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US20110294859A1 - Substituted pyridoxine-lactam carboxylate salts - Google Patents

Substituted pyridoxine-lactam carboxylate salts Download PDF

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US20110294859A1
US20110294859A1 US13/056,943 US200913056943A US2011294859A1 US 20110294859 A1 US20110294859 A1 US 20110294859A1 US 200913056943 A US200913056943 A US 200913056943A US 2011294859 A1 US2011294859 A1 US 2011294859A1
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Rina Yamin
Dalia Megiddo
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Arcturus Therapeutics Ltd
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Alcobra Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C07D213/66—One oxygen atom attached in position 3 or 5 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
    • C07D213/67—2-Methyl-3-hydroxy-4,5-bis(hydroxy-methyl)pyridine, i.e. pyridoxine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones 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 other ring carbon atoms
    • C07D207/277—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D207/28—2-Pyrrolidone-5- carboxylic acids; Functional derivatives thereof, e.g. esters, nitriles
    • 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
    • C07D211/68—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—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 one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to salt adducts comprising at least one pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring and uses thereof.
  • Alcohol-induced liver diseases are a common disorder in modern communities and societies. For example, in Europe there are more than 45 million individuals showing signs of alcohol-related damage such as liver disease and myopathies. Chronic alcohol consumption increases hepatic accumulation of triglycerides and leads to hepatic steatosis, which is the earliest and most common response to severe alcohol intoxication.
  • Metadoxine is a salt of the corresponding anion of L-2-pyrrolidone-5-carboxylic acid (L-2-pyroglutamic acid) (1) and the protonated derivative of pyridoxine (vitamin B6) (2), having the following structures:
  • WO 2008/066353 discloses the use of Metadoxine in the treatment of alcohol intoxication either alone or in combination with other active agents.
  • WO 2008/066353 mentions that metadoxine does not inhibit the expression and activation of an alcohol-induced cytochrome P450 2E1, which is the key enzyme involved in alcohol-induced toxicity. Thus, the use of metadoxine may be limited.
  • the present invention provides, inter alia, salt adducts comprising at least one pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, methods of their preparation, medicaments comprising those compounds, therapeutic treatments utilizing salt adducts of the invention and uses thereof in the preparation of pharmaceutical compositions.
  • the invention provides a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted; provided that when said carboxylated lactam ring is an L-2-pyroglutamate (compound (1)), said positively charged moiety is other than pyridoxine (compound (2)).
  • the invention provides a pharmaceutical composition comprising a salt adduct of the invention.
  • the invention provides a use of a salt adduct of the disclosure for the preparation of a pharmaceutical composition for the treatment or prevention of a disease or disorder associated with or inflicted by alcohol consumption.
  • the invention also provides a use of a salt adduct of the invention for the preparation of a pharmaceutical composition capable of shortening the half-life of ethanol in the blood of a subject.
  • the invention provides a method for treating or preventing a disease or disorder associated with or inflicted by alcohol consumption, comprising administering to a subject in need thereof an effective amount of a salt adduct of the invention.
  • the invention provides methods of shortening the half-life of ethanol in the blood of a subject, comprising administering to a subject in need thereof an effective amount of a salt adduct of the invention.
  • the invention provides a kit for reducing the effect of alcohol intoxication, comprising at least one container comprising a salt adduct of the invention, and instructions for use thereof.
  • the present invention provides a salt adduct comprising at least one positively charged moiety being a pyridoxine or a derivative thereof and at least one carboxylated 5- to 7-membered lactam ring, optionally additionally substituted; provided that when said carboxylated lactam ring is an L-2-pyroglutamate (compound (1)), said positively charged moiety is other than pyridoxine (compound (2)).
  • salt adduct is meant to encompass a salt product of a direct addition of two or more distinct ions, wherein the overall charge of the salt adduct is zero.
  • the salt adduct comprises one positively charged moiety having a single positive charge functional group (i.e., the positively charged moiety is charged with +1 net charge) and one negatively charged moiety having a single negative charge functional group (i.e., the negatively charged moiety is charged with ⁇ 1 net charge).
  • the salt adduct comprises one positively charged moiety having two positively charged functional groups, which may be the same or different (i.e., the positively charged moiety is charged with +2 net charge) and two negatively charged moieties, which may be the same or different, and each having a single negative charged functional group (i.e., each negatively charged moiety is charged with ⁇ 1 net charge).
  • the salt adduct comprises two positively charged moieties, which may be the same or different, having each one positively charged functional group (i.e., each positively charged moiety is charged with +1 net charge) and one negatively charged moiety, having two negatively charged functional groups, being the same or different (i.e., the negatively charged moiety is charged with ⁇ 2 net charge).
  • the salt adduct comprises a positively charged moiety charged with +n net charge (originating from one or more positively charged functional groups, which may be the same or different), and a negatively charge moiety having ⁇ n (originating from one or more negatively charged functional groups, which may be the same or different) net charge, wherein n is an integer which may be equal to 1, 2, 3, 4, 5 or 6.
  • a “positively charged moiety of a salt adduct” of the invention is the corresponding acid of pyridoxine, or any derivative thereof.
  • the positive charge of the positively charged moiety stems from the protonated basic nitrogen atom of pyridoxine (as for example in compound (2)) or any derivative thereof (such as for example compounds of formula (I)).
  • the positively charged pyridoxine derivative is substituted with a positively charged functional group such as for example —NH 3 + , —CH 2 NH 3 + , —NH 2 R + , —NHR 2 + (wherein each R is independently a C 1 -C 6 alkyl), which may, in some embodiments, be present in addition to the positively charged protonated basic aromatic nitrogen atom in the pyridine ring.
  • a positively charged functional group such as for example —NH 3 + , —CH 2 NH 3 + , —NH 2 R + , —NHR 2 + (wherein each R is independently a C 1 -C 6 alkyl), which may, in some embodiments, be present in addition to the positively charged protonated basic aromatic nitrogen atom in the pyridine ring.
  • a “carboxylated 5- to 7-membered lactam ring” of a salt adduct of the invention is meant to encompass a ⁇ -lactam, ⁇ -lactam or ⁇ -lactam rings, having a negatively charged carboxylate group (—COO ⁇ ) substituted thereto.
  • said carboxylate group is substituted at the lactam ring carbon atom adjacent to the amide nitrogen.
  • said carboxylated lactam ring is a L-2-pyrrolidone-5-carboxylate (compound (1)).
  • said carboxylate group is substituted on any position of the lactam ring.
  • said carboxylated 5- to 7-membered lactam ring may be substituted by another substituent at any position on the lactam ring.
  • the present invention encompasses a salt adduct as described herein above and below, provided that when said carboxylated lactam ring is an L-2-pyroglutamate, i.e. compound (1), said positively charged moiety is other than pyridoxine, i.e. compound (2).
  • said positively charged moiety of a salt adduct of the invention is a compound of formula (I):
  • said carboxylated lactam ring of a salt adduct of the invention is selected from the group consisting of:
  • said carboxylated lactam ring is a compound of formula (II):
  • R 6 , R 7 , R 8 , R 9 and R 10 are as defined above.
  • R 6 is C 1 -C 6 alkyl.
  • R 9 is C 1 -C 6 alkyl.
  • said carboxylated lactam ring of a salt adduct is a compound of formula (II):
  • R 6 , R 7 , R 8 , R 9 and R 10 are as defined above.
  • said carboxylated lactam ring of a salt adduct is compound (1):
  • R 1 , R 2 , R 3 and R 4 are as defined above.
  • R 1 is a C 1 -C 6 alkyl and R 2 , R 3 and R 4 are as defined above.
  • R 2 is selected from hydroxyl and C 1 -C 6 alkoxy; and R 1 , R 3 and R 4 are as defined above.
  • R 3 is —CH 2 R 15 , wherein R 15 is selected from —C 1 -C 6 alkoxy, —OH and —NH 3 + ; and R 1 , R 2 and R 4 are as defined above.
  • R 4 is selected from formyl and —CH 2 R 16 , wherein R 16 is selected from —C 1 -C 6 alkoxy and —OH; and R 1 , R 2 and R 3 are as defined above.
  • said carboxylated lactam ring is a compound of formula (III):
  • said carboxylated lactam ring is a compound of formula (IV):
  • said positively charged moiety is a compound of formula (2):
  • the salt adduct is selected from:
  • halogen as used herein means F, Cl, Br or I.
  • C 1 -C 6 alkyl represents a saturated, branched or straight hydrocarbon chain having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • Typical C 1-6 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and the like.
  • C 2 -C 6 alkenyl represents a branched or straight hydrocarbon chain having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond positioned between any two carbons of the chain.
  • Examples of such groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1,3-butadienyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl and the like.
  • C 2 -C 6 alkynyl represents a branched or straight hydrocarbon chain having 2, 3, 4, 5 or 6 carbon atoms and at least one triple bond positioned between any two carbons of the chain.
  • Examples of such groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl and the like.
  • C 1 -C 6 alkoxy refers to the radical —O—C 1-6 alkyl, wherein C 1-6 alkyl is as defined above.
  • Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • C 1 -C 6 alkylthio refers to the radical —S—C 1-6 alkyl, wherein C 1-6 alkyl is as defined above. Representative examples are methylthio, ethylthio, isopropylthio, n-propylthio, butylthio, pentylthio and the like.
  • cycloalkyl as used herein represents a monocyclic, carbocyclic group having 3, 4, 5, 6, 7 or 8 carbon atoms, but may also include heteroatoms such as N, O and/or S. Representative examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • aryl as used herein is intended to include carbocyclic aromatic ring systems such as phenyl, biphenylyl, naphthyl, anthracenyl, phenanthrenyl, fluorenyl, indenyl, pentalenyl, azulenyl and the like.
  • Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic systems enumerated above. Non-limiting examples of such partially hydrogenated derivatives are 1,2,3,4-tetrahydronaphthyl, 1,4-dihydronaphthyl and the like.
  • heteroaryl refers to ring systems in which at least one ring is an aromatic ring in which at least one atom is a non-carbon atom, either substituted or non-substituted, where the non-carbon atom may be, for example, a nitrogen, sulfur or oxygen atom.
  • C 1 -C 6 alkoxycarbonyl refers to the radical —C(O)O—C 1-6 alkyl, wherein C 1-6 alkyl is as defined above.
  • C 1 -C 6 alkoxy and “C 1 -C 6 alkylthio” as used herein refers to the radicals C 1-6 —O— and C 1-6 —S—, respectively, wherein C 1-6 alkyl is as defined above.
  • hydroxyl refers to the radical —OH.
  • thiol refers to the radical —SH.
  • formyl refers to the radical —COH.
  • cyano refers to the radical —CN.
  • nitro refers to the radical —NO 2 .
  • amine refers to —NH 3 or any primary (—NH 2 R), secondary (—NHR 2 ), tertiary (—NR 3 ) or quarternary amines (—NR 4 + ), wherein each R may be the same or different and independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl as defined herein above.
  • C 1 -C 6 carboxyalkyl refers to the radical —CO—(C 1 -C 6 alkyl), wherein C 1-6 alkyl is as defined above.
  • aminocarbonyl refers to the radical —CONR 2 , wherein each of groups R is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl as defined herein above.
  • alkoxycarbonylalkyl refers to the radical —OCO—(C 1 -C 6 alkyl), wherein C 1-6 alkyl is as defined above.
  • amino refers to the radical —C( ⁇ NH)—NH 2 .
  • Such substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, an alkylthio, an acyloxy, a phosphoryl, a phosphate, a phosphonate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aryl or heteroaryl moiety.
  • moieties of a salt adduct of the invention may contain each at least one chiral center, and thus may exist in, and be isolated as, any stereoisomer thereof including, enantiomers, diastereomers or any mixtures thereof including, but not limited to racemic mixtures.
  • the present invention includes any possible stereoisomer (e.g. enantiomers, diastereomers), any mixtures thereof including, but not limited to, racemic mixtures, of any of the individual moieties of a salt adduct of the invention.
  • each of the moieties of a salt adduct of the invention may be separated by conventional techniques, such as preparative chromatography.
  • the moieties of a salt adduct of the invention may be each prepared in any mixture of possible stereoisomers thereof, including but not limited to racemic mixtures thereof, or individual stereoisomers (e.g. enantiomers, diastereomers) may be prepared either by enantiospecific synthesis or by chiral chromatographic separation of a racemate.
  • the invention should be understood to encompass natural and non-natural amino acids or any derivative thereof.
  • non-natural amino acid refers herein to amino acids, or any derivative thereof, that are not among the amino acids which are the building blocks of proteins having L as well as D-configurations, while “natural amino acids”, refer to amino acids or any derivative thereof, which are the building blocks of proteins, having L as well as D-configurations.
  • Carboxylated 5- to 7-membered lactam rings which may be optionally substituted as defined hereinabove, may be synthetically prepared by any method known to a person skilled in the art or by methods described herein.
  • said carboxylated lactam may be prepared from the corresponding amino acids, such as by methods described herein.
  • the amino dioic acid of formula (IVa) may be in the (R) or (S) configuration or any mixture thereof, such as for example the equimolar racemic mixture.
  • the invention provides methods of preparing a salt adduct including a positively charged pyridoxine moiety, or a derivative thereof, and a carboxylated 5- to 7-membered lactam ring, including the steps of:
  • a decolorizing of step (b) may be carried out by using a decolorizing agent such as activated carbon.
  • a crystallization of step (d) may be carried out by dissolving the product in an organic solvent and precipitating the purified product by cooling.
  • the solvent used in step (d) may include an alcohol such as, e.g., methanol, ethanol, isopropanol, n-butanol or a ketone such as acetone or methyl ethyl ketone, or a mixture of solvents thereof.
  • a solvent mixture of step (e) includes a mixture of an alcohol such as methanol, ethanol, isopropanol and the like, and water.
  • N-substituted L-pyroglutamic acid and the carboxylate thereof such as, for example, N-methyl-L-pyroglutamic acid (1-methyl-L-pyroglutamic acid), starting from L-pyroglutamic acid ethyl ester, as depicted in Scheme 3 below.
  • the invention further provides methods of preparing a salt adduct of the invention, wherein said positively charged moiety is a substituted pyridoxine, as depicted in Scheme 4 below.
  • the starting reagent is 2-methyl-3-hydroxy-4-methoxymethyl-5-hydroxymethyl-pyridine hydrochloride (Compound (V)).
  • the preparation of the corresponding salt is described in Example 1.
  • the invention further provides methods of preparing a salt adduct of the invention, wherein said positively charged moiety is a substituted pyridoxine, as depicted in Scheme 5 below.
  • the starting reagent in scheme 5 is 2-methyl-3-hydroxy-4-methoxymethyl-5-hydroxymethyl-pyridine hydrochloride (Compound V).
  • the preparation of the corresponding salt is described in Example 2.
  • Table 1 depicts several examples of salt adducts of the present invention.
  • the salt adducts of the invention may be useful, e.g., for preventing, treating or ameliorating one or more various diseases, conditions or disorders, particularly those associated with or inflicted by alcohol consumption.
  • the expression “associated with” as used herein includes “caused by” or “linked to” or “(usually) occurring together” or “believed to have an impact on” or otherwise linked.
  • alcohol consumption When referring to diseases, conditions or disorders associated with or inflicted by alcohol consumption, it should be understood to encompass any disease, condition or disorder which is associated with any amount or level of alcohol consumption by a subject, including, for example, a minimal amount of alcohol consumption, a moderate amount of alcohol consumption or an excessive amount of alcohol consumption. Additionally, said alcohol consumption may be, for example, sporadic, occasional, continuous, sustained or chronic (or alcohol dependence) over any period of time. In certain embodiments, alcohol consumption by a subject includes, but is not limited to social drinking, session drinking or binge drinking.
  • Diseases, conditions or disorders associated with or inflicted by alcohol consumption at any of the above amounts or levels include but are not limited to: alcohol intoxication, alcoholism, cardiovascular disease, hypertension, coronary heart disease, ischemic stroke, nutrient malabsorption, chronic pancreatitis, liver diseases (such as, for example, fatty liver, hepatitis and cirrhosis), cancer, damage to the central nervous system, damage to peripheral nervous system, malignant neoplasms, psychiatric disorders (such as for example major depression, dysthymia, mania, hypomania, panic disorder, phobias, generalized anxiety disorder, personality disorders, schizophrenia, suicide and brain damage).
  • alcohol intoxication alcoholism
  • cardiovascular disease hypertension
  • coronary heart disease ischemic stroke
  • nutrient malabsorption chronic pancreatitis
  • liver diseases such as, for example, fatty liver, hepatitis and cirrhosis
  • cancer damage to the central nervous system
  • damage to peripheral nervous system damage to peripheral nervous system
  • the invention provides a pharmaceutical composition comprising a salt adduct of the invention.
  • a pharmaceutical composition comprising a salt adduct of the invention, for use in the treatment or prevention of a disease or disorder associated with or inflicted by alcohol consumption.
  • said pharmaceutical composition comprising a salt adduct of the invention is intended for use in shortening the half-life of ethanol in the blood of a subject.
  • the invention provides a use of a salt adduct according to the invention, for the preparation of a pharmaceutical composition for the treatment or prevention of a disease or disorder associated with or inflicted by alcohol consumption.
  • said disease or disorder is selected from alcohol intoxication, alcoholism, cardiovascular disease, hypertension, coronary heart disease, ischemic stroke, nutrient malabsorption, pancreatitis, liver diseases, cancer, CNS damage, neuropsychiatric or neurological impairment, neoplasms and psychiatric disorders or any combination thereof.
  • the invention provides a use of a salt adduct of the invention, for the preparation of a pharmaceutical composition capable of shortening the half-life of ethanol in the blood of a subject.
  • ethanol half-life in the blood of a subject When referring to the shortening the half-life of ethanol in the blood of a subject, it should be understood to encompass the ability of a salt adduct of the invention and pharmaceutical compositions comprising it to reduce the time ethanol is cleared from a subject's blood by any amount.
  • the effects of ethanol half-life in the blood may result for example in faster onset of recovery from alcohol intoxication as compared with non-medicated recovery from alcohol intoxication.
  • the invention further provides a method for treating or preventing a disease or disorder associated with or inflicted by alcohol consumption, comprising administering to a subject in need thereof an effective amount of a salt adduct of the invention.
  • said disease or disorder is selected from alcohol intoxication, alcoholism, cardiovascular disease, hypertension, coronary heart disease, ischemic stroke, nutrient malabsorption, pancreatitis, liver diseases, cancer, CNS damage, neuropsychiatric or neurological impairment, neoplasms and psychiatric disorders or any combination thereof.
  • a method of shortening the half-life of ethanol in the blood of a subject comprising administering to a subject in need thereof an effective amount of a salt adduct of the invention.
  • the invention provides a method for decreasing or preventing symptoms or effects of alcohol consumption in a subject in need thereof.
  • said subject has not reached intoxication, and said method comprises administering a composition comprising a salt adduct according to the invention.
  • the invention provides a method for preventing alcohol intoxication in a subject in need thereof, comprising administering a composition comprising a salt adduct according to the invention. Additional methods of treating a subject are disclosed in PCT Publication No. WO2009004629, incorporated herein by reference.
  • the composition may comprise a salt adduct according to the invention formulated for immediate release, sustained release, controlled release, or a combination of any of the foregoing.
  • the administration is non-chronic administration.
  • a salt adduct according to the invention is formulated for non-chronic administration, and preferably for non-invasive administration.
  • the invention provides a method for increasing the mean t max of a salt adduct according to the invention in the blood of a subject in need thereof comprising administering a salt adduct according to the invention of the invention formulated for sustained release or controlled release, optionally including a portion of the salt adduct according to the invention formulated for immediate release.
  • the invention provides a use of any one of the compositions of the invention in the manufacture of a therapeutic composition useful for practicing each of the methods of the invention as described herein, e.g., for reducing or preventing symptoms or effects of alcohol consumption; for preventing alcohol intoxication; for reducing or eliminating blood alcohol levels in a subject, or for increasing the mean t max of a salt adduct according to the invention in the blood of a subject, among others.
  • kits for reducing the effect of alcohol intoxication comprising at least one container comprising a salt adduct of the invention, and instructions for use thereof.
  • said kit further comprises means for administering said salt adduct.
  • kits comprising a salt adduct or composition according to the invention, and methods for their use in the treatment or prevention of alcohol consumption related symptoms.
  • Kits may optionally include means for measuring or monitoring blood alcohol concentration (BAC) levels before, during or after administration of a salt adduct according to the invention.
  • BAC blood alcohol concentration
  • treatment refers to therapeutic treatment.
  • Those in need of treatment are mammalian subjects suffering from any pathologic condition, particularly conditions associated with excessive alcohol consumption or induced by alcohol.
  • patient or “subject in need” is meant any mammal who may be affected by the above-mentioned conditions, and to whom the treatment methods herein described are desired, particularly humans.
  • Administration of one or more compounds or compositions of the invention to the patient includes both self-administration and administration to the patient by another person.
  • the active ingredient(s) used by the invention or any composition thereof may be administered via any mode of administration, for example, buccal, nasal, oral, inhalation, intravenous, intramuscular, subcutaneous, intraperitoneal, parenteral, transmucosal, transdermal, intravaginal, intranasal, mucosal, sublingual, topical, rectal or subcutaneous administration, or any combination thereof.
  • Suitable modes of administration are well known in the art and may be selected by the skilled practitioner in view of the subject and condition to be treated.
  • terapéuticaally effective amount as used herein is intended to mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • Specific therapeutically effective amounts of the drug administered daily or otherwise by the methods of the invention may range from about 0.005 mg/kg to about 40 mg/kg of body weight, specifically, between about 0.01 to 35 mg/kg, about 0.05 to 30 mg/kg, or about 0.1 to 20 mg/kg.
  • the effective amount may be about 1, about 10, about 100, or about 1500 mg, preferably, per day.
  • the effective amount may be about 5 to 1200 mg per day, such as, for example, about 10, about 100, about 500, or about 1000 mg per day.
  • the effective amount may be about 1, about 10, about 100, about 200, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1100, about 1200, about 1300, about 1400, or about 1500 mg, preferably, per day. It should be appreciated that such effective amount may be specific for a human subject.
  • human doses may be calculated by dividing doses (mg/kg) in mice by, for example, about 12 to derive respective Human Equivalent Doses (HED) (mg/kg), and further divided by, for example, 10 (Safety Factor in extrapolating from mice to human), in accordance with the Guidance for Industry, Estimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers. [Food and Drug Administration (FDA) and Center for Drug Evaluation and Research (CDER), July (2005)].
  • the effective amount of the drug is preferably comprised within a dosage unit form.
  • the administration of the drugs according to the invention may be periodical, for example, the periodic administration may be effective twice daily, three times daily or at least once daily for at least about, for example, two days, three days, four days, five days, six day, seven days or more to one month, two months, three months, four months, or more.
  • advantages of lower doses evident to those of skill in the art, that may include, for example, inter alia, a lower risk of side effects, especially in long-term use, and a lower risk of the patients' becoming desensitized to the treatment.
  • unit dosage forms used according to invention may be either for a single or for repeated administration. Administration of said dosage unit form may be repeated, for example, about every one to about five, about ten or about twenty four hours, e.g., for a therapeutically sufficient period of time.
  • the unit dosage form may be a sustained-released dosage unit form which provides continued pH-independent drug release for a considerable period of time after administration, e.g., 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, or 12 hours or more.
  • Therapeutic formulations may be administered in any conventional dosage formulation.
  • Formulations typically comprise at least one active ingredient, as defined herein, together with one or more acceptable carriers thereof.
  • compositions of the invention may comprise a buffering agent, an agent which adjusts the osmolarity thereof, and optionally, one or more pharmaceutically acceptable carriers, excipients and/or additives as known in the art.
  • Supplementary active ingredients may also be incorporated into the compositions.
  • the carrier may be solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity may be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • pharmaceutically acceptable carrier may include any solvent, dispersion media, coatings, antibacterial and antifungal agents and the like.
  • the use of such media and agents for pharmaceutical active substances is well known in the art. Except as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic composition is contemplated.
  • Compounds or compositions of the invention may be administered orally.
  • the active compounds or compositions of the invention employed in therapy may be administered in various oral forms including, but not limited to, tablets, capsules, pills, lozenges, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions.
  • the compounds or compositions of the invention may be delivered by any pharmaceutically acceptable route and in any pharmaceutically acceptable dosage form. These include, but are not limited to the use of oral conventional rapid-release, time controlled-release, and delayed-release pharmaceutical dosage forms.
  • the active drug components may be administered in a mixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as “carrier” materials) suitably selected to with respect to the intended form of administration.
  • composition for oral administration is in the form of a tablet or capsule
  • the compounds or compositions of the invention may be combined with a non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methylcellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and other reducing and non-reducing sugars, magnesium stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, calcium stearate and the like.
  • a non-toxic pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, modified sugars, modified starches, methylcellulose and its derivatives, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, and other reducing and non-reducing sugars, magnesium stearate, stearic acid, sodium stearyl fumarate, glyce
  • the compounds or compositions of the invention may be combined with non-toxic pharmaceutically acceptable inert carriers such as ethanol, glycerol, water and the like.
  • suitable binders, lubricants, disintegrating agents and coloring and flavoring agents may also be incorporated into the mixture.
  • Stabilizing agents such as antioxidants, propyl gallate, sodium ascorbate, citric acid, calcium metabisulphite, hydroquinone, and 7-hydroxycoumarin may also be added to stabilize the dosage forms.
  • Other suitable compounds may include gelatin, sweeteners, natural and synthetic gums such as acacia, tragacanth, or alginates, carboxymethylcellulose, polyethylene, glycol, waxes and the like.
  • the compounds or compositions of the invention may be administered in controlled release formulations such as a slow release or a fast release formulation.
  • controlled release formulations may be prepared using methods known to those skilled in the art. The method of administration may be determined by the attending physician or other person skilled in the art after an evaluation of the subject's condition and requirements.
  • solutions in sesame or peanut oil or in aqueous propylene glycol may be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts.
  • aqueous solutions may be suitably buffered, if necessary, and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions may be especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal injection purposes.
  • the sterile aqueous media employed may be readily obtainable by standard techniques known to those skilled in the art. Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art.
  • the invention further provides a method for preventing or reducing the risk of developing a disease, disorder or pathological conditions associated with or inflicted by alcohol consumption.
  • Such method comprises the administration of a prophylactically effective amount of at least one compound of the invention or of any composition comprising the same, to a person at risk of developing any of the said conditions.
  • prophylactically effective amount as used herein is intended to mean that amount of a the drug of the invention or a pharmaceutical composition comprising the same, that will prevent or reduce the risk of occurrence or recurrence of the biological or medical event that is sought to be prevented in a tissue, a system, animal or human.
  • the therapeutically effective amount, or dosage may be dependent on the severity and responsiveness of the disease state to be treated, with the course of treatment lasting from, for example, several days to several months, or until a cure is effected or a diminution of the disease state is achieved.
  • Optimal dosing schedules may be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. In general, dosage is calculated according to body weight, and may be given once or more daily, weekly, monthly or yearly, or even once every 2 to 20 years.
  • the invention relates to the use of a therapeutically effective amount of at least one compound or composition of the invention or any combination or mixture thereof, in the preparation of a medicament for the treatment or prevention of a disorder, disease or condition associated with or inflicted by alcohol consumption, particularly excessive alcohol consumption as described herein.
  • the drug is formulated in an enteric coated dosage form
  • a substantial release of the compound from the dosage form after oral administration to a patient may be delayed until passage of the dosage form through the stomach.
  • pyridoxamine dihydrochloride (Aldrich) was dissolved in 6 mL water in an Erlenmeyer and a solution of 1 g sodium bicarbonate (12 mmol) in 15 mL water was added with liberation of CO 2 . The solution was cooled to 0° C. to afford crystallization. After some time, the precipitated crystals were collected by filtration, washed with cold water and dried to yield 0.73 g (87%) of the pyridoxamine free base.
  • 25 g of chemically pure (2S,3S)-3-methyl glutamic acid are suspended in 25 mL of water in an autoclave and heated at 140° C. for 5 hours.
  • the warm solution is decolorized with activated carbon and cooled gradually to room temperature and then to 4° C., during which time a precipitate is formed.
  • the precipitate is isolated by filtration and crystallized from acetone to obtain white crystals.
  • L-pyroglutamic acid ethyl ester (10 g, 0.07 mole) is dissolved in tetrahydrofuran (100 mL) and cooled to 0° C.
  • Sodium hydride (2 g, in a 60% suspension in oil, 0.084 mole) is added to the mixture, followed by addition of methyl iodide (5.2 mL, 0.084 mole) under constant mixing.
  • the mixture is allowed to warm up to ambient temperature and mixed for an additional hour.
  • the solvent is evaporated under reduced pressure and water is added (10 mL).
  • the aqueous layer is extracted with dichloromethane, which is evaporated to yield the crude 1-methyl-L-pyroglutamic acid ethyl ester.
  • the obtained crude 1-methyl-L-pyroglutamic acid ethyl ester is dissolved in methanol (100 mL) and a solution of 2N sodium hydroxide (35 mL) is added. The mixture is heated at reflux for 3 hours then cooled and the methanol is evaporated. The resulting aqueous solution is acidified to pH 2 using HCl 1M, washed with dichloromethane and evaporated to yield 1-methyl-L-pyroglutamic acid.
  • Standard curves are established using known GSH dilutions.
  • Reduced (GSH) is measured by glutathione reductase and NADPH followed by reduction of the colorimetric reagent 5-50-dithio-bis-(2-nitrobenzoic acid) by GSH.
  • the efficacy of the compounds of the invention is tested according to the method described by Calabrese, V. et al. in Int. J. Tiss. Reac . XVII (3) 101-108 (1995).
  • Two groups of male Wistar rats weighing 250-300 g are treated with a dose of 2 g/kg body weight of 20% ethanol solution for seven days.
  • One group is treated with the tested salt 1 hour before ethanol administration.
  • the second group serves as a control.
  • blood samples are removed at different times by cardiac puncture.
  • the blood is centrifuged and plasma samples are analysed for ethanol content by head-space gas-chromatography. Ethanol concentrations are calculated based on a standard curve comparing peak height between standads and tested samples.

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BRPI1015231A2 (pt) * 2009-06-25 2018-02-20 Alcobra Ltd método para tratamento, suavização de sintomas, alívio, melhoria e prevenção de uma doença, distúrbio ou condição cognitiva
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