin, pazufloxacin, sitafloxacin, sparfloxacin, trovafloxacin, tosufloxacin, ceftobiprole (active metabolite of ceftobiprole medocaril), ceftaroline (active metabolite of ceftaroline fosamil) cefixime, ceftriaxone, cefotaxime, cefadroxi and memantine.
  • an amine (1 ° or 2°
  • the drug is derivatised by attaching the linker to the oxygen of an enolisable carbonyl and is selected from the group consisting of: donepezil, tipranavir and propafenone. Most preferably the drug is donepezil.
  • the drug may contain: more than one hydroxyl group; more than one amino group; more than one enolisable carbonyl group; a hydroxyl and an amino group; a hydroxyl and an enolisable carbonyl group; an amino group and an enolisable carbonyl group; or a hydroxyl, amino and an enolisable group in the same molecule.
  • the prodrugging entity e.g. a dicarboxylate bridge + amino acid(s)
  • the drug may contain: more than one hydroxyl group; more than one amino group; more than one enolisable carbonyl group; a hydroxyl and an amino group; a hydroxyl and an enolisable carbonyl group; an amino group and an enolisable carbonyl group; or a hydroxyl, amino and an enolisable group in the same molecule.
  • the prodrug of the invention when the drug molecule includes more than one possible position of derivatisation, has only a single -L-R group conjugated to the drug molecule.
  • the present invention embraces any position of substitution by -L-R on the drug molecule.
  • the position nearest the pharmacophoric region is conjugated to -L-R.
  • D is selected from the group consisting of:
  • the prodrug is a prodrug of donepezil and has the formula:
  • the prodrug has the formula:
  • R and R 2 are selected from the group consisting of: H and Ci_ 4 alkyl.
  • R is selected from the group consisting of: -OR a and -NR a R .
  • the systemic disease treatable using a prodrug of Formula I includes a disorder selected from the group consisting of: a bacterial infection, an arrhythmia, Gauchers disease, Alzheimer's disease, rheumatoid arthritis, depression, cancer, osteoporosis, a viral infection and diabetes.
  • the drug, D is anyone one of a diverse collection for treating a variety of different diseases such as Alzheimer's drugs, e.g. donepezil, antibiotics, e.g. metronidazole, non-steroidal anti- inflammatory drugs, e.g. piroxicam, and Gauchers disease, e.g. miglustat.
  • Alzheimer's drugs e.g. donepezil
  • antibiotics e.g. metronidazole
  • non-steroidal anti- inflammatory drugs e.g. piroxicam
  • Gauchers disease e.g. miglustat.
  • the prodrug is a single amino acid prodrug of donepezil.
  • Single amino acid prodrugs of donepezil include donepezil -[succinyl-(S)-isoleucine] enol ester, donepezil-[succinyl-(S)-leucine] enol ester, donepezil -[succinyl-(S)-aspartic acid] enol ester, donepezil-[succinyl-(S)-methionine] enol ester, donepezil -[succinyl-(S)-histidine] enol ester, donepezil-[succinyl-(S)-tyrosine] enol ester, donepezil -[succinyl-(S)-phenylalanine] enol ester, donepezil-[succinyl-(S)-phenylalanine
  • the prodrug is a donepezil dipeptide prodrug.
  • Dipeptide donepezil prodrugs include donepezil-[succinyl-(S)-valine-valine] enol ester, donepezil -[succinyl-(S)-isoleucine-isoleucine] enol ester and donepezil -[succinyl-(S)- leucine-leucine] enol ester. Similar conjugates in which the donepezil above is replaced by one of the aforementioned drugs can also be prepared in accordance with the invention.
  • the prodrug is dicarboxylic acid linked prodrug of fluvoxamine.
  • the prodrug is fluvoxamine-glutaryl-PABA or fluvoxamine-succinyl-valine:
  • amino acid residue is intended to mean a moiety having an amine group and a carboxylic acid group.
  • the amino acid residue may have one or more amine groups and one or more carboxylic acid groups.
  • amino acid residue is intended to include both natural and synthetic amino acids.
  • the class of natural amino acids includes both proteinogenic amino acids and also naturally occurring non-proteinogenic amino acids. These naturally occurring non-proteinogenic amino acids are those that may be found, for example, in the body or in food stuffs, but which do not participate in protein biosynthesis. There are twenty-two proteinogenic amino acids and of the twenty-two, only twenty are directly encoded by the universal genetic code.
  • amino acid residue is therefore intended to include the following: Alanine, Cysteine, Aspartic Acid, Glutamic Acid, Phenylalanine, Glycine, Histidine, Isoleucine, Lysine, Leucine, Methionine, Asparagine, Proline, Glutamine, Arginine, Serine, Threonine, Valine, Tryptophan, Tyrosine, Selenocysteine and Pyrrolysine.
  • the amino acid residue can be bound to L via a suitable carboxylic acid, amine, hydroxyl, thiol, guanidine or carboxamide group on its side chain or alternatively the carboxylic acid or amine group of the non-side chain portion of the amino acid.
  • a suitable carboxylic acid, amine, hydroxyl, thiol, guanidine or carboxamide group on its side chain or alternatively the carboxylic acid or amine group of the non-side chain portion of the amino acid if the amino acid residue were, for example, arginine, cysteine, glutamine or tyrosine the amino acid can be bound to L at any one of the positions illustrated in the figure below:
  • amino acid residues having a terminal carboxylic acid or amine group are also intended to include: an amino acid alkyl ester (e.g. an amino acid C -6 alkyl ester); an amino acid aryl ester; an N-alkylated amino acid (e.g. a Ci_ 6 N-alkylated amino acid such as N-methylated amino acid or an N-methylcyclopropylated amino acid); an ⁇ , ⁇ -dialkylated amino acid (e.g.
  • a Ci_ 6 N,N-dialkylated amino acid which can include ⁇ , ⁇ -dimethylcyclopropylated amino acids), preferably the ⁇ , ⁇ -dialkylated amino acid is an N,N-dimethylated amino acid; an N-acylated amino acid (e.g. a Ci_ 6 N-acylated amino acid); an N-arylated amino acid; an N-alkylated amino acid ester; an N-acylated amino acid ester; an N-arylated amino acid ester; an O-alkylated amino acid (e.g.
  • Ci_ 6 O-alkylated amino acid an O-arylated amino acid; an O-acylated amino acid; an O-alkylated amino acid ester; an O-arylated amino acid ester; an O-acylated amino acid ester; an S-alkylated amino acid; an S-acylated amino acid; an S-arylated amino acid; an S-alkylated amino acid ester; an S-acylated amino acid ester; or an S-arylated amino acid ester.
  • the invention also envisages amino acid derivatives such as those mentioned above which have been functional ized by simple synthetic transformations known in the art (e.g.
  • alkyl groups may be the same or different.
  • the side chains of the above amino acids can be in either the (R) or the (S) configuration.
  • both L- and D- amino acids are within the scope of the present invention, though the D- amino acids are of course not naturally occurring.
  • amino acid residue also includes non-proteinogenic amino acids such as amino acids which can be incorporated into proteins during translation (including pyrrolysine, ornithine and selenocysteine).
  • non-proteinogenic amino acid also includes homologues of proteinogenic amino acids such as, but not limited to, homoarginine.
  • non-proteinogenic amino acid also includes beta amino acids such as, but not limited to, beta alanine.
  • amino acid also includes lactam analogues of natural amino acids such as, but not limited to, pyroglutamine.
  • non-proteinogenic amino acid is an organic compound which is an amino acid, but is not among those encoded by the standard genetic code, or incorporated into proteins during translation.
  • Non-proteinogenic amino acids thus, include amino acids or analogues of amino acids other than the 20 proteinogenic amino acids and include, but are not limited to, the D-isostereomers of proteinogenic amino acids.
  • non-proteinogenic amino acids include, but are not limited to: citrulline, homocitrulline, hydroxyproline, homoarginine, homoserine, homotyrosine, homoproline, ornithine, 4-amino-phenylalanine, sarcosine, biphenylalanine, homophenylalanine, 4-nitro-phenylalanine, 4-fluoro-phenylalanine, 2,3,4,5,6-pentafluoro-phenylalanine, norleucine, cyclohexylalanine, N-acetic acid, O-methyl serine (i.e., an amino acid side chain having the formula ), acetylamino alanine (i.e., an amino acid side chain
  • peptide refers to an amino acid chain consisting of 2 to 10 amino acids (bound via peptide bonds), unless otherwise specified.
  • the peptide used in the present invention is 2 or 3 amino acids in length.
  • at least one amino acid side chain in the peptide is bound to another amino acid (either through one of the termini or the side chain).
  • amino refers to a -NH 2 group.
  • alkyl refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms.
  • alkyl refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms.
  • alkyl is used without reference to a number of carbon atoms, it is to be understood to refer to a C-I-C-IO alkyl.
  • C ⁇ o alkyl means a straight or branched alkyl containing at least 1 , and at most 10, carbon atoms.
  • alkyl examples include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, t-butyl, hexyl, heptyl, octyl, nonyl and decyl.
  • substituted alkyl denotes alkyl radicals wherein at least one hydrogen is replaced by one more substituents such as, but not limited to, hydroxy, carboxyLalkoxy, aryl (for example, phenyl), heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amide (e.g., -C(0)NH-R where R is an alkyl such as methyl), amidine, amido (e.g., -NHC(0)-R where R is an alkyl such as methyl), carboxamide, carbamate, carbonate, ester, alkoxyester (e.g., -C(0)0-R where R is an alkyl such as methyl) and acyloxyester (e.g., -OC(0)-R where R is an alkyl such as methyl).
  • substituents such as, but not limited to, hydroxy, carboxyLalkoxy, aryl (for
  • heterocycle refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulphur.
  • cycloalkyl group refers to a non-aromatic monocyclic hydrocarbon ring of 3 to 8 carbon atoms such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.
  • substituted cycloalkyl denotes a cycloalkyl group further bearing one or more substituents as set forth herein, such as, but not limited to, hydroxy, carboxyl, alkoxy, aryl (for example, phenyl), heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amide (e.g., -C(0)NH-R where R is an alkyl such as methyl), amidine, amido (e.g., -NHC(0)-R where R is an alkyl such as methyl), carboxamide, carbamate, carbonate, ester, alkoxyester (e.g., -C(0)0-R where R is an alkyl such as methyl) and acyloxyester (e.g., -OC(0)-R where R is an alkyl such as methyl).
  • substituents as set forth herein, such as, but not limited to,
  • enolisable carbonyl and could easily identify enolisable carbonyl groups on a drug molecule.
  • linker refers to the group between the drug, D, and -OR a or -NR a R , or the amino acid/peptide moiety.
  • the left hand carbonyl group of the linker (as drawn above) is bound to an oxygen or nitrogen atom in the drug, while the right hand carbonyl (as drawn above) or amine of the linker is bound to -OR a or -NR a R , or the peptide or amino acid.
  • Prodrug moieties described herein may be referred to based on their linkage structure and their amino acid or peptide portion (if they have an amino acid or peptide portion).
  • the amino acid or peptide in such a reference should be assumed to be bound via an amino, hydroxyl or carboxyl ic acid terminus on the amino acid or peptide to one carbonyl (originally part of a carboxyl group of the linker) or one amine group of the linker while the other end of the linker is attached to the drug via an ester or amide bond, unless otherwise specified.
  • the linker may or may not be variously substituted as stipulated earlier.
  • carrier refers to a diluent, excipient, and/or vehicle with which an active compound is administered.
  • the pharmaceutical compositions of the invention may contain combinations of more than one carrier.
  • Such pharmaceutical carriers can be sterile liquids, such as water, saline solutions, aqueous dextrose solutions, aqueous glycerol solutions, and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin, 18 th Edition.
  • pharmaceutically acceptable refers to molecular entities and compositions that are generally regarded as safe.
  • pharmaceutically acceptable carriers used in the practice of this invention are physiologically tolerable and do not typically produce an allergic or similar untoward reaction (for example, gastric upset, dizziness and the like) when administered to a patient.
  • pharmaceutically acceptable means approved by a regulatory agency of the appropriate governmental agency or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • a "pharmaceutically acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable excipient” as used in the present application includes both one and more than one such excipient.
  • the term "treating” includes: (1 ) preventing the appearance of clinical symptoms of the state, disorder or condition developing in an animal that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; (2) inhibiting the state, disorder or condition (e.g., arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and/or (3) relieving the condition (i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms).
  • the benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician.
  • subject includes humans and other mammals, such as domestic animals (e.g., dogs and cats).
  • Effective amount means an amount of a prodrug or composition of the present invention sufficient to result in the desired therapeutic response.
  • the therapeutic response can be any response that a user (e.g., a clinician) will recognize as an effective response to the therapy. It is further within the skill of one of ordinary skill in the art to determine appropriate treatment duration, appropriate doses, and any potential combination treatments, based upon an evaluation of therapeutic response.
  • active ingredient unless specifically indicated, is to be understood as referring to the drug portion of a prodrug of the present invention, as described herein.
  • salts can include acid addition salts or addition salts of free bases.
  • Suitable pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium potassium and cesium salts; alkaline earth metal salts such as calcium and magnesium salts; organic amine salts such as triethylamine, guanidine and N-substituted guanidine salts, acetamidine and /V-substituted acetamidine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, and ⁇ , ⁇ '-dibenzylethylenediamine salts.
  • Pharmaceutically acceptable salts include, but are not limited to inorganic acid salts such as the hydrochloride, hydrobromide, sulfate, phosphate; organic acid salts such as trifluoroacetate and maleate salts; sulfonates such as methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphor sulfonate and naphthalenesulfonate; and amino acid salts such as arginate, gluconate, galacturonate, alaninate, asparginate and glutamate salts (see, for example, Berge, et al. "Pharmaceutical Salts," J. Pharma. Sci. 1977;66:1 ).
  • An -OH (hydroxyl) group can be esterified with a dicarboxylic acid such as, but not limited to, malonic, succinic, glutaric, adipic or other longer chain dicarboxylic acid, or substituted derivative thereof (for example, see Tables 1 and 2).
  • a keto group can be enolized and then esterifed with a dicarboxylic acid such as the ones described above.
  • an amino group (-NH 2 ) can be reacted with a dicarboxylic acid by to form a peptide bond.
  • the amino acid or peptide may then be attached to the remaining carboxyl group via the N-terminal nitrogen on the peptide/amino acid, or a nitrogen present in an amino acid side chain (e.g., a lysine side chain) although other connectivities are possible.
  • an amino acid side chain e.g., a lysine side chain
  • Another embodiment is directed to prodrugs linked to an amino acid or peptide through a dicarboxylic acid linker having a double bond.
  • maleic acid, fumaric acid, citraconic acid, aconitic acid, crotonic acid or glutaconic acid can be used as a dicarboxylic acid linker.
  • the proteinogenic amino acid side chain is selected from valine, leucine and isoleucine.
  • Yet another embodiment is directed to prodrugs linked to an amino acid or peptide through a substituted maleic acid, fumaric acid, or citraconic acid dicarboxylic acid linker.
  • the linker is selected from 3,3-dimethylmaleic acid, 2,3-dimethylfumaric acid, Z-methoxybutenedioic acid and E-methoxybutenedioic acid.
  • Itaconic acid, ketoglutaric and 2-methylene glutaric acid can also be used as a dicarboxylic acid linker in some embodiments.
  • Ri and R 2 on one of the carbons of the linker, L, taken together, is a methylene group.
  • the prodrug of the present invention is linked to an amino acid or peptide through a dicarboxylic acid linker having an aromatic ring.
  • a dicarboxylic acid linker having an aromatic ring for example phthalic acid (benzene-1 ,2-dicarboxylic acid) and terephthalic acid (benzene-1 ,4-dicarboxylic acid) can be used as a dicarboxylic acid linker.
  • Another embodiment includes prodrugs linked to a peptide or amino acid through a
  • dicarboxylic acid linker substituted with an acetyl (* N c CH3 ) group or a carboxylic acid group.
  • the dicarboxylic acid linker is further substituted with an 0H group.
  • the drug is linked to a peptide or prodrug through a citric acid linker.
  • the citric acid linker can be any one of 6 isomers, as provided herein in Table 1 b.
  • Peptides comprising any of the proteinogenic amino acids, as well as non-proteinogenic amino acids, can be used in the present invention.
  • non-proteinogenic amino acids are given above.
  • Non-proteinogenic amino acids can be present in a peptide with only non-proteinogenic amino acids, or alternatively, with both proteinogenic and non-proteinogenic amino acids.
  • a ketone When a ketone is present in the drug scaffold, as stated above, the ketone can be converted to its corresponding enolate and reacted with a modified peptide reactant (which can be a modified amino acid) to form a prodrug. Upon peptide cleavage, the prodrug will revert back to the original drug molecule, with the keto group present.
  • a modified peptide reactant which can be a modified amino acid
  • the dicarboxylic acid linker is succinic acid.
  • Other dicarboxylic acid linkers within the scope of the invention include, but are not limited to malonic acid, glutaric acid, adipic acid, or other longer chain dicarboxylic acids or substituted derivatives thereof (see Tables 1 and 2).
  • substituted dicarboxylic acid linkers may be employed.
  • methyl malonic acid may be used.
  • substituted dicarboxylic acid linkers would preferably be naturally occurring in the subject to be treated, i.e., non-xenobiotic. Suitable substituted dicarboxylic acids are given in Table 1 b.
  • Antibiotics prodrugs of the present invention e.g. metronidazole
  • antibiotics include: 2-, 3- or 4- clindamycin, lincamycin, ampicillin, amoxicillin, and cephalosporins such as cefixime, ceftriaxone, cefoperazone, cefotaxime, cefadroxil, ceftabiprole, (active metabolite of ceftabiprole medocaril), ceftaroline (active metabolite of ceftaroline fosamil).
  • the dicarboxylate bridge is attached via an amide linkage to any free amino function in the drug.
  • Class 1 anti-arrhythmic prodrugs excluding mexiletine
  • propafenone may be conjugated via enolisation of the carbonyl group as shown below:
  • Glucosylceramide synthase inhibitor prodrugs of the present invention e.g. miglustat prodrugs
  • similar conjugates can be made of other Alzheimer's drugs including memantine.
  • the dicarboxylate bridge is attached via an amide linkage to the free primary amino function in the drug molecule .
  • the single amino acid prodrug of donepezil is the trifluoroacetate salt shown below).
  • Non steroidal anti-inflammatory prodrugs of the present invention e.g. piroxicam
  • Anticancer agents e.g. tyrosine kinase inhibitors
  • prodrugs of the present invention e.g. pazopanib prodrug
  • Antiviral prodrugs of the present invention e.g. amprenavir
  • Biguanide antidiabetic agents prodrugs of the present invention e.g. metformin prodrugs
  • both the drug's basic centre and the prodruging moiety acidic centre may be ionised resulting in a molecule which will less effectively traverse cell membranes and reach those pharmacological receptors within the Gl tract.
  • absorption of the prodrug from the Gl tract will, it is belived, be largely unimpeded since this is likely effected by one or more nutrient transporters, especially for prodrugs having a terminal amino acid group.
  • Another contributory mechanism for such prodrugs being inactive is the likely three dimensional distortion of the drug molecule resulting from the attachment of a medium or longer chain linker to which is appended a terminal amino acid or peptide residue.
  • Oral administration of a temporarily inactivated drug would, during the absorption process of the intact prodrug, preclude access of active drug species to the relevant receptor(s)/enzymes within the gut wall.
  • the gut microfloral population would be protected from the direct local actions of the drug.
  • the integrity of the gut epithelial cells would be preserved if only inactive prodrug was present in the lumen.
  • the direct irritant properties of these drugs may be avoided by the use of such prodrugs.
  • the prodrug of the present invention would be metabolized by plasma and liver esterases/peptidases/amidases to the pharmacologically active species, which can then elicit the desired therapeutic effects.
  • the amino acid or peptide portion of some of the prodrugs of the present invention e.g., the amino acid or peptide portion of any of Formula I
  • the active drug is subsequently released from the amino acid or peptide prodrug by hepatic and extrahepatic hydrolases that are in part, present in plasma.
  • Improvement in the pharmacokinetics of the compounds described herein is another advantage of the prodrugs of the present invention. Administration of such a prodrug could not only result in more efficient absorption of normally poorly absorbed compounds but also lead to maintenance of plasma drug levels as the result of continuing generation of the active drug from a plasma reservoir of the prodrug.
  • One embodiment of the present invention is a method of treating a disorder in a subject in need thereof.
  • the method comprises orally administering a therapeutically effective amount of a prodrug of the present invention to the subject, or a pharmaceutically acceptable salt thereof.
  • the disorder may be one treatable with the drug.
  • the prodrugs encompassed by the present invention may be administered in conjunction with other therapies and/or in combination with other complementary active agents. In such combination therapies, the prodrugs encompassed by the present invention may be administered prior to, concurrent with, or subsequent to the other therapy and/or active agent.
  • the prodrug and other active agent(s) may also be incorporated into a single dosage form.
  • the present invention is directed to a method for minimizing the gastrointestinal side effects normally associated with administration of a drug, wherein the drug has a derivatisable group.
  • the method comprises orally administering a prodrug or a pharmaceutically acceptable salt thereof to a subject in need thereof, and wherein upon oral administration, the prodrug or pharmaceutically acceptable salt minimizes, if not completely avoids, the gastrointestinal side effects usually seen after oral administration of the unbound drug.
  • the amount of the drug is preferably a therapeutically effective amount.
  • the prodrug includes the same active as the discontinued drug.
  • the prodrug can be any prodrug of Formula I or a pharmaceutically acceptable salt thereof.
  • the prodrug can be selected from any succinyl-valine ester or glutaryl para-amino benzoic acid ester presented herein wherein the succinyl and glutaryl portions are bound to the derivatisable group on the drug.
  • the present invention is directed to a method for improving the efficiency of drug absorption compared to that after administering the non-conjugated drug.
  • the method comprises administering to a subject in need thereof, a prodrug or a pharmaceutically acceptable salt thereof, and wherein upon oral administration plasma drug levels are at least 20% higher than when the underivatised drug is administered.
  • the amount of the drug is preferably a therapeutically effective amount.
  • the prodrug can be any prodrug of Formula I or a pharmaceutically acceptable salt thereof.
  • the prodrug can be selected from any succinyl-valine ester or glutaryl para-amino benzoic acid ester presented herein.
  • the present invention is directed to a method for sustaining plasma drug levels for a significantly longer period than when the non-conjugated drug is administered alone.
  • the method comprises administering, to a subject in need thereof, a prodrug or a pharmaceutically acceptable salt thereof to a subject in need thereof, and wherein upon oral administration, plasma drug levels are sustained for at least 50% longer than when the underivatised drug is administered.
  • the amount of the drug is preferably a therapeutically effective amount.
  • the prodrug can be any prodrug of Formula I or a pharmaceutically acceptable salt thereof.
  • the prodrug can be selected from any succinyl-valine ester or glutaryl para-amino benzoic acid ester presented herein.
  • the compounds, compositions and methods of the present invention further encompass the use of salts and solvates of the prodrugs described herein.
  • the invention disclosed herein is meant to encompass all pharmaceutically acceptable salts of prodrugs (including those of the carboxyl terminus of the amino acid as well as those of any basic nitrogen).
  • a pharmaceutically acceptable salt of a prodrug of the present invention is prepared by reaction of the prodrug with a desired acid or base, as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • an aqueous solution of an acid such as hydrochloric acid may be added to an aqueous suspension of the prodrug and the resulting mixture evaporated to dryness (lyophilized) to obtain the acid addition salt as a solid.
  • the prodrug may be dissolved in a suitable solvent, for example an alcohol such as isopropanol, and the acid may be added in the same solvent or another suitable solvent.
  • the resulting acid addition salt may then be precipitated directly, or by addition of a less polar solvent such as diisopropyl ether or hexane, and isolated by filtration.
  • the acid addition salts of the prodrugs may be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt in the conventional manner.
  • the free base form may be regenerated by contacting the salt form with a base and isolating the free base in the conventional manner.
  • the free base forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free base for purposes of the present invention.
  • Base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, and the like.
  • suitable amines are ⁇ , ⁇ '-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine.
  • the base addition salts of the acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid.
  • Compounds useful in the practice of the present invention may have both a basic and an acidic centre and may therefore be in the form of zwitterions.
  • the prodrug of the present invention may be administered as the bulk substance, it is preferable to present the active ingredient in a pharmaceutical formulation, e.g., wherein the agent is in admixture with a pharmaceutically acceptable carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a composition comprising a prodrug of the present invention (e.g., a prodrug of any of Formulae 1-x) is provided.
  • the composition comprises at least one prodrug selected from Formula 1-x, and at least one pharmaceutically acceptable excipient or carrier.
  • the formulations of the invention may be immediate-release dosage forms, i.e., dosage forms that release the prodrug at the site of absorption immediately, or controlled-release dosage forms, i.e., dosage forms that release the prodrug over a predetermined period of time.
  • Controlled release dosage forms may be of any conventional type, e.g., in the form of reservoir or matrix-type diffusion-controlled dosage forms; matrix, encapsulated or enteric-coated dissolution-controlled dosage forms; or osmotic dosage forms. Dosage forms of such types are disclosed, e.g., in Remington, The Science and Practice of Pharmacy, 20 th Edition, 2000, pp. 858-914.
  • prodrugs which do not result in sustained plasma drugs levels due to continuous generation of active agent from a plasma reservoir of prodrug - but which may offer other advantages - gastroretentive or mucoretentive formulations analogous to those used in metformin products such as Glumetz® or Gluphage XR® may be useful.
  • the former exploits a drug delivery system known as Gelshield DiffusionTM Technology while the latter uses a so-called AcuformTM delivery system. In both cases the concept is to retain drug in the stomach, slowing drug passage into the ileum maximizing the period over which absorption take place and effectively prolonging plasma drug levels.
  • Other drug delivery systems affording delayed progression along the Gl tract may also be of value.
  • formulations of the present invention can be administered from one to six times daily, depending on the dosage form and dosage.
  • the present invention provides a pharmaceutical composition comprising at least one active pharmaceutical ingredient (i.e. , a prodrug), or a pharmaceutically acceptable derivative (e.g., a salt or solvate) thereof, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one prodrug of the present invention, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable carrier or excipient.
  • the prodrug employed in the present invention may be used in combination with other therapies and/or active agents. Accordingly, the present invention provides, in another embodiment, a pharmaceutical composition comprising at least one compound useful in the practice of the present invention, or a pharmaceutically acceptable salt or solvate thereof, a second active agent, and, optionally a pharmaceutically acceptable carrier or excipient.
  • the two compounds are preferably stable in the presence of, and compatible with each other and the other components of the formulation.
  • they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • the prodrugs presented herein may be formulated for administration in any convenient way for use in human or veterinary medicine.
  • the invention therefore includes pharmaceutical compositions comprising a compound of the invention adapted for use in human or veterinary medicine.
  • Such compositions may be presented for use in a conventional manner with the aid of one or more suitable carriers.
  • Acceptable carriers for therapeutic use are well-known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • the choice of pharmaceutical carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the pharmaceutical compositions may comprise as, in addition to, the carrier any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), and/or solubilising agent(s).
  • Preservatives, stabilizers, dyes and even flavouring agents may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, ascorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may also be used.
  • the compounds used in the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds may be prepared by processes known in the art, see, e.g., International Patent Application No. WO 02/00196 (SmithKline Beecham).
  • compositions of the present invention are intended to be administered orally (e.g., as a tablet, sachet, capsule, pastille, pill, bolus, powder, paste, granules, bullets or premix preparation, ovule, elixir, solution, suspension, dispersion, gel, syrup or as an ingestible solution).
  • compounds may be present as a dry powder for constitution with water or other suitable vehicle before use, optionally with flavouring and colouring agents.
  • Solid and liquid compositions may be prepared according to methods well-known in the art. Such compositions may also contain one or more pharmaceutically acceptable carriers and excipients which may be in solid or liquid form.
  • Dispersions can be prepared in a liquid carrier or intermediate, such as glycerin, liquid polyethylene glycols, triacetin oils, and mixtures thereof.
  • the liquid carrier or intermediate can be a solvent or liquid dispersive medium that contains, for example, water, ethanol, a polyol (e.g., glycerol, propylene glycol or the like), vegetable oils, non-toxic glycerine esters and suitable mixtures thereof. Suitable flowability may be maintained, by generation of liposomes, adm inistration of a suitable particle size in the case of dispersions, or by the addition of surfactants.
  • the tablets may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia.
  • excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
  • disintegrants such as starch (preferably corn, potato or tapioca starch), sodium starch glycolate, croscarmellose sodium and certain complex silicates
  • granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose
  • lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
  • Examples of pharmaceutically acceptable disintegrants for oral compositions useful in the present invention include, but are not limited to, starch, pre-gelatinized starch, sodium starch glycolate, sodium carboxymethylcellulose, croscarmellose sodium, microcrystalline cellulose, alginates, resins, surfactants, effervescent compositions, aqueous aluminum silicates and crosslinked polyvinylpyrrolidone.
  • binders for oral compositions useful herein include, but are not limited to, acacia, cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose; gelatin, glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, alginates, magnesium aluminum silicate, polyethylene glycol or bentonite.
  • acacia cellulose derivatives, such as methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose or hydroxyethylcellulose
  • gelatin glucose, dextrose, xylitol, polymethacrylates, polyvinylpyrrolidone, sorbitol, starch, pre-gelatinized starch, tragacanth, xanthane resin, algina
  • Examples of pharmaceutically acceptable fillers for oral compositions useful herein include, but are not limited to, lactose, anhydrolactose, lactose monohydrate, sucrose, dextrose, mannitol, sorbitol, starch, cellulose (particularly microcrystalline cellulose), dihydro- or anhydro-calcium phosphate, calcium carbonate and calcium sulfate.
  • Examples of pharmaceutically acceptable lubricants useful in the compositions of the invention include, but are not limited to, magnesium stearate, talc, polyethylene glycol, polymers of ethylene oxide, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, and colloidal silicon dioxide.
  • Suitable pharmaceutically acceptable odorants for the oral compositions include, but are not limited to, synthetic aromas and natural aromatic oils such as extracts of oils, flowers, fruits (e.g., banana, apple, sour cherry, peach) and combinations thereof, and similar aromas. Their use depends on many factors, the most important being the organoleptic acceptability for the population that will be taking the pharmaceutical compositions.
  • suitable pharmaceutically acceptable dyes for the oral compositions include, but are not limited to, synthetic and natural dyes such as titanium dioxide, beta-carotene and extracts of grapefruit peel.
  • Examples of useful pharmaceutically acceptable coatings for the oral compositions typically used to facilitate swallowing, modify the release properties, improve the appearance, and/or mask the taste of the compositions include, but are not limited to, hydroxypropylmethylcellulose, hydroxypropylcellulose and acrylate-methacrylate copolymers.
  • Suitable examples of pharmaceutically acceptable sweeteners for the oral compositions include, but are not limited to, aspartame, saccharin, saccharin sodium, sodium cyclamate, xylitol, mannitol, sorbitol, lactose and sucrose.
  • Suitable examples of pharmaceutically acceptable buffers useful herein include, but are not limited to, citric acid, sodium citrate, sodium bicarbonate, dibasic sodium phosphate, magnesium oxide, calcium carbonate and magnesium hydroxide.
  • Suitable examples of pharmaceutically acceptable surfactants useful herein include, but are not limited to, sodium lauryl sulfate and polysorbates.
  • compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the agent may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • Suitable examples of pharmaceutically acceptable preservatives include, but are not limited to, various antibacterial and antifungal agents such as solvents, for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (such as methyl paraben, ethyl paraben, propyl paraben, etc.).
  • solvents for example ethanol, propylene glycol, benzyl alcohol, chlorobutanol, quaternary ammonium salts, and parabens (such as methyl paraben, ethyl paraben, propyl paraben, etc.).
  • Suitable examples of pharmaceutically acceptable stabilizers and antioxidants include, but are not limited to, ethylenediaminetetriacetic acid (EDTA), thiourea, tocopherol and butyl hydroxyan [0243]
  • EDTA ethylenediaminetetriacetic acid
  • thiourea thiourea
  • tocopherol thiourea
  • butyl hydroxyan ethylenediaminetetriacetic acid
  • the pharmaceutical compositions of the invention may contain from 0.01 to 99% weight per volume of the prodrugs encompassed by the present invention.
  • Appropriate patients to be treated according to the methods of the invention include any human or animal in need of such treatment.
  • Methods for the diagnosis and clinical evaluation of the disease condition including its severity in an animal or human will be well known in the art.
  • the patient is preferably a mammal, more preferably a human, but can be any subject or animal, including a laboratory animal in the context of a clinical trial, screening, or activity experiment employing an animal model.
  • the methods and compositions of the present invention are particularly suited to administration to any animal or subject, particularly a mammal, and including, but not limited to, domestic animals, such as feline or canine subjects, farm animals, such as but not limited to bovine, equine, caprine, ovine, and porcine subjects, research animals, such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc., avian species, such as chickens, turkeys, songbirds, etc.
  • domestic animals such as feline or canine subjects
  • farm animals such as but not limited to bovine, equine, caprine, ovine, and porcine subjects
  • research animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, etc.
  • avian species such as chickens, turkeys, songbirds, etc.
  • a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • a suitable therapeutically effective and safe dosage can be administered to subjects.
  • the daily dosage level of the prodrug may be in single or divided doses.
  • the duration of treatment may be determined by one of ordinary skill in the art, and should reflect the nature of the condition and/or the rate and degree of therapeutic response to the treatment. Typically, a physician will determine the actual dosage which will be most suitable for an individual subject.
  • the specific dose level and frequency of dosage for any particular individual may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual undergoing therapy.
  • the daily dose requirement may, for example, range from 0.5 to 50 mg, preferably from 1 to 25 mg, and more preferably from 1 mg to 10 mg.
  • the daily dose requirement may, for example, range from 1 mg to 1600 mg, preferably from 1 mg to 800 mg and more preferably from 1 mg to 400 mg.
  • the prodrugs encompassed by the present invention may be administered in conjunction with other therapies and/or in combination with other active agents.
  • the prodrugs encompassed by the present invention may be administered to a patient in combination with other active agents used to treat that condition.
  • the prodrugs encompassed by the present invention may be administered prior to, concurrent with, or subsequent to the other therapy and/or active agent.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • administration is sequential, either the prodrugs encompassed by the present invention or the second active agent may be administered first.
  • the prodrugs encompassed by the present invention may be administered in a sequential manner in a regimen that will provide beneficial effects of the drug combination.
  • administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.
  • a prodrug encompassed by the present invention and another active agent may be administered in a substantially simultaneous manner, such as in a single capsule or tablet having a fixed ratio of these agents, or in multiple separate dosage forms for each agent.
  • the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those of ordinary skill in the art.
  • R is tBu or Bn
  • R is tBu or Bn
  • (S)-Valine ferf-butyl ester hydrochloride was treated with succinic anhydride in the presence of triethylamine to give succinyl-(S)-valine ferf-butyl ester which was then coupled to metronidazole via a ⁇ /, ⁇ /'-dicyclohexylcarbodi-imide (DCC) mediated reaction to give metronidazole-[succinyl-(S)-valine ferf-butyl ester].
  • DCC ⁇ /, ⁇ /'-dicyclohexylcarbodi-imide
  • the ferf-butyl ester was cleaved by treatment with trifluoroacetic acid to give metronidazole-[succinyl-(S)-valine] ester free base in > 95 % purity by HPLC and NMR.
  • PABA fert-butyl ester was treated glutaric anhydride in the presence of triethylamine to give glutaryl-PABA iert-butyl ester which was then coupled to metronidazole using ⁇ /, ⁇ /'-dicyclohexylcarbodi-imide to give metronidazole-(glutaryl-PABA iert-butyl ester).
  • the fert-butyl ester was cleaved using trifluoroacetic acid to give the required metronidazole-(glutaryl-PABA) ester free base in > 95 % purity by HPLC and NMR.
  • the prodrug should not undergo premature chemical or enzymic cleavage back to the parent dug while within the gut lumen.
  • the prodrugs were incubated with USP SGF (simulated gastric fluid), FeSSIF (fed state simulated intestinal fluid) and FaSSIF (fasted state simulated intestinal fluid) and remaining prodrug and any generated active drug assayed by use of a qualified LC-MS/MS analytical method.
  • Method - Prodrug 20 g/mL in the FaSSIF cocktail comprising sodium taurocholate 3mM, lecithin 0.75mM, NaOH 8.7mM, NaH 2 P0 4 . H 2 0 28.7mM, NaCI 106mM, pancreatin 1 % (overall pH 6.5) was incubated for 2h at 37°C. After acidifying the incubation to stop any reaction the amount of prodrug remaining and drug generated were determined using a qualified LC-MS/MS method.
  • the corresponding FeSSIF cocktail which was used in comparable manner, comprised sodium taurocholate 15mM, lecithin 3.75mM, NaOH 101 mM, acetic acid 144mM, and NaCI 202mM (overall pH 5.0). Pancreatin was again added at 1 %.
  • the USP simulated gastric juice comprised NaCI 34mM, HCI ⁇ 70nM, pepsin 0.32% (overall pH1 .1 ) and was incubated with prodrug (20 g/mL) for 1 h at 37°C. Remaining prodrug and any generated active drug were assayed using a qualified LC-MS/MS method. Results - The results shown in Table 2 indicate that both metronidazole prodrugs were chemically and enzymically stable under the conditions likely to prevail the Gl tract. As such there should minimal potential for direct interaction between active drug and the gut microfloral population.
  • Example 5 Assessment of the antimicrobial activity of prodrugs of metronidazole
  • Prodrugging which results in transient chemical inactivation of antibiotics should serve to avoid disturbance of the normal microbial balance in the human gut. It is well known that overgrowth of C. difficile resulting from such disturbance is associated with profound diarrhoea and dehydration. Introduction of a bulky amino acid substituent into an antibiotic structure would likely inactivate the drug. Consequently a prototypic antibiotic, metronidazole, was chosen for investigation and derivatized in this way.
  • Clindamycin is a valuable antibiotic especially useful in the treatment of multidrug-resistant Staphylococcus aureus (MRSA) infections. Few antibiotics have been found to be effective in MRSA and, although clindamycin is one such agent, regrettably its use is frequently marred by adverse Gl events.
  • MRSA multidrug-resistant Staphylococcus aureus
  • Transient inactivation of clindamycin by synthesis of its dicarboxyate amino acid prodrug should enable drug to be delivered to the systemic circulation while minimising the direct adverse effects on the gut. Subsequent to absorption plasma and liver esterase activity would release the active drug.
  • the resulting solid was purified using a Biotage Isolera automated chromatography system under reversed-phase conditions (Ci 8 column, gradient of 0 ⁇ 100 % MeCN in 0.1 % aqueous trifluoroacetic acid) with detection at 210 nm to afford, after freeze-drying, clindamycin-2-[succinyl-(S)-valine] ester trifluoroacetate (0.17 g, 57 %), as a white solid.
  • Clindamycin-2-(glutaryl-PABA) ester trifluoroacetate was synthesised from clindamycin by a procedure involving 3 reaction steps shown in the scheme 8 below.
  • the resulting solid was purified using a Biotage Isolera automated chromatography system under reversed-phase conditions (Ci 8 column, gradient of 0 ⁇ 100 % MeCN in 0.1 % aqueous trifluoroacetic acid) with detection at 269 nm to afford, after freeze-drying, clindamycin-2-(glutaryl-PABA) ester trifluoroacetate (0.51 g, 62 % over three steps), as a white solid.
  • the prodrug should not undergo premature chemical or enzymic cleavage back to the parent dug while within the gut lumen.
  • the prodrugs were incubated with USP SGF (simulated gastric fluid), FeSSIF (fed state simulated intestinal fluid) and FaSSIF (fasted state simulated intestinal fluid) and remaining prodrug and any generated active drug assayed by use of a qualified LC-MS/MS analytical method.
  • Method - Prodrug 20 g/mL in the FaSSIF cocktail comprising sodium taurocholate 3mM, lecithin 0.75mM, NaOH 8.7mM, NaH 2 P0 4 . H 2 0 28.7mM, NaCI 106mM, pancreatin 1 % (overall pH 6.5) was incubated for 2h at 37°C. After acidifying the incubation to stop any reaction the amount of prodrug remaining and drug generated were determined using a qualified LC-MS/MS method.
  • the corresponding FeSSIF cocktail which was used in comparable manner, comprised sodium taurocholate 15mM, lecithin 3.75mM, NaOH 101 mM, acetic acid 144mM, and NaCI 202m M (overall pH 5.0). Pancreatin was again added at 1 %.
  • the USP simulated gastric juice comprised NaCI 34mM, HCI ⁇ 70nM, pepsin 0.32% (overall pH1 .1 ) and was incubated with prodrug (20 g/mL) for 1 h at 37°C. Remaining prodrug and any generated active drug were assayed using a qualified LC-MS/MS method.
  • Results - The results are presented in Table 8 and show a dramatic reduction in anti-microbial activity of these prodrugs compared to the parent drug. This should ensure that while resident in the gut lumen these prodrugs are unlikely to directly alter the delicate microbial balance.
  • Table 8 Minimum inhibitory concentration (ug/ml_)of clindamycin-succinyl-S-valine ester and clindmycin-glutaryl-PABA ester and clindamycin itself against various bacteria
  • Fusobacterium necrophorum - clinical isolate 1 0.12 ⁇ 0.03
  • Veillonella spp.- clinical isolate 1 0.5 ⁇ 0.03
  • Campylobacter jejuni - clinical isolate ⁇ 0.03 ⁇ 0.03 ⁇ 0.03
  • Table 8 Minimum inhibitory concentration (ug/ml_)of clindamycin-succinyl-S-valine ester and clindmycin-glutaryl-PABA ester and clindamycin itself against various bacteria
  • Prodrug 1 clindamycin succinyl valine ester
  • Prodrug 2 clindamycin glutaryl PABA ester
  • Example 10 Bioavailability of clindamycin from its succinyl valine and qlutaryl para-amino benzoic acid ester prodrugs in the rat
  • a comparative bioavailability study was undertaken in the rat.
  • Nausea and vomiting associated with the antiarrhythmic propafenone are experienced in >10% of patients treated with the drug for supraventricular arrhythmias. This effect is believed to be a consquence of reduction in stomach slow wave activity and resultant gastric stasis and can be overcome by the use of transiently inactivated prodrugs decribed below.
  • Propafenone-[succinyl-(S)-valine] ester hydrochloride was prepared in four steps (Schemes 9 and10). Initially, propafenone hydrochloride was treated with di-iert-butyl dicarbonate to affordV-Boc-propafenone.
  • Part of this material (0.63 g) was purified using a Biotage Isolera automated chromatography system under reversed-phase conditions (C-
  • Propafenone hydrochloride was reacted with di-fert-butyl di-carbonate to giveV-Boc-propafenone in excellent yield.
  • the propafenone hydro xyl group was protected as its silyl ether using iert-butyldiphenylchlorosilane to give the fully protected propafenone.
  • This residual oil was purified by medium-pressure chromatography on silica eluting with a gradient of 10 ⁇ 20 % ethyl acetate in petrol to give /V-Boc-O-TBDPS-propafenone [succinyl-(S)-valine ferf-butyl ester] enol ester (780 mg, 19 %), as a white solid.
  • PABA iert-butyl ester was treated with triethylamine and glutaric anhydride to give glutaryl-PABA fert-butyl ester which was treated with ⁇ /, ⁇ /'-dicyclohexylcarbodiimide andV-Boc-propafenone to give /V-Boc-propafenone-(glutaryl-PABA iert-butyl ester) ester.
  • the fert-butyl ester and Boc group were cleaved using trifluoroacetic acid. Reversed-phase chromatography (with aqueous HCI in the mobile phase) afforded the desired propafenone-(glutaryl-PABA) ester hydrochloride as a white solid.
  • V-Boc-Propafenone-(glutaryl-PABA iert-butyl ester) ester (1 .08 g, 1 .48 mmol) in trifluoroacetic acid (15 mL) was stirred at room temperature for 1 h. The mixture was evaporated to dryness and residual trifluoroacetic acid was removed azeotropically with chloroform (5 ⁇ 35 mL) to afford a pale yellow gummy semi-solid (1 .21 g).
  • Example 12 Assessment of chemical/biological stability of propafenone prodrugs
  • the prodrug should not undergo premature chemical or enzymb cleavage back to the parent drug while within the gut lumen.
  • the prodrugs were incubated with USP SGF (simulated gastric fluid), FeSSIF (fed state simulated intestinal fluid) and FaSSIF (fasted state simulated intestinal fluid) and remaining prodrug, and any generated active drug, assayed by use of a qualified LC-MS/MS analytical method.
  • Prodrug ( 20 g/mL) in the FaSSIF cocktail comprising sodium taurocholate 3mM, lecithin 0.75mM, NaOH 8.7mM, NaH 2 P0 4 . H 2 0 28.7mM, NaCI 106mM, pancreatin 1 % (overall pH 6.5) was incubated for 2h at 37°C. After acidifying the incubation to stop any reaction the amount of prodrug remaining and drug generated were determined using a qualified LC-MS/MS method.
  • the corresponding FeSSIF cocktail which was used in comparable manner comprised sodium taurocholate 15mM, lecithin 3.75mM, NaOH 101 mM, acetic acid 144mM, and NaCI 202m M (overall pH 5.0). Pancreatin was again added at 1 %.
  • the USP simulated gastric juice comprised NaCI 34mM, HCI ⁇ 70nM, pepsin 0.32% (overall pH1 .1 ) and was incubated with prodrug (20 g/mL) for 1 h at 37°C. Remaining prodrug and any generated active drug were assayed using a qualified LC-MS/MS method.
  • Example 13 Effects of propafenone and two propafenone amino acid prodrugs on cloned Nav1.1 channels expressed in mammalian cells
  • Blockade of hNav1 .1 channel was measured using a stimulus voltage pattern shown in the diagram below: Voltage potentials are indicated in Table 13. The pulse pattern was repeated twice: before and 5 minutes after TA addition and peak current amplitudes at three test pulses were measured (ITP1 , TP11 and ITP12). Command Voltage
  • the tonic block was calculated as:
  • % Block (Tonic) (1 - l TP1 , TA / l TP1, control) x 100%, where ITPI, control and ⁇ , ⁇ are the inward peak Na + currents elicited by the TP1 in control and in the presence of a test article, respectively.
  • Block - the frequency-dependent block at stimulation frequency 10 Hz was calculated as:
  • % BlOCk (10 HZ) (1 - IT 11, A / ⁇ 11, Control)) x 100%, where ITPH , control and ITPH.
  • TA are the inward peak Na + currents elicited by the TP1 1 in control and in the presence of a test article, respectively.
  • the inactivation state block was calculated as:
  • % Block (inactivation state) (1 - (ITPI2, TA / ITPI2, TA) X 100%, where l TP12, control and l TP12, TA are the inward peak Na + currents elicited by the TP12 in control and in the presence of a test article, respectively.
  • % Block ⁇ 1 -1 /[1 +([Test]/IC 50 ) N ] ⁇ *100%, where [Test] is the concentration of test article, IC 50 is the concentration of the test article producing half-maximal inhibition, N is the Hill coefficient, and % Block is the percentage of ion channel current inhibited at each concentration of the test article.
  • Nonlinear least squares fits were solved with the Solver add-in for Excel 2000 (Microsoft, Redmond, WA).
  • ceramide synthase inhibitory activity of miglustat is not only responsible for its therapeutic activity but also the unwanted Gl adverse events due to direct interaction with gut disaccharidases.
  • Transient inactivation by substitution at the 2-position known to be critical for the drug's activity [Boucheron C et al (2006) Tetrahedron: Asymmetry 16 1747-1756]), while the drug is still present in the gut lumen, should minimise this effect .
  • Miglustat HCI 70 mg, 0.27 mmol
  • triethylamine 71 mg, 0.70 mmol
  • acetonitrile 4 imL
  • the suspension was gently warmed to give a solution.
  • a mixture of benzylvaline succinic acid (2) (80 mg, 0.27 mmol), DMAP (10 mg, 0.08 mmol) and EDCI.HCI 67 mg, 0.35 mmol) in acetonitrile (2mL) was charged and the resulting mixture stirred at 15-25 C for 17 hours.
  • the mixture was partitioned between ethyl acetate (40 imL), saturated brine (40 imL) and 2N sodium hydroxide solution (5 mL).
  • the ethyl acetate phase was dried over magnesium sulphate and evaporated in vacuo at 40 C to yield a clear yellow oil (133 mg) which was analysed by LCMS and shown to contain a component consistent with the desired product.
  • the oil was dissolved in ethyl acetate (20 mL) and was extracted into 2M aqueous hydrochloric acid (10 mL) and then water (10 mL). The aqueous phases were combined and the pH was adjusted to 9 with saturated aqueous sodium hydrogen carbonate (20 mL). The aqueous phase was then extracted with ethyl acetate (2x 35 mL), dried over magnesium sulphate and evaporated in vacuo at 40 C to yield a clear oil (52.8 mg).
  • the oil was purified by column chromatography on silica (40 g) eluting with 5%MeOH/DCM (75x 25 mL) to yield benzyl
  • Donepezil was treated with potassium iert-butoxide and the resulting enolate was then quenched with glutaric anhydride. Purification was accomplished by reversed-phase chromatography. Treatment with cyanuric fluoride in the presence of pyridine gave the acid fluoride which was reacted with (S)-valine ethyl ester. The crude product was purified by normal phase chromatography to give the desired donepezil (glutaryl-(S)-valine ethyl ester) enol ester in ⁇ 90 % purity by H NMR and HPLC.
  • the resulting mixture was concentrated and the gummy residue purified using a Biotage Isolera automated chromatography system under reversed-phase conditions (C-
  • Donepezil was treated with potassium iert-butoxide and the resulting enolate was then quenched with glutaric anhydride. Purification was accomplished by reversed-phase chromatography. Treatment with cyanuric fluoride in the presence of pyridine gave the acid fluoride which was reacted with para-aminobenzoic acid ethyl ester. The crude product was purified by normal phase chromatography to give the desired donepezil (glutaryl-PABA ethyl ester) enol ester as a yellow gum.
  • the resulting mixture was concentrated and the gummy residue purified using a Biotage Isolera automated chromatography system under reversed-phase conditions (C-
  • Donepezil was treated with potassium iert-butoxide in THF to give donepezil enolate which was quenched with glutaric anhydride.
  • the free base was purified at this stage by normal phase chromatography. Conversion to the acid fluoride was achieved by addition of cyanuric fluoride to a solution of the free base in acetonitrile in the presence of pyridine. Reaction of the acid fluoride with (S)-valinamide hydrochloride in the presence of Hunig's base followed by normal phase chromatography gave donepezil [glutaryl-(S)-valinamide] enol ester as an orange glassy semi-solid.
  • the prodrug should not undergo premature chemical or enzymic cleavage back to the parent dug while within the gut lumen.
  • the prodrugs were incubated with USP SGF (simulated gastric fluid), FeSSIF (fed state simulated intestinal fluid) and FaSSIF (fasted state simulated intestinal fluid) and remaining prodrug and any generated active drug assayed by use of a qualified LC-MS/MS analytical method.
  • Prodrug (20 g/mL) in the FaSSIF cocktail comprising sodium taurocholate 3mM, lecithin 0.75mM, NaOH 8.7mM, NaH 2 P0 4 . H 2 0 28.7mM, NaCI 106mM, pancreatin 1 % (overall pH 6.5) was incubated for 2h at 37°C. After acidifying the incubation to stop any reaction the amount of prodrug remaining and drug generated were determined using a qualified LC-MS/MS method.
  • the corresponding FeSSIF cocktail which was used in comparable manner, comprised sodium taurocholate 15mM, lecithin 3.75mM, NaOH 101 mM, acetic acid 144mM, and NaCI 202m M (overall pH 5.0). Pancreatin was again added at 1 %.
  • the USP simulated gastric juice comprised NaCI 34mM, HCI ⁇ 70nM, pepsin 0.32% (overall pH1 .1 ) and was incubated with prodrug (20 g/mL) for 1 h at 37°C. Remaining prodrug and any generated active drug were assayed using a qualified LC-MS/MS method.
  • Example 16 In Vitro activity of donepezil, donepezil glutaryl enol ester, donepezil qlutaryl valine(OEt) enol ester, donepezil qlutaryl valinamide enol ester and qlutaryl PABA(OEt) enol ester prodrugs on human acetylcholine esterase.
  • the prodrugs had IC50 values for hAChE activity ranging from 10-121 -fold less potent than the IC50 value for the parent drug suggesting that they should have reduced effects on eliciting the emesis seen with the parent drug.
  • Example 17 Bioavailability of donepezil from its glutaryl valine (as ethyl ester) and glutaryl para-amino benzoic acid (as ethyl ester) prodrugs in the rat
  • Example 18 Bioavailability of donepezil from its glutaryl enol ester and glutaryl-(S)-valinamide enol ester prodrugs in the male beagle dog and cynomolqus monkey
  • Tmax (h) 1 .0 0.5 2.0 2.0 2.0 2.0 (0.5-2)
  • Venlafaxine free base was coupled with succinyl-(S)-valine iert-butyl ester via a ⁇ /, ⁇ /'-dicyclohexylcarbodi-imide (DCC) mediated reaction to give venlafaxine [succinyl-(S)-valine iert-butyl ester] ester.
  • DCC dicyclohexylcarbodi-imide
  • the iert-butyl ester was cleaved using trifluoroacetic acid to give, after column purification, venlafaxine [succinyl-(S)-valine] ester trifluoroacetate.
  • Reagents and Solvents i, PhCH 2 OCOCI, aq NaOH; ii, PhCH 2 OCOCH'PrNHCO(CH 2 ) 3 COF, aq NaOH; iii, Pd/H 2 , THF.
  • didanosine [succinyl-(S)-valine] ester was achieved in two steps (Scheme 25). Succinyl-(S)-valine benzyl ester was reacted with didanosine using A/,A/-dicyclohexylcarbodiimide (DCC) as coupling agent to afford didanosine [succinyl-(S)-valine benzyl ester] ester, following purification by normal phase chromatography.
  • DCC A/,A/-dicyclohexylcarbodiimide
  • Example 26 Synthesis of selected meformin prodrugs
  • the crude solid was purified using a Biotage Isolera automated chromatography system under normal phase conditions (silica column, gradient of 0 ⁇ 25 % methanol in dichloromethane) with detection at 254 nm to afford acetazolamide [succinyl-(S)-valine-ierf-butyl ester] amide (0.14 g, 16 %), as a white solid.
  • Acetazolamide [succinyl-(S)-valine-ierf-butyl ester] amide (94 mg, 0.20 mmol) in trifluoroacetic acid (10 mL) was stirred at room temperature for 30 min. The mixture was evaporated to dryness and residual trifluoroacetic acid was removed azeotropically using chloroform (4 ⁇ 20 mL). The crude residual solid was triturated with diethyl ether, collected by suction filtration and dried in vacuo to afford acetazolamide [succinyl-(S)-valine] amide (90 mg, quantitative), as an off-white solid.
  • the combined organic extracts were washed with water (3 x 50 imL) and saturated brine (50 imL), dried (MgS0 4 ) and concentrated to give a white solid (0.73 g).
  • the crude solid was purified using a Biotage Isolera automated chromatography system under normal phase conditions (silica column, gradient of 0 ⁇ 25 % methanol in dichloromethane) with detection at 254 nm to afford acetazolamide (glutaryl-PABA ferf-butyl ester) amide (0.27 g, 27 %) as a white solid.

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Abstract

La présente invention concerne des promédicaments d'une grande variété de médicaments et compositions pharmaceutiques contenant de tels promédicaments. La présente invention concerne en outre des procédés pour réduire au minimum des événements gastro-intestinaux indésirables à médiation locale (de l'intérieur de la lumière intestinale) associés au médicament non dérivé et augmenter la durabilité de taux plasmatiques de médicament avec les promédicaments mentionnés ci-dessus. Par conséquent, la présente invention concerne l'utilisation de promédicaments d'une grande variété de médicaments (autres que des opioïdes) pour inactiver de façon transitoire ceux-ci et réduire ainsi directement, des effets secondaires gastro-intestinaux (GI) à médiation locale apparents après administration du composé parent. De plus, de tels promédicaments peuvent conférer une pharmacocinétique améliorée.
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CN116253666A (zh) * 2017-09-05 2023-06-13 北京强新生物科技有限公司 中枢神经系统疾病的新疗法
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