Indian Patents. 228103:ESTER DERIVATIVES OF A DECAHYDROISOQUINOLINE-3-CARBOXYLIC ACID AS ANALGESICS

Title of Invention	ESTER DERIVATIVES OF A DECAHYDROISOQUINOLINE-3-CARBOXYLIC ACID AS ANALGESICS
Abstract	The present invention provides compounds of formula (I). The present invention further provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a neurological disorder. The present invention further provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment of pain or migraine.

Full Text	FIELD OF THE INVENTION The present invention relates to novel prodrug forms of (3S,4aR,6R,8aR)-6-[2- (l(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid, to pharmaceutical compositions containing the prodrug forms, and to methods of using the prodrug forms. BACKGROUND OF THE INVENTION United States Patent No. 5,670,516 discloses that certain decahydroisoquinoline derivatives are AMPA receptor antagonists, and as such are useful in the treatment of many different conditions, including pain and migraine. In addition, WO 01/02367 A3, published January 11, 2001, discloses diester prodrug forms of the selective GluR5 antagonist 3S,4aR,6R,8aR-6-(((4-carboxy)phenyl)methyl)-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylicacid. It is an object of the present invention to provide monoesters of (3S,4aR,6R,8aR)- 6-[2-(1(2)H-tetrazole-5-yl)ethyl 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid which provide improved bioavailability of the parent monoacid in a patient In addition, it is an object of the present invention to provide monoesters of (3S,4aR,6R,8aR)-6-[2-(l(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,Sa- decahydroisoquinoline-3-carboxylic acid which are substantially converted to the parent monoacid in the patient. SUMMARY OF THE INVENTION It has now been discovered that the novel monoesters of the monoacid, (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid provide significantly improved bioavailability of the monoacid as compared to that provided by administration of the monoacid itself. In addition, the monoesters are substantially converted to the monoacid in the patient. The monoacid is disclosed in U.S. Patent 5,670,516, issued September 23, 1997. Thus, the present invention provides compounds of formula I: wherein R represents C1-C20 alkyl, C2-C6 alkenyl, C1-C6 alkyl-aryl, C1-C6 alkyl-(C3- C10)cycloalkcyl, C1-C6 alkyl-N,N-C1-C6 dialkylamine, C1-C6 alkyl-pyrrolidine, C1-C6 alkyl-piperidine, C1-C6 alkyl-morpholine or a pharmaceutically acceptable salt thereof. The present invention further provides a method of antagonizing the AMPA or GluR5 receptor, which comprises administering to a patient an effective amount of a compound of formula I. In addition, the present invention provides a method for the treatment of a neurological disorder, which comprises administering to a patient in need thereof an effective amount of a compound of formula I. The present invention further provides a method for the treatment of pain or migraine, which comprises administering to a patient in need thereof an effective amount of a compound of formula I. The present invention further provides the use of a compound of formula I for the manufacture of a medicament for the treatment of a neurological disorder. The present invention further provides the use of a compound of formula I for the manufacture of a medicament for the treatment of pain or migraine. DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "prodrug" refers to a monoester derivative of a carboxylic acid functional drug, which derivative, when administered to a patient is converted into the monoacid (drug). The enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the parent monocarboxylic acid (drug ) is released. As used herein the term "Compound A" refers to (3S,4aR,6R,8aR)-6-[2-(1(2)H- tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid. As used herein the term "Compound B" refers to 6-[2-(2H-Tetrazol-5-yl)-ethyl]- decahydro-isoquinoline-3-carboxylic acid ethyl ester. As used herein the term "Compound C" refers to 6-[2-(1H-Tetrazol-5-yl)-ethyl]- decahydro-isoquinoline-3-carboxylic acid 2-ethyl-butyl ester. As used herein the term "Compound D" refers to 6-[2-(1H-Tetrazol-5-yl)-ethyl]- decahydro-isoquinoline-3-carboxyIic acid isobutyl ester . As used herein the term "Compound E" refers to 6-[2-(2H-Tetrazol-5-yl)-ethyl]- decahydro-isoquinoline-3-carboxyIic acid 3-methyl-butyl ester. As used herein the term "Compound F" refers to 6-[2-(1H-Tetrazol-5-yl)-ethyl]- decahydro-isoquinoline-3-carboxylic acid decyl ester. As used herein the term "C1-C4 alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like. As used herein the term "C1-C6 alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like. It will be understood that the term "C1-C4 alkyl" is included within the definition of "C1-C6 alkyl". As used herein the term "C1-C10 alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl, isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl, octyl, 4-methyl-3-heptyl and the like. It will be understood that the terms "C1-C4 alkyl" and "C1-C6 alkyl" are included within the definition of "C1-C10 alkyl". As used herein the term "C1-C20 alkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n- dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-nonadecyl, n- eicosyl and the like. It will be understood that the terms "C1-C4 alkyl" , "C1-C6 alkyl" , and "C1-C10alkyl" are included within the definition of "C1-C20 alkyl". As used herein, the terms "Me", "Et", "Pr", "iPr", "Bu" and "t-Bu" refer to methyl, ethyl, propyl, isopropyl, butyl and tert-butyl respectively. As used herein the term "C2-C6 alkenyl" refers to a straight or branched, monovalent, unsaturated aliphatic chain having from two to six carbon atoms. Typical C2-C6 alkenyl groups include ethen'yl (also known as vinyl), 1-methylethenyl, 1-methyl-1- propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl, 2-pentenyl, and the like. As used herein, the term "aryl" refers to monovalent carbocyclic group containing one or more fused or non-fused phenyl rings and includes, for example, phenyl, 1- or 2- naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and the like. As used herein, the term "C1-C6 alkyl-aryl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an aryl group attached to the aliphatic chain. Included within the term "C1-C6 alkyl-aryl" are the following: and the like. As used herein the term "(C3-C10)cycloalkyl" refers to a saturated hydrocarbon ring structure containing from three to ten carbon atoms. Typical C3-C10 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. It is understood that "(C3-C8)cyc]oalkyr and "(C4-C6)cycloalkyl" is included within the term "(C3-C10)cycloalkyl". As used herein, the term "C1-C6 allcyl-(C3-C10)cycloalkyl" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a (C3- C10)cycloalkyl attached to the aliphatic chain. Included within the term "C1-C6 alkyl-(C3 C10)cycloalkyl" are the following: and the like. As used herein the term "N,N-C1-C6 dialkylamine" refers to a nitrogen atom substituted with two straight or branched, monovalent, saturated aliphatic chains of 1 to 6 carbon atoms. Included within the term "N,N-C1-C6 dialkylamine" are -N(CH3)2, - N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH2CH2CH2CH3)2, and the like. As used herein the term "C1-C6 alkyl-N,N-C1-C6 dialkylamine" refers to straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an N,N-C1-C6 dialkylamine attached to the aliphatic chain. Included within the term "C1-C6 alkyl-N,N-C1-C6 dialkylamine" are the following: and the like. As used herein the term "C1-C6 alkyl-pyrrolidine" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a pyrrolidine attached to the aliphatic chain. Included within the scope of the term "C1-C6 alkyl- pyrrolidine" are the following: and the like. As used herein the term "C1-C6 alkyl-piperidine" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a piperidine attached to the aliphatic chain. Included within the scope of the term "C1-C6 alkyl- piperidine" are the following: and the like. As used herein the tenia "C1-C6 alkyl-morpholine" refers to a straight or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms winch has a morpholine attached to the aliphatic chain. Included within the scope of the term "C1-C6 alkyl- morpholine" are the following: and the like. The compounds of the present invention contain a tetrazole ring, which is known to exist as tautomeric structures. The tetrazole, having the double bond on the nitrogen atom at the 1-position and the hydrogen on the nitrogen atom at the 2-position is named as a 2H tetrazole and is represented by the following structure. The corresponding tautomeric form wherein the hydrogen is at the nitrogen atom at the 1- position and the double bond on the nitrogen atom at the 4-position is named as a 1H- tetrazole. The 1H-tetrazole is represented by the following formula. Mixtures of the two tautomers are referred to herein as 1(2)H-tetrazoles. The present invention contemplates both tautomeric forms as well as the combination of the two tautomers. The designation refers to a bond that protrudes forward out of the plane of the page. The designation refers to a bond that protrudes backward out of the plane of the page. This invention includes the hydrates and the pharmaceutically acceptable salts of the compounds of formula I. A compound of this invention can possess a sufficiently basic functional group which can react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt. The term "pharmaceutically acceptable salt" as used herein, refers to salts of the compounds of formula I which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts. Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, trifluoroacetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, trifluoroacetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-1,6- dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, a-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred pharmaceutically acceptable acid addition salts are those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid, oxalic acid, triofluoroacetic acid, and methanesulfonic acid. It should be recognized that the particular counterion forming a part of any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate. As used herein, the terra "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term "enantiomer" refers to two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term "chiral center" refers to a carbon atom to which four different groups are attached. As used herein, the term "diastereomers" refers to stereoisomers which are not enantiomers. In addition, two diastereomers winch have a different configuration at only one chiral center are referred to herein as "epimers". The terms "racemate", "racemic mixture" or "racemic modification" refer to a mixture of equal parts of enantiomers. The term "enantiomeric enrichment" as used herein refers to the increase in the amount of one enantiomer as compared to the other. A convenient method of expressing the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee", which is found using the following equation: wherein E1 is the amount of the first enantiomer and E2 is the amount of the second enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of 50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than 90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than 99% is most especially preferred. Enantiomeric enrichment is readily determined by one of ordinary skill in the art using standard techniques and procedures, such as gas or high performance liquid chromatography with a chiral column. Choice of the appropriate chiral column, eluent and conditions necessary to effect separation of the enantiomeric pair is well within the knowledge of one of ordinary skill in the art. In addition, the enantiomers of compounds of formula I can be resolved by one of ordinary skill in the art using standard techniques well known in the art, such as those described by J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981. The compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention. The terms "R" and "S" are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center. The term "R" (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon their atomic number (in order of decreasing atomic number). A partial list of priorities and a discussion of stereochemistry is contained in "Nomenclature of Organic Compounds: Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages 103-120. The specific stereoisomers and enantiomers of compounds of formula (I) can be prepared by one of ordinary skill in the art utilizing well known techniques and processes, such as those disclosed by Eliel and Wilen, "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., 1994, Chapter 7, Separation of Stereoisomers. Resolution. Racemization, and by Collet and Wilen, "Enantiomers, Racemates, and Resolutions", John Wiley & Sons, Inc., 1981. For example, the specific stereoisomers and enantiomers can be prepared by stereospecific syntheses using enantiomerically and geometrically pure, or enantiomerically or geometrically enriched starting materials. In addition, the specific stereoisomers and enantiomers can be resolved and recovered by techniques such as chromatography on chiral stationary phases, enzymatic resolution or fractional recrystallization of addition salts formed by reagents used for that purpose. The compounds of formula I can be prepared by techniques and procedures readily available to one of ordinary skill in the art. More specifically, compounds of Formula I can be chemically prepared, for example, by following the synthetic routes set forth in the Scheme below. However, the following discussion is not intended to be limiting to the scope of the present invention in any way. For example, the specific synthetic steps for the route described herein may be combined in different ways to prepare the compounds of Formula I. All substituents, unless otherwise indicated, are as previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. For example, certain starting materials can be prepared by one of ordinary skill in the art following procedures disclosed in United States Patents Nos. 5,356,902 (issued October 18, 1994) and 5,446,051 (issued August 29, 1995) and 5,670,516 (issued September 23, 1997) the entire contents, all of which, are herein incorporated by reference. Other necessary reagents and starting materials for the below procedures may be made by procedures which are selected from standard techniques of organic and heterocyclic chemistry, techniques which are analogous to the syntheses of known structurally similar compounds, and the procedures described in the Examples, including any novel procedures. In Scheme I, compound A is esterified to provide the monoester of formula I under standard conditions well known in the art. For example, compound A is dissolved in a suitable organic solvent and treated with a suitable acid, such as hydrochloric acid. Examples of suitable organic solvents include, methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, t-butyl alcohol, pentyl alcohol, isopentyl alcohol, hexyl alcohol, 3-methylpentyl alcohol, 2-ethylbutyl alcohol, n- heptyl alcohol, n-octyl alcohol, decyl alcohol and the like. The reaction is heated at about 40°C to about 60°C for about 4 hours to about 16 hours. The product is then isolated and purified using techniques well known to one of ordinary skill in the art, such as extraction techniques and chromatography. For example, the above reaction is cooled, diluted with a suitable organic solvent, such as ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the compound of formula I. This material may be further purified by flash chromatography on silica gel with a suitable eluent such as ethyl acetate/hexane. Alternatively, compound A is dissolved in a suitable organic solvent and treated with an excess of thionyl chloride. Examples of suitable organic solvents are anhydrous methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, t-butyl alcohol, pentyl alcohol, isopentyl alcohol, hexyl alcohol, 3-methylpentyl alcohol, ?.-ethylbutyl alcohol, n-heptyl alcohol, n-octyl alcohol, decyl alcohol and the like. The solution is stirred at reflux for about 1 to 3 hours, and at room temperature for about 8 to 16 hr. The mixture is then concentrated under vacuum, and the residue is purified in a manner analogous to the procedures described above to provide the prodrug monoester of formula I. The pharmaceutically acceptable salts of formula I are readily prepared by one of ordinary skill in the art using standard techniques and procedures. For example, the above product is suspended in diethyl ether, which has been saturated with HC1 gas. The mixture is stirred for about 1 to 3 hours. The precipitate is then filtered and washed with diethyl ether under vacuum to provide the pharmaceutically acceptable salt of the prodrug monoester of formula I. The following examples represent typical syntheses of the compounds of formula I as described generally above. These examples are illustrative only and are not intended to limit the invention in any way. The reagents and starting materials are readily available to one of ordinary skill in the art. As used herein, the following terms have the meanings indicated: "eq" or "equiv." refers to equivalents; "g" refers to grams; "mg" refers to milligrams; "L" refers to liters; "mL" refers to milliliters; "µL" refers to microliters; "mol" refers to moles; "mmol" refers to millimoles; "psi" refers to pounds per square inch; "min" refers to minutes; "h" refers to hours; "°C" refers to degrees Celsius; "TLC" refers to thin layer chromatography; "HPLC" refers to high performance liquid chromatography; "5"refers to part per million down-field from tetramethylsilane; "THF" refers to tetrahydrofuran; "DMF" refers to N,N-dimethylformamide; "DMSO" refers to methyl sulfoxide; "aq" refers to aqueous; "EtOAc" refers to ethyl acetate; "iPrOAc" refers to isopropyl acetate; "MeOH" refers to methanol; "MTBE" refers to tert-butyl methyl ether, and "RT" refers to room temperature. Example 1 To a solution of 2.5 g (8.4 mmol) of 6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro- isoquinoline-3-carboxylic acid monohydrate (prepared as described in J. Med. Chem., 39 (11), pp. 2232-2244, (1996) or U.S. Patent No. 5,670,516 (issued September 23, 1997)) in 20 ml of 2-ethyl-1-butanol, 6.8 ml (92.8 mmol) of thionyl chloride is added. The solution is stirred at 120°C for 3 hr. The mixture is concentrated in vacuo and the residue washed with ethyl ether. The residue is purified by SPE (Oasis HLB) to afford the title compound. Electrospray Mass Spectrum: M+l=364. Example 2 6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acid isobutyl ester Prepared according to the procedures essentially as described in Example 1, above, using 20 mL of 2-methyl-1-propanol to afford of the title compound. Electrospray Mass Spectrum: M+l = 336. Prepared according to the procedures essentially as described in Example 1, above, using using 20 mL of 3-methyl-l-butanol to afford of the title compound. Electrospray Mass Spectrum: M+l =350. A solution of 2.5 g (S.4 mmol) of 6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro- isoquinoline-3-carboxylic acid monohydrate in 50 ml decyl alcohol saturated with hydrogen chloride (g) is heated at 120°C overnight. The mixture is concentrated in vacuo and the residue purified by SPE (Oasis HLB) to afford the title compound. Electrospray Mass Spectrum: M+l =420. Example 5 A solution of 6.0 g (21.5 mmol) of 6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro- isoquinoline-3-carboxylic acid monohydrate in 70 mL of ethanol saturated with hydrogen chloride (g) is heated at reflux overnight. The mixture is concentrated in vacuo, suspended in diethyl ether, and again concentrated in vacuo. The residue is suspended in diethyl ether and heated at reflux for 3 hr. The solid is filtered and rinsed with diethyl ether to afford 7.4 g (100%) of the title compound. Electrospray Mass Spectrum: M+l = 308. Particular Aspects of the compounds of Formula I: The following list sets out several groupings of particular substituents of the compounds of Formula I. It will be understood that the compounds of Formula I having such particular substituents represent particular aspects of the present invention. It will be further understood that each of these groupings may be combined with other provided groupings, to create still additional particular aspects of the present invention. Thus, a particular aspect of the novel compounds of Formula I is one wherein: (a) R represents C1-C10 alkyl, C2-C6 alkenyl, C1-C6 alkyl-aryl, C1-C6 alkyl-(C3- C10)cycloalkyl, C1-C6 alkyl-N,N-C1-C6 dialkylamine, C1-C6 alkyl- pyrrolidine, C1-C6 alkyl-piperidine, C1-C6 alkyl-morpholine; (b) R represents C1-C10 alkyl or C2-C6 alkenyl; (c) R represents C1-C10 alkyl or C1-C6 alkyl-aryl; (d) R represents C1-C10 alkyl or C1-C6 alkyl-(C3-C10)cycloalkyl; (e) R represents C1-C10 alkyl or C1-C6 alkyl-N,N-C1-C6 dialkylamine; (f) R represents C1-C10 alkyl or C1-C6 alkyl-pyrrolidine; (g) R represents C1-C10 alkyl or C1-C6 alkyl-piperidine; (h) R represents C1-C10 alkyl or C1-C6 alkyl-morpholine; (i) R represents C1-C10 alkyl; (j) R represents 2-ethyl butyl, isobutyl, 3-methyl butyl, decyl, or ethyl; or (k) R represents ethyl Pharmacological Results The following in vivo data, in rats, dogs and monkeys, exemplify the improvement in bioavailability of the monoester prodrugs of the present invention over the monoacid of (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid. Percent bioavailability is determined using the following equation: wherein AUC represents the area under the curve, p.o. represents oral dose, and i.v. represents intravenous dose. Bioavailability in Dogs: Beagle dogs (2 male and 1 female) are administered an oral dose, and later an iv dose of (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid (10 mg/Kg p.o; 1mg/Kg i.v.) to determine oral bioavailability. Subsequently, the same three dogs are administered an oral 10 mg/kg dose of an ester prodrug (for example (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl- l,2,3,4,4a,5,6,7,8,8a-decahydroisoqumoline-3-carboxylic acid ethyl ester, HCL salt) to determine whether the prodrug would increase bioavailability of the parent acid. The plasma concentrations of (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl- l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid are determined by LC/MS/MS. Study Methods: Live Phase: (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid (HC1 salt) is dissolved in dilute sodium hydroxide for oral administration (30 mg/ml) and in 10% ethanol/water for iv administration (10 mg/ml). (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl- 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid ethyl ester, HCL salt is dissolved in water for oral administration (30 mg/ml). Dogs weighed between 12 to 15 kg. Results: The oral bioavailability for 3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl- l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid was determined to be 18% in dogs. When 3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid ethyl ester(HCL salt) was administered, bioavailability increased to 33.1%. The use of the prodrug form 3S,4aR,6R,8aR)-6-[2- (1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid ethyl ester (HCL salt), provided approximately a 2 fold increase in bioavailability over the parent acid. Tables 1 below summarizes the pharmacokinetic parameters found for Compounds A and B following 1 mg/kg administration (i.v.) or 10 mg/kg administration (p.o.) to Beagle Dogs. Bioavailability in Rats Male Fischer Rats are administered either an oral or iv dose of (3S,4aR,6R,8aR)-6- [2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (30 mg/Kg p.o; 10mg/Kg i.v.) to determine oral bioavailability. A separate group of rats are administered an oral 10 mg/kg dose of an ester prodrug (for example (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid ethyl ester, HCL salt) to determine whether the prodrug would increase bioavailability of the parent acid. The plasma concentrations of (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid are determined by LC/MS/MS. Study Methods: Live Phase: (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinolme-3-carboxylic acid (HO salt) is dissolved in dilute sodium hydroxide for oral administration (15 mg/ml) and in 10% ethanol/water for iv administration (10 mg/ml). (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl- l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid ethyl ester, HCL salt is dissolved in water for oral administration (15 mg/ml). Fischer male 344 rats weighing between 218 to 244 g are utilized. Plasma samples are collected at 0.5, 1, 2, 4, 6, 8, 10 and 24 hr (3 rats per time point). Results: The oral bioavailability for 3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl- l,2,3,4,4a,5,6,7,8,Sa-decahydroisoquinoline-3-carboxylic acid was determined to be 3.6% in rats. When 3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl- l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid ethyl ester(HCL salt) was administered, bioavailability increased to 17.7%. The use of the prodrug form 3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid ethyl ester (HCL salt), provided approximately a 5 fold increase in bioavailability over the parent acid. Tables 2 below summarizes the pharmacokinetic parameters found for Compounds A and B following 10 mg/kg administration (i.v.) or 30 mg/kg administration (p.o.)to Fischer Rats. Bioavailability in Cynomolgus Monkeys Two male and two female monkeys are administered an oral, and later, an iv dose of(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid (oral: 3 mg/kg; iv: 0.3 mg/kg) to determine oral bioavailability. The same animals are also subsequently administered an oral 3 mg/kg dose of (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid ethyl ester to determine if the ester prodrug form increases bioavailability of the parent acid. The plasma concentrations of the parent acid are determined by LC/MS/MS. Study Design Four cynomolgus monkeys (2/sex) are given a single oral dose of (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,S,8a- decahydroisoquinoline-3-carboxylic acid (3 mg/kg) on day 0, a single iv dose of (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid (0.3 mg/kg) on day 4 and a single oral dose of (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid ethyl ester (3 mg/kg) on day 8. Blood samples are collected at 0.5, 1, 2, 3, 4, 5, 6 and 8 hours post dose for oral dosing and 0.167, 0.33, 0.67, 1, 1.5,2, 3 and 4 hours post dose for iv dosing. Dosing solutions for both the acid and ester arere prepared in 0.9% sodium chloride. Results: The oral bioavailability for (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl- l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid was determined to be 4.5% in monkeys. When (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl- l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid ethyl ester(HCL salt) was administered, bioavailability increased to 11.4%. The use of the prodrug form (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a- decahydroisoquinoline-3-carboxylic acid ethyl ester (HCL salt), provided approximately a 2.5 fold increase in bioavailability over the parent acid. Table 3 below summarizes the pharmacokinetic parameters found for Compounds A and B following i.v. or oral administration to Cynomolgus Monkeys. Table 3. Pharmacokinetic Parameters of Compound A in Cynomolgus Monkeys after an i.v. and p.o. Dose of Compound A or the ester Prodrug, Compound B. The present invention further provides a method of antagonizing the AMPA or GluR5 receptors, of the larger class of excitatory amino acid receptors, which comprises administering to a patient an effective amount of a compound of formula I. The excessive or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell damage or loss by way of a mechanism known as excitotoxicity. This process has been suggested to mediate neuronal degeneration in a variety of neurological disorders and conditions. The medical consequences of such neuronal degeneration makes the abatement of these degenerative neurological processes an important therapeutic goal. For instance, excitatory amino acid receptor excitotoxicity has been implicated in the pathophysiology of numerous neurological disorders, including the etiology of cerebral deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord lesions resulting from trauma or inflammation, perinatal hypoxia, cardiac arrest, and hypoglycemic neuronal damage. In addition, excitotoxicity has been implicated in chronic neurodegenerative conditions including Alzheimer's Disease, Huntington's Chorea, inherited ataxias, AIDS-induced dementia, amyotrophic lateral sclerosis, idiopathic and drug-induced Parkinson's Disease, as well as ocular damage and retinopathy. Other neurological disorders implicated with excitotoxicity and/or glutamate dysfunction include muscular spasticity including tremors, drug tolerance and withdrawal, brain edema, convulsive disorders including epilepsy, depression, anxiety and anxiety related disorders such as post-traumatic stress syndrome, tardive dyskinesia, and psychosis related to depression, schizophrenia, bipolar disorder, mania, and drug intoxication or addiction (see generally United States Patent No. 5,446,051 and 5,670,516). Excitatory amino acid receptor antagonists may also be useful as analgesic agents and for treating or preventing various forms of headache, including cluster headache, tension-type headache, and chronic daily headache. In addition, published International Patent application WO 98/45720 reports that excitatory amino acid receptor excitotoxicity participates in the etiology of acute and chronic pain states including severe pain, intractable pain, neuropathic pain, post-traumatic pain. It is also known that trigeminal ganglia, and their associated nerve pathways, are associated with painful sensations of the head and face such as headache and, in particular, migraine. Moskowitz (Cephalalgia, 12, 5-7, (1992) proposed that unknown triggers stimulate the trigeminal ganglia which in turn innervate vasculature within cephalic tissue, giving rise to the release of vasoactive neuropeptides from axons innervating the vasculature. These neuropeptides initiate a series of events leading to neurogenic inflammation of the meninges, a consequence of which is pain. This neurogenic inflammation is blocked by sumatriptan at doses similar to those required to treat acute migraine in humans. However, such doses of sumatriptan are associated with contraindications as a result of sumatriptan's attendant vasoconstrictive properties.(see MacIntyre, P.D., et al., British Journal of Clinical Pharmacology, 34, 541-546 (1992); Chester, A.H., et al, Cardiovascular Research, 24, 932-937 (1990); Conner, H.E., et al., European Journal of Pharmacology, 161, 91-94 (1990)). Recently, it has been reported that all five members of the kainate subtype of ionotropic glutamate receptors are expressed on rat trigeminal ganglion neurons, and in particular, high levels of GluR5 and KA2 have been observed. (Sahara et al., The Journal of Neuroscience, 17(17), 6611 (1997)). As such, migraine presents yet another neurological disorder which may be implicated with glutamate receptor excitotoxicity. The use of a neuroprotective agent, such as an excitatory amino acid receptor antagonist, is believed to be useful in treating or preventing all of the aforementioned disorders and/or reducing the amount of neurological damage associated with these disorders. For example, studies have shown that AMPA receptor antagonists are neuroprotective in focal and global ischemia models. The competitive AMPA receptor antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline) has been reported effective in preventing global and focal ischemic damage. Sheardown et al., Science, 247, 571 (1900); Buchan et al, Neuroreport, 2, 473 (1991); LePeillet et al., Brain Research, 571, 115 (1992). The noncompetitive AMPA receptor antagonists GKYI 52466 has been shown to be an effective neuroprotective agent in rat global ischemia models. LaPeillet et al., Brain Research, 571, 115 (1992). European Patent Application Publication No. 590789A1 and United States Patents No. 5,446,051 and 5,670,516 disclose that certain decahydroisoquinoline derivative compounds are AMPA receptor antagonists and, as such, are useful in the treatment of a multitude of disorders conditions, including pain and migraine headache. WO 98/45270 discloses that certain decahydroisoquinoline derivative compounds are selective antagonists of the iGluR5 receptor and are useful for the treatment of various types of pain, including; severe, chronic, intractable, and neuropathic pain. As such, the compounds of the present invention are believed to be useful for treating neurological disorders, as discussed above. Such compounds could address a long felt need for safe and effective treatments for neruological disorders, without attending side effects. Thus, the present invention further provides a method for the treatment of a neurological disorder, which comprises administering to a patient in need thereof, an effective amount of a compound of formula I. More particularly, the present invention further provides a method for the treatment of pain or migraine, which comprises administering to a patient in need thereof, an effective amount of a compound of formula I. The treatment of neurological disorders and neurodegenerative diseases is hereby furthered. As used herein the term "patient" refers to a mammal, such a mouse, guinea pig, rat, dog, monkey, or human. It is understood that the preferred patient is a human. The term "treating" (or "treat") as used herein includes its generally accepted meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping, or reversing progression, severity, of a resultant symptom. As such, the methods of this invention encompass both therapeutic and prophylactic administration. As used herein the term "effective amount" refers to the amount or dose of the compound, upon single or multiple dose administration to the patient, which provides the desired effect in the patient under diagnosis or treatment. An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose of compound administered, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of mammal; its size, age, and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg. In effecting treatment of a patient afflicted with a condition, disease or disorder described above, a compound of formula (I) can be administered in any form or mode which makes the parent monoacid compound bioavailable in effective amounts, including oral and parenteral routes. For example, compounds of formula (I) can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally, buccally, and the like. Alternatively, the compound may be administered by continuous infusion. Oral administration is generally preferred. One skilled in the art of preparing formulations can readily select the proper form and mode of administration depending upon the particular characteristics of the compound selected, the disease state to be treated, the stage of the disease, and other relevant circumstances. It will be understood by the skilled reader that all of the compounds used in the present invention are capable of forming salts, and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free bases. In all cases, the use of the pharmaceuticals described above as salts is contemplated in the description herein, and often is preferred, and the pharmaceutically acceptable salts of all of the compounds are included in the names of them. According to another aspect, the present invention provides a pharmaceutical composition, which comprises a compound of formula I or a pharmaceutically acceptable salt thereof as defined hereinabove and a pharmaceutically acceptable diluent or carrier. The pharmaceutical compositions are prepared by known procedures using well- known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. Some examples of suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates, tragcanth, gelatin, calcium silicate, micro-crystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil. The formulations can additionally include lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 mg to about 500 mg, more preferably about 5 mg to about 300 mg (for example 25 mg) of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way. Formulation 1 Hard gelatin capsules are prepared using the following ingredients: The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities. Formulation 2 Tablets each containing 60 mg of active ingredient are made as follows: The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 rnesh U.S. sieve. The granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. We Claim: 1. A compound of the formula: wherein R represents C2-C10 alkyl, or a pharmaceutically acceptable salt thereof. 2. A compound or salt as claimed in claim 1, wherein R represents 2-ethyl butyl, isobutyl, 3-methyl butyl, decyl, or ethyl. 3. A compound or salt as claimed in claim 2, wherein R represents 2-ethyl butyl, 4. A compound or salt as claimed in claim 2, wherein R represents isobutyl. 5. A compound or salt as claimed in claim 2, wherein R represents 3-methyl butyl. 6. A compound or salt as claimed in claim 2, wherein R represents decyl. 7. A compound or salt according to claim 2, wherein R represents ethyl. 8. A compound as claimed in Claim 1 which is (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5- yl)-ethyl] -l,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid 2-ethyl-butyl ester. 9. A compound as claimed in Claim 1 which is (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5- yl)-ethyl] -l,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid isobutyl ester. 10. A compound as claimed in Claim 1 which is (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5- yl)-ethyl] -l,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid 3-methyl butyl ester. 11. A compound as claimed in Claim 1 which is (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5- yl)-ethyl] -l,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid decyl ester. 12. A compound as claimed in Claim 1 which is (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5- yl)-ethyl] -l,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid ethyl ester. 13. A salt as claimed in any one of Claims 3-6 that is the trifluoroacetate salt. 14. A salt as claimed in Claim 7 that is the hydrochloride salt. 15. A pharmaceutical composition, which comprises a compound or salt as claimed in any one of Claims 1-14 or (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl] - 1.2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid methyl ester, and a pharmaceutically acceptable diluent or carrier. The present invention provides compounds of formula (I). The present invention further provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment of a neurological disorder. The present invention further provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment of pain or migraine.

Full Text

FIELD OF THE INVENTION
The present invention relates to novel prodrug forms of (3S,4aR,6R,8aR)-6-[2-
(l(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid,
to pharmaceutical compositions containing the prodrug forms, and to methods of using
the prodrug forms.
BACKGROUND OF THE INVENTION
United States Patent No. 5,670,516 discloses that certain decahydroisoquinoline
derivatives are AMPA receptor antagonists, and as such are useful in the treatment of
many different conditions, including pain and migraine. In addition, WO 01/02367 A3,
published January 11, 2001, discloses diester prodrug forms of the selective GluR5
antagonist 3S,4aR,6R,8aR-6-(((4-carboxy)phenyl)methyl)-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylicacid.
It is an object of the present invention to provide monoesters of (3S,4aR,6R,8aR)-
6-[2-(1(2)H-tetrazole-5-yl)ethyl 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic
acid which provide improved bioavailability of the parent monoacid in a patient In
addition, it is an object of the present invention to provide monoesters of
(3S,4aR,6R,8aR)-6-[2-(l(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,Sa-
decahydroisoquinoline-3-carboxylic acid which are substantially converted to the parent
monoacid in the patient.
SUMMARY OF THE INVENTION
It has now been discovered that the novel monoesters of the monoacid,
(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid provide significantly improved bioavailability
of the monoacid as compared to that provided by administration of the monoacid itself.
In addition, the monoesters are substantially converted to the monoacid in the patient.
The monoacid is disclosed in U.S. Patent 5,670,516, issued September 23, 1997.
Thus, the present invention provides compounds of formula I:
wherein R represents C1-C20 alkyl, C2-C6 alkenyl, C1-C6 alkyl-aryl, C1-C6 alkyl-(C3-
C10)cycloalkcyl, C1-C6 alkyl-N,N-C1-C6 dialkylamine, C1-C6 alkyl-pyrrolidine, C1-C6
alkyl-piperidine, C1-C6 alkyl-morpholine or a pharmaceutically acceptable salt thereof.
The present invention further provides a method of antagonizing the AMPA or
GluR5 receptor, which comprises administering to a patient an effective amount of a
compound of formula I.
In addition, the present invention provides a method for the treatment of a
neurological disorder, which comprises administering to a patient in need thereof an
effective amount of a compound of formula I.
The present invention further provides a method for the treatment of pain or
migraine, which comprises administering to a patient in need thereof an effective amount
of a compound of formula I.
The present invention further provides the use of a compound of formula I for the
manufacture of a medicament for the treatment of a neurological disorder.
The present invention further provides the use of a compound of formula I for the
manufacture of a medicament for the treatment of pain or migraine.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "prodrug" refers to a monoester derivative of a carboxylic
acid functional drug, which derivative, when administered to a patient is converted into
the monoacid (drug). The enzymatic and/or chemical hydrolytic cleavage of the
compounds of the present invention occurs in such a manner that the parent
monocarboxylic acid (drug ) is released.
As used herein the term "Compound A" refers to (3S,4aR,6R,8aR)-6-[2-(1(2)H-
tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylicacid.
As used herein the term "Compound B" refers to 6-[2-(2H-Tetrazol-5-yl)-ethyl]-
decahydro-isoquinoline-3-carboxylic acid ethyl ester.
As used herein the term "Compound C" refers to 6-[2-(1H-Tetrazol-5-yl)-ethyl]-
decahydro-isoquinoline-3-carboxylic acid 2-ethyl-butyl ester.
As used herein the term "Compound D" refers to 6-[2-(1H-Tetrazol-5-yl)-ethyl]-
decahydro-isoquinoline-3-carboxyIic acid isobutyl ester .
As used herein the term "Compound E" refers to 6-[2-(2H-Tetrazol-5-yl)-ethyl]-
decahydro-isoquinoline-3-carboxyIic acid 3-methyl-butyl ester.
As used herein the term "Compound F" refers to 6-[2-(1H-Tetrazol-5-yl)-ethyl]-
decahydro-isoquinoline-3-carboxylic acid decyl ester.
As used herein the term "C1-C4 alkyl" refers to a straight or branched, monovalent,
saturated aliphatic chain of 1 to 4 carbon atoms and includes, but is not limited to methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl and the like.
As used herein the term "C1-C6 alkyl" refers to a straight or branched, monovalent,
saturated aliphatic chain of 1 to 6 carbon atoms and includes, but is not limited to methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like. It will
be understood that the term "C1-C4 alkyl" is included within the definition of "C1-C6
alkyl".
As used herein the term "C1-C10 alkyl" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 10 carbon atoms and includes, but is not
limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tertiary butyl, pentyl,
isopentyl, hexyl, 2,3-dimethyl-2-butyl, heptyl, 2,2-dimethyl-3-pentyl, 2-methyl-2-hexyl,
octyl, 4-methyl-3-heptyl and the like. It will be understood that the terms "C1-C4 alkyl"
and "C1-C6 alkyl" are included within the definition of "C1-C10 alkyl".
As used herein the term "C1-C20 alkyl" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 20 carbon atoms and includes, but is not
limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl,
hexyl, 3-methylpentyl, 2-ethylbutyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-
dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-nonadecyl, n-
eicosyl and the like. It will be understood that the terms "C1-C4 alkyl" , "C1-C6 alkyl" ,
and "C1-C10alkyl" are included within the definition of "C1-C20 alkyl".
As used herein, the terms "Me", "Et", "Pr", "iPr", "Bu" and "t-Bu" refer to methyl,
ethyl, propyl, isopropyl, butyl and tert-butyl respectively.
As used herein the term "C2-C6 alkenyl" refers to a straight or branched,
monovalent, unsaturated aliphatic chain having from two to six carbon atoms. Typical
C2-C6 alkenyl groups include ethen'yl (also known as vinyl), 1-methylethenyl, 1-methyl-1-
propenyl, 1-butenyl, 1-hexenyl, 2-methyl-2-propenyl, 1-propenyl, 2-propenyl, 2-butenyl,
2-pentenyl, and the like.
As used herein, the term "aryl" refers to monovalent carbocyclic group containing
one or more fused or non-fused phenyl rings and includes, for example, phenyl, 1- or 2-
naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and the like.
As used herein, the term "C1-C6 alkyl-aryl" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an aryl group
attached to the aliphatic chain. Included within the term "C1-C6 alkyl-aryl" are the
following:
and the like.
As used herein the term "(C3-C10)cycloalkyl" refers to a saturated hydrocarbon
ring structure containing from three to ten carbon atoms. Typical C3-C10 cycloalkyl
groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,
and the like. It is understood that "(C3-C8)cyc]oalkyr and "(C4-C6)cycloalkyl" is
included within the term "(C3-C10)cycloalkyl".
As used herein, the term "C1-C6 allcyl-(C3-C10)cycloalkyl" refers to a straight or
branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a (C3-
C10)cycloalkyl attached to the aliphatic chain. Included within the term "C1-C6 alkyl-(C3
C10)cycloalkyl" are the following:
and the like.
As used herein the term "N,N-C1-C6 dialkylamine" refers to a nitrogen atom
substituted with two straight or branched, monovalent, saturated aliphatic chains of 1 to 6
carbon atoms. Included within the term "N,N-C1-C6 dialkylamine" are -N(CH3)2, -
N(CH2CH3)2, -N(CH2CH2CH3)2, -N(CH2CH2CH2CH3)2, and the like.
As used herein the term "C1-C6 alkyl-N,N-C1-C6 dialkylamine" refers to straight
or branched, monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has an
N,N-C1-C6 dialkylamine attached to the aliphatic chain. Included within the term "C1-C6
alkyl-N,N-C1-C6 dialkylamine" are the following:
and the like.
As used herein the term "C1-C6 alkyl-pyrrolidine" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a pyrrolidine
attached to the aliphatic chain. Included within the scope of the term "C1-C6 alkyl-
pyrrolidine" are the following:
and the like.
As used herein the term "C1-C6 alkyl-piperidine" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 6 carbon atoms which has a piperidine
attached to the aliphatic chain. Included within the scope of the term "C1-C6 alkyl-
piperidine" are the following:
and the like.
As used herein the tenia "C1-C6 alkyl-morpholine" refers to a straight or branched,
monovalent, saturated aliphatic chain of 1 to 6 carbon atoms winch has a morpholine
attached to the aliphatic chain. Included within the scope of the term "C1-C6 alkyl-
morpholine" are the following:
and the like.
The compounds of the present invention contain a tetrazole ring, which is known
to exist as tautomeric structures. The tetrazole, having the double bond on the nitrogen
atom at the 1-position and the hydrogen on the nitrogen atom at the 2-position is named as
a 2H tetrazole and is represented by the following structure.
The corresponding tautomeric form wherein the hydrogen is at the nitrogen atom at the 1-
position and the double bond on the nitrogen atom at the 4-position is named as a 1H-
tetrazole. The 1H-tetrazole is represented by the following formula.
Mixtures of the two tautomers are referred to herein as 1(2)H-tetrazoles. The present
invention contemplates both tautomeric forms as well as the combination of the two
tautomers.
The designation refers to a bond that protrudes forward out of the plane
of the page.
The designation refers to a bond that protrudes backward out of the
plane of the page.
This invention includes the hydrates and the pharmaceutically acceptable salts of
the compounds of formula I. A compound of this invention can possess a sufficiently
basic functional group which can react with any of a number of inorganic and organic
acids, to form a pharmaceutically acceptable salt.
The term "pharmaceutically acceptable salt" as used herein, refers to salts of the
compounds of formula I which are substantially non-toxic to living organisms. Typical
pharmaceutically acceptable salts include those salts prepared by reaction of the
compounds of the present invention with a pharmaceutically acceptable mineral or
organic acid. Such salts are also known as acid addition salts.
Acids commonly employed to form acid addition salts are inorganic acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and
the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-
bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic
acid, trifluoroacetic acid, and the like. Examples of such pharmaceutically acceptable
salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate,
monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide,
iodide, acetate, trifluoroacetate, propionate, decanoate, caprylate, acrylate, formate,
hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate,
malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-1,6-
dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate,
phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate,
lactate, a-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate,
naphthalene-1-sulfonate, napththalene-2-sulfonate, mandelate and the like. Preferred
pharmaceutically acceptable acid addition salts are those formed with mineral acids such
as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as
maleic acid, oxalic acid, triofluoroacetic acid, and methanesulfonic acid.
It should be recognized that the particular counterion forming a part of any salt of
this invention is usually not of a critical nature, so long as the salt as a whole is
pharmacologically acceptable and as long as the counterion does not contribute undesired
qualities to the salt as a whole. It is further understood that such salts may exist as a
hydrate.
As used herein, the terra "stereoisomer" refers to a compound made up of the same
atoms bonded by the same bonds but having different three-dimensional structures which
are not interchangeable. The three-dimensional structures are called configurations. As
used herein, the term "enantiomer" refers to two stereoisomers whose molecules are
nonsuperimposable mirror images of one another. The term "chiral center" refers to a
carbon atom to which four different groups are attached. As used herein, the term
"diastereomers" refers to stereoisomers which are not enantiomers. In addition, two
diastereomers winch have a different configuration at only one chiral center are referred to
herein as "epimers". The terms "racemate", "racemic mixture" or "racemic modification"
refer to a mixture of equal parts of enantiomers.
The term "enantiomeric enrichment" as used herein refers to the increase in the
amount of one enantiomer as compared to the other. A convenient method of expressing
the enantiomeric enrichment achieved is the concept of enantiomeric excess, or "ee",
which is found using the following equation:

wherein E1 is the amount of the first enantiomer and E2 is the amount of the second
enantiomer. Thus, if the initial ratio of the two enantiomers is 50:50, such as is present in
a racemic mixture, and an enantiomeric enrichment sufficient to produce a final ratio of
50:30 is achieved, the ee with respect to the first enantiomer is 25%. However, if the final
ratio is 90:10, the ee with respect to the first enantiomer is 80%. An ee of greater than
90% is preferred, an ee of greater than 95% is most preferred and an ee of greater than
99% is most especially preferred. Enantiomeric enrichment is readily determined by one
of ordinary skill in the art using standard techniques and procedures, such as gas or high
performance liquid chromatography with a chiral column. Choice of the appropriate
chiral column, eluent and conditions necessary to effect separation of the enantiomeric
pair is well within the knowledge of one of ordinary skill in the art. In addition, the
enantiomers of compounds of formula I can be resolved by one of ordinary skill in the art
using standard techniques well known in the art, such as those described by J. Jacques, et
al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981.
The compounds of the present invention have one or more chiral centers and may
exist in a variety of stereoisomeric configurations. As a consequence of these chiral
centers, the compounds of the present invention occur as racemates, mixtures of
enantiomers and as individual enantiomers, as well as diastereomers and mixtures of
diastereomers. All such racemates, enantiomers, and diastereomers are within the scope
of the present invention.
The terms "R" and "S" are used herein as commonly used in organic chemistry to
denote specific configuration of a chiral center. The term "R" (rectus) refers to that
configuration of a chiral center with a clockwise relationship of group priorities (highest
to second lowest) when viewed along the bond toward the lowest priority group. The
term "S" (sinister) refers to that configuration of a chiral center with a counterclockwise
relationship of group priorities (highest to second lowest) when viewed along the bond
toward the lowest priority group. The priority of groups is based upon their atomic
number (in order of decreasing atomic number). A partial list of priorities and a
discussion of stereochemistry is contained in "Nomenclature of Organic Compounds:
Principles and Practice", (J.H. Fletcher, et al., eds., 1974) at pages 103-120.
The specific stereoisomers and enantiomers of compounds of formula (I) can be
prepared by one of ordinary skill in the art utilizing well known techniques and processes,
such as those disclosed by Eliel and Wilen, "Stereochemistry of Organic Compounds",
John Wiley & Sons, Inc., 1994, Chapter 7, Separation of Stereoisomers. Resolution.
Racemization, and by Collet and Wilen, "Enantiomers, Racemates, and Resolutions",
John Wiley & Sons, Inc., 1981. For example, the specific stereoisomers and enantiomers
can be prepared by stereospecific syntheses using enantiomerically and geometrically
pure, or enantiomerically or geometrically enriched starting materials. In addition, the
specific stereoisomers and enantiomers can be resolved and recovered by techniques such
as chromatography on chiral stationary phases, enzymatic resolution or fractional
recrystallization of addition salts formed by reagents used for that purpose.
The compounds of formula I can be prepared by techniques and procedures readily
available to one of ordinary skill in the art. More specifically, compounds of Formula I
can be chemically prepared, for example, by following the synthetic routes set forth in the
Scheme below. However, the following discussion is not intended to be limiting to the
scope of the present invention in any way. For example, the specific synthetic steps for
the route described herein may be combined in different ways to prepare the compounds
of Formula I. All substituents, unless otherwise indicated, are as previously defined.
The reagents and starting materials are readily available to one of ordinary skill in the art.
For example, certain starting materials can be prepared by one of ordinary skill in the art
following procedures disclosed in United States Patents Nos. 5,356,902 (issued October
18, 1994) and 5,446,051 (issued August 29, 1995) and 5,670,516 (issued September 23,
1997) the entire contents, all of which, are herein incorporated by reference. Other
necessary reagents and starting materials for the below procedures may be made by
procedures which are selected from standard techniques of organic and heterocyclic
chemistry, techniques which are analogous to the syntheses of known structurally similar
compounds, and the procedures described in the Examples, including any novel
procedures.
In Scheme I, compound A is esterified to provide the monoester of formula I under
standard conditions well known in the art. For example, compound A is dissolved in a
suitable organic solvent and treated with a suitable acid, such as hydrochloric acid.
Examples of suitable organic solvents include, methyl alcohol, ethyl alcohol, propyl
alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, t-butyl alcohol, pentyl
alcohol, isopentyl alcohol, hexyl alcohol, 3-methylpentyl alcohol, 2-ethylbutyl alcohol, n-
heptyl alcohol, n-octyl alcohol, decyl alcohol and the like. The reaction is heated at about
40°C to about 60°C for about 4 hours to about 16 hours. The product is then isolated and
purified using techniques well known to one of ordinary skill in the art, such as extraction
techniques and chromatography.
For example, the above reaction is cooled, diluted with a suitable organic solvent,
such as ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over
anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the
compound of formula I. This material may be further purified by flash chromatography
on silica gel with a suitable eluent such as ethyl acetate/hexane.
Alternatively, compound A is dissolved in a suitable organic solvent and treated
with an excess of thionyl chloride. Examples of suitable organic solvents are anhydrous
methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl
alcohol, t-butyl alcohol, pentyl alcohol, isopentyl alcohol, hexyl alcohol, 3-methylpentyl
alcohol, ?.-ethylbutyl alcohol, n-heptyl alcohol, n-octyl alcohol, decyl alcohol and the like.
The solution is stirred at reflux for about 1 to 3 hours, and at room temperature for about
8 to 16 hr. The mixture is then concentrated under vacuum, and the residue is purified in
a manner analogous to the procedures described above to provide the prodrug monoester
of formula I.
The pharmaceutically acceptable salts of formula I are readily prepared by one of
ordinary skill in the art using standard techniques and procedures. For example, the above
product is suspended in diethyl ether, which has been saturated with HC1 gas. The
mixture is stirred for about 1 to 3 hours. The precipitate is then filtered and washed with
diethyl ether under vacuum to provide the pharmaceutically acceptable salt of the prodrug
monoester of formula I.
The following examples represent typical syntheses of the compounds of formula I
as described generally above. These examples are illustrative only and are not intended to
limit the invention in any way. The reagents and starting materials are readily available to
one of ordinary skill in the art. As used herein, the following terms have the meanings
indicated: "eq" or "equiv." refers to equivalents; "g" refers to grams; "mg" refers to
milligrams; "L" refers to liters; "mL" refers to milliliters; "µL" refers to microliters; "mol"
refers to moles; "mmol" refers to millimoles; "psi" refers to pounds per square inch;
"min" refers to minutes; "h" refers to hours; "°C" refers to degrees Celsius; "TLC" refers
to thin layer chromatography; "HPLC" refers to high performance liquid chromatography;
"5"refers to part per million down-field from tetramethylsilane; "THF" refers to
tetrahydrofuran; "DMF" refers to N,N-dimethylformamide; "DMSO" refers to methyl
sulfoxide; "aq" refers to aqueous; "EtOAc" refers to ethyl acetate; "iPrOAc" refers to
isopropyl acetate; "MeOH" refers to methanol; "MTBE" refers to tert-butyl methyl ether,
and "RT" refers to room temperature.
Example 1
To a solution of 2.5 g (8.4 mmol) of 6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-
isoquinoline-3-carboxylic acid monohydrate (prepared as described in J. Med. Chem., 39
(11), pp. 2232-2244, (1996) or U.S. Patent No. 5,670,516 (issued September 23, 1997)) in
20 ml of 2-ethyl-1-butanol, 6.8 ml (92.8 mmol) of thionyl chloride is added. The solution
is stirred at 120°C for 3 hr. The mixture is concentrated in vacuo and the residue washed
with ethyl ether. The residue is purified by SPE (Oasis HLB) to afford the title
compound.
Electrospray Mass Spectrum: M+l=364.
Example 2
6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-isoquinoline-3-carboxylic acid isobutyl ester
Prepared according to the procedures essentially as described in Example 1,
above, using 20 mL of 2-methyl-1-propanol to afford of the title compound.
Electrospray Mass Spectrum: M+l = 336.
Prepared according to the procedures essentially as described in Example 1,
above, using using 20 mL of 3-methyl-l-butanol to afford of the title compound.
Electrospray Mass Spectrum: M+l =350.
A solution of 2.5 g (S.4 mmol) of 6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-
isoquinoline-3-carboxylic acid monohydrate in 50 ml decyl alcohol saturated with
hydrogen chloride (g) is heated at 120°C overnight. The mixture is concentrated in vacuo
and the residue purified by SPE (Oasis HLB) to afford the title compound.
Electrospray Mass Spectrum: M+l =420.
Example 5
A solution of 6.0 g (21.5 mmol) of 6-[2-(1H-Tetrazol-5-yl)-ethyl]-decahydro-
isoquinoline-3-carboxylic acid monohydrate in 70 mL of ethanol saturated with hydrogen
chloride (g) is heated at reflux overnight. The mixture is concentrated in vacuo,
suspended in diethyl ether, and again concentrated in vacuo. The residue is suspended in
diethyl ether and heated at reflux for 3 hr. The solid is filtered and rinsed with diethyl
ether to afford 7.4 g (100%) of the title compound.
Electrospray Mass Spectrum: M+l = 308.
Particular Aspects of the compounds of Formula I:
The following list sets out several groupings of particular substituents of the
compounds of Formula I. It will be understood that the compounds of Formula I having
such particular substituents represent particular aspects of the present invention. It will be
further understood that each of these groupings may be combined with other provided
groupings, to create still additional particular aspects of the present invention.
Thus, a particular aspect of the novel compounds of Formula I is one wherein:
(a) R represents C1-C10 alkyl, C2-C6 alkenyl, C1-C6 alkyl-aryl, C1-C6 alkyl-(C3-
C10)cycloalkyl, C1-C6 alkyl-N,N-C1-C6 dialkylamine, C1-C6 alkyl-
pyrrolidine, C1-C6 alkyl-piperidine, C1-C6 alkyl-morpholine;
(b) R represents C1-C10 alkyl or C2-C6 alkenyl;
(c) R represents C1-C10 alkyl or C1-C6 alkyl-aryl;
(d) R represents C1-C10 alkyl or C1-C6 alkyl-(C3-C10)cycloalkyl;
(e) R represents C1-C10 alkyl or C1-C6 alkyl-N,N-C1-C6 dialkylamine;
(f) R represents C1-C10 alkyl or C1-C6 alkyl-pyrrolidine;
(g) R represents C1-C10 alkyl or C1-C6 alkyl-piperidine;
(h) R represents C1-C10 alkyl or C1-C6 alkyl-morpholine;
(i) R represents C1-C10 alkyl;
(j) R represents 2-ethyl butyl, isobutyl, 3-methyl butyl, decyl, or ethyl; or
(k) R represents ethyl
Pharmacological Results
The following in vivo data, in rats, dogs and monkeys, exemplify the improvement
in bioavailability of the monoester prodrugs of the present invention over the monoacid of
(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid.
Percent bioavailability is determined using the following equation:

wherein AUC represents the area under the curve, p.o. represents oral dose, and i.v.
represents intravenous dose.
Bioavailability in Dogs:
Beagle dogs (2 male and 1 female) are administered an oral dose, and later an iv
dose of (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid (10 mg/Kg p.o; 1mg/Kg i.v.) to determine oral
bioavailability. Subsequently, the same three dogs are administered an oral 10 mg/kg
dose of an ester prodrug (for example (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoqumoline-3-carboxylic acid ethyl ester, HCL salt) to
determine whether the prodrug would increase bioavailability of the parent acid. The
plasma concentrations of (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid are determined by
LC/MS/MS.
Study Methods:
Live Phase: (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid (HC1 salt) is dissolved in dilute sodium
hydroxide for oral administration (30 mg/ml) and in 10% ethanol/water for iv
administration (10 mg/ml). (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-
1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid ethyl ester, HCL salt is
dissolved in water for oral administration (30 mg/ml). Dogs weighed between 12 to 15
kg.
Results:
The oral bioavailability for 3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid was determined to be 18%
in dogs. When 3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid ethyl ester(HCL salt) was administered,
bioavailability increased to 33.1%. The use of the prodrug form 3S,4aR,6R,8aR)-6-[2-
(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
ethyl ester (HCL salt), provided approximately a 2 fold increase in bioavailability over the
parent acid.
Tables 1 below summarizes the pharmacokinetic parameters found for
Compounds A and B following 1 mg/kg administration (i.v.) or 10 mg/kg administration
(p.o.) to Beagle Dogs.
Bioavailability in Rats
Male Fischer Rats are administered either an oral or iv dose of (3S,4aR,6R,8aR)-6-
[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic
acid (30 mg/Kg p.o; 10mg/Kg i.v.) to determine oral bioavailability. A separate group of
rats are administered an oral 10 mg/kg dose of an ester prodrug (for example
(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid ethyl ester, HCL salt) to determine whether the
prodrug would increase bioavailability of the parent acid. The plasma concentrations of
(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-1,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid are determined by LC/MS/MS.
Study Methods:
Live Phase: (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinolme-3-carboxylic acid (HO salt) is dissolved in dilute sodium
hydroxide for oral administration (15 mg/ml) and in 10% ethanol/water for iv
administration (10 mg/ml). (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid ethyl ester, HCL salt is
dissolved in water for oral administration (15 mg/ml). Fischer male 344 rats weighing
between 218 to 244 g are utilized. Plasma samples are collected at 0.5, 1, 2, 4, 6, 8, 10
and 24 hr (3 rats per time point).
Results:
The oral bioavailability for 3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-
l,2,3,4,4a,5,6,7,8,Sa-decahydroisoquinoline-3-carboxylic acid was determined to be
3.6% in rats. When 3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid ethyl ester(HCL salt) was
administered, bioavailability increased to 17.7%. The use of the prodrug form
3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid ethyl ester (HCL salt), provided approximately a
5 fold increase in bioavailability over the parent acid.
Tables 2 below summarizes the pharmacokinetic parameters found for
Compounds A and B following 10 mg/kg administration (i.v.) or 30 mg/kg administration
(p.o.)to Fischer Rats.
Bioavailability in Cynomolgus Monkeys
Two male and two female monkeys are administered an oral, and later, an iv dose
of(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid (oral: 3 mg/kg; iv: 0.3 mg/kg) to determine oral
bioavailability. The same animals are also subsequently administered an oral 3 mg/kg
dose of (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid ethyl ester to determine if the ester prodrug form
increases bioavailability of the parent acid. The plasma concentrations of the parent acid
are determined by LC/MS/MS.
Study Design
Four cynomolgus monkeys (2/sex) are given a single oral dose of
(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,S,8a-
decahydroisoquinoline-3-carboxylic acid (3 mg/kg) on day 0, a single iv dose of
(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid (0.3 mg/kg) on day 4 and a single oral dose of
(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid ethyl ester (3 mg/kg) on day 8. Blood samples
are collected at 0.5, 1, 2, 3, 4, 5, 6 and 8 hours post dose for oral dosing and 0.167, 0.33,
0.67, 1, 1.5,2, 3 and 4 hours post dose for iv dosing. Dosing solutions for both the acid
and ester arere prepared in 0.9% sodium chloride.
Results:
The oral bioavailability for (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid was determined to be
4.5% in monkeys. When (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-
l,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid ethyl ester(HCL salt) was
administered, bioavailability increased to 11.4%. The use of the prodrug form
(3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl-l,2,3,4,4a,5,6,7,8,8a-
decahydroisoquinoline-3-carboxylic acid ethyl ester (HCL salt), provided approximately a
2.5 fold increase in bioavailability over the parent acid.
Table 3 below summarizes the pharmacokinetic parameters found for Compounds A and
B following i.v. or oral administration to Cynomolgus Monkeys.
Table 3. Pharmacokinetic Parameters of Compound A in Cynomolgus Monkeys after an
i.v. and p.o. Dose of Compound A or the ester Prodrug, Compound B.
The present invention further provides a method of antagonizing the AMPA or
GluR5 receptors, of the larger class of excitatory amino acid receptors, which comprises
administering to a patient an effective amount of a compound of formula I. The excessive
or inappropriate stimulation of excitatory amino acid receptors leads to neuronal cell
damage or loss by way of a mechanism known as excitotoxicity. This process has been
suggested to mediate neuronal degeneration in a variety of neurological disorders and
conditions. The medical consequences of such neuronal degeneration makes the
abatement of these degenerative neurological processes an important therapeutic goal.
For instance, excitatory amino acid receptor excitotoxicity has been implicated in the
pathophysiology of numerous neurological disorders, including the etiology of cerebral
deficits subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia,
spinal cord lesions resulting from trauma or inflammation, perinatal hypoxia, cardiac
arrest, and hypoglycemic neuronal damage. In addition, excitotoxicity has been
implicated in chronic neurodegenerative conditions including Alzheimer's Disease,
Huntington's Chorea, inherited ataxias, AIDS-induced dementia, amyotrophic lateral
sclerosis, idiopathic and drug-induced Parkinson's Disease, as well as ocular damage and
retinopathy. Other neurological disorders implicated with excitotoxicity and/or glutamate
dysfunction include muscular spasticity including tremors, drug tolerance and withdrawal,
brain edema, convulsive disorders including epilepsy, depression, anxiety and anxiety
related disorders such as post-traumatic stress syndrome, tardive dyskinesia, and
psychosis related to depression, schizophrenia, bipolar disorder, mania, and drug
intoxication or addiction (see generally United States Patent No. 5,446,051 and
5,670,516). Excitatory amino acid receptor antagonists may also be useful as analgesic
agents and for treating or preventing various forms of headache, including cluster
headache, tension-type headache, and chronic daily headache. In addition, published
International Patent application WO 98/45720 reports that excitatory amino acid receptor
excitotoxicity participates in the etiology of acute and chronic pain states including severe
pain, intractable pain, neuropathic pain, post-traumatic pain.
It is also known that trigeminal ganglia, and their associated nerve pathways, are
associated with painful sensations of the head and face such as headache and, in
particular, migraine. Moskowitz (Cephalalgia, 12, 5-7, (1992) proposed that unknown
triggers stimulate the trigeminal ganglia which in turn innervate vasculature within
cephalic tissue, giving rise to the release of vasoactive neuropeptides from axons
innervating the vasculature. These neuropeptides initiate a series of events leading to
neurogenic inflammation of the meninges, a consequence of which is pain. This
neurogenic inflammation is blocked by sumatriptan at doses similar to those required to
treat acute migraine in humans. However, such doses of sumatriptan are associated with
contraindications as a result of sumatriptan's attendant vasoconstrictive properties.(see
MacIntyre, P.D., et al., British Journal of Clinical Pharmacology, 34, 541-546 (1992);
Chester, A.H., et al, Cardiovascular Research, 24, 932-937 (1990); Conner, H.E., et al.,
European Journal of Pharmacology, 161, 91-94 (1990)). Recently, it has been reported
that all five members of the kainate subtype of ionotropic glutamate receptors are
expressed on rat trigeminal ganglion neurons, and in particular, high levels of GluR5 and
KA2 have been observed. (Sahara et al., The Journal of Neuroscience, 17(17), 6611
(1997)). As such, migraine presents yet another neurological disorder which may be
implicated with glutamate receptor excitotoxicity.
The use of a neuroprotective agent, such as an excitatory amino acid receptor
antagonist, is believed to be useful in treating or preventing all of the aforementioned
disorders and/or reducing the amount of neurological damage associated with these
disorders. For example, studies have shown that AMPA receptor antagonists are
neuroprotective in focal and global ischemia models. The competitive AMPA receptor
antagonist NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]quinoxaline) has been
reported effective in preventing global and focal ischemic damage. Sheardown et al.,
Science, 247, 571 (1900); Buchan et al, Neuroreport, 2, 473 (1991); LePeillet et al.,
Brain Research, 571, 115 (1992). The noncompetitive AMPA receptor antagonists GKYI
52466 has been shown to be an effective neuroprotective agent in rat global ischemia
models. LaPeillet et al., Brain Research, 571, 115 (1992). European Patent Application
Publication No. 590789A1 and United States Patents No. 5,446,051 and 5,670,516
disclose that certain decahydroisoquinoline derivative compounds are AMPA receptor
antagonists and, as such, are useful in the treatment of a multitude of disorders conditions,
including pain and migraine headache. WO 98/45270 discloses that certain
decahydroisoquinoline derivative compounds are selective antagonists of the iGluR5
receptor and are useful for the treatment of various types of pain, including; severe,
chronic, intractable, and neuropathic pain.
As such, the compounds of the present invention are believed to be useful for
treating neurological disorders, as discussed above. Such compounds could address a
long felt need for safe and effective treatments for neruological disorders, without
attending side effects. Thus, the present invention further provides a method for the
treatment of a neurological disorder, which comprises administering to a patient in need
thereof, an effective amount of a compound of formula I. More particularly, the present
invention further provides a method for the treatment of pain or migraine, which
comprises administering to a patient in need thereof, an effective amount of a compound
of formula I. The treatment of neurological disorders and neurodegenerative diseases is
hereby furthered.
As used herein the term "patient" refers to a mammal, such a mouse, guinea pig,
rat, dog, monkey, or human. It is understood that the preferred patient is a human.
The term "treating" (or "treat") as used herein includes its generally accepted
meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping,
or reversing progression, severity, of a resultant symptom. As such, the methods of this
invention encompass both therapeutic and prophylactic administration.
As used herein the term "effective amount" refers to the amount or dose of the
compound, upon single or multiple dose administration to the patient, which provides the
desired effect in the patient under diagnosis or treatment.
An effective amount can be readily determined by the attending diagnostician, as
one skilled in the art, by the use of known techniques and by observing results obtained
under analogous circumstances. In determining the effective amount or dose of
compound administered, a number of factors are considered by the attending
diagnostician, including, but not limited to: the species of mammal; its size, age, and
general health; the specific disease involved; the degree of or involvement or the severity
of the disease; the response of the individual patient; the particular compound
administered; the mode of administration; the bioavailability characteristics of the
preparation administered; the dose regimen selected; the use of concomitant medication;
and other relevant circumstances.
A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the
active compound of this invention. Preferably, daily doses will be about 0.05 mg/kg to
about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.
In effecting treatment of a patient afflicted with a condition, disease or disorder
described above, a compound of formula (I) can be administered in any form or mode
which makes the parent monoacid compound bioavailable in effective amounts, including
oral and parenteral routes. For example, compounds of formula (I) can be administered
orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally,
rectally, buccally, and the like. Alternatively, the compound may be administered by
continuous infusion. Oral administration is generally preferred. One skilled in the art of
preparing formulations can readily select the proper form and mode of administration
depending upon the particular characteristics of the compound selected, the disease state
to be treated, the stage of the disease, and other relevant circumstances.
It will be understood by the skilled reader that all of the compounds used in the
present invention are capable of forming salts, and that the salt forms of pharmaceuticals
are commonly used, often because they are more readily crystallized and purified than are
the free bases. In all cases, the use of the pharmaceuticals described above as salts is
contemplated in the description herein, and often is preferred, and the pharmaceutically
acceptable salts of all of the compounds are included in the names of them.
According to another aspect, the present invention provides a pharmaceutical
composition, which comprises a compound of formula I or a pharmaceutically acceptable
salt thereof as defined hereinabove and a pharmaceutically acceptable diluent or carrier.
The pharmaceutical compositions are prepared by known procedures using well-
known and readily available ingredients. In making the compositions of the present
invention, the active ingredient will usually be mixed with a carrier, or diluted by a
carrier, or enclosed within a carrier, and may be in the form of a capsule, sachet, paper, or
other container. When the carrier serves as a diluent, it may be a solid, semi-solid, or
liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
The compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets,
elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for
example, up to 10% by weight of active compound, soft and hard gelatin capsules,
suppositories, sterile injectable solutions, and sterile packaged powders.
Some examples of suitable carriers, excipients, and diluents include lactose,
dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alginates,
tragcanth, gelatin, calcium silicate, micro-crystalline cellulose, polyvinylpyrrolidone,
cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc,
magnesium stearate, and mineral oil. The formulations can additionally include
lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents,
sweetening agents, or flavoring agents. Compositions of the invention may be formulated
so as to provide quick, sustained, or delayed release of the active ingredient after
administration to the patient by employing procedures well known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage
containing from about 1 mg to about 500 mg, more preferably about 5 mg to about 300
mg (for example 25 mg) of the active ingredient. The term "unit dosage form" refers to a
physically discrete unit suitable as unitary dosages for human subjects and other
mammals, each unit containing a predetermined quantity of active material calculated to
produce the desired therapeutic effect, in association with a suitable pharmaceutical
carrier, diluent, or excipient. The following formulation examples are illustrative only
and are not intended to limit the scope of the invention in any way.
Formulation 1
Hard gelatin capsules are prepared using the following ingredients:
The above ingredients are mixed and filled into hard gelatin capsules in 460 mg
quantities.
Formulation 2
Tablets each containing 60 mg of active ingredient are made as follows:
The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S.
sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the
resultant powders which are then passed through a No. 14 rnesh U.S. sieve. The granules
so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60
mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a
tablet machine to yield tablets each weighing 150 mg.
We Claim:
1. A compound of the formula:
wherein R represents C2-C10 alkyl, or a pharmaceutically acceptable salt thereof.
2. A compound or salt as claimed in claim 1, wherein R represents 2-ethyl butyl,
isobutyl, 3-methyl butyl, decyl, or ethyl.
3. A compound or salt as claimed in claim 2, wherein R represents 2-ethyl butyl,
4. A compound or salt as claimed in claim 2, wherein R represents isobutyl.
5. A compound or salt as claimed in claim 2, wherein R represents 3-methyl butyl.
6. A compound or salt as claimed in claim 2, wherein R represents decyl.
7. A compound or salt according to claim 2, wherein R represents ethyl.
8. A compound as claimed in Claim 1 which is (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-
yl)-ethyl] -l,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid 2-ethyl-butyl
ester.
9. A compound as claimed in Claim 1 which is (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-
yl)-ethyl] -l,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid isobutyl ester.
10. A compound as claimed in Claim 1 which is (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-
yl)-ethyl] -l,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid 3-methyl butyl
ester.
11. A compound as claimed in Claim 1 which is (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-
yl)-ethyl] -l,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid decyl ester.
12. A compound as claimed in Claim 1 which is (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-
yl)-ethyl] -l,2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid ethyl ester.
13. A salt as claimed in any one of Claims 3-6 that is the trifluoroacetate salt.
14. A salt as claimed in Claim 7 that is the hydrochloride salt.
15. A pharmaceutical composition, which comprises a compound or salt as claimed in
any one of Claims 1-14 or (3S,4aR,6R,8aR)-6-[2-(1H-Tetrazol-5-yl)-ethyl] -
1.2,3,4,4a,5,6,7,8,8a-decahydro-isoquinoline-3-carboxylic acid methyl ester, and a
pharmaceutically acceptable diluent or carrier.
The present invention provides compounds of formula (I). The present invention
further provides the use of a compound of formula (I) for the manufacture of a
medicament for the treatment of a neurological disorder. The present invention
further provides the use of a compound of formula (I) for the manufacture of a
medicament for the treatment of pain or migraine.

Documents:

1342-KOLNP-2004-(19-01-2012)-FORM 27.pdf

1342-KOLNP-2004-CORRESPONDENCE.pdf

1342-KOLNP-2004-FORM 27.pdf

1342-kolnp-2004-granted-abstract.pdf

1342-kolnp-2004-granted-assignment.pdf

1342-kolnp-2004-granted-claims.pdf

1342-kolnp-2004-granted-correspondence.pdf

1342-kolnp-2004-granted-description (complete).pdf

1342-kolnp-2004-granted-examination report.pdf

1342-kolnp-2004-granted-form 1.pdf

1342-kolnp-2004-granted-form 18.pdf

1342-kolnp-2004-granted-form 2.pdf

1342-kolnp-2004-granted-form 3.pdf

1342-kolnp-2004-granted-form 5.pdf

1342-kolnp-2004-granted-gpa.pdf

1342-kolnp-2004-granted-pa.pdf

1342-kolnp-2004-granted-reply to examination report.pdf

1342-kolnp-2004-granted-specification.pdf

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Patent Number

228103

Indian Patent Application Number

1342/KOLNP/2004

PG Journal Number

05/2009

Publication Date

30-Jan-2009

Grant Date

28-Jan-2009

Date of Filing

13-Sep-2004

Name of Patentee

ELI LILLY AND COMPANY

Applicant Address

AN AMERICAN COMPANY OF LILLY CORPORATE CENTER, DROP CO DE 1104 INDIANAPOLIS, IN

Inventors:

#	Inventor's Name	Inventor's Address
1	ORNSTEIN PAUL LESLIE	10441 BOSAHAN COURT, CARMEL, IN 46032

PCT International Classification Number

C07D 401/06

PCT International Application Number

PCT/US2003/10466

PCT International Filing date

2003-04-14

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/376,120	2002-04-26	U.S.A.