Claims
- 1. A compound of the formula: ##STR13## in which X is represented by a substituent selected from the group consisting of O, S, or NH; n is represented by an integer from 0 to 6; R.sub.1 and R.sub.2 are each independently represented by a substituent selected from the group consisting of --NR.sub.4 R.sub.4, --OH, --OH.sub.5, --OCH.sub.2 OCOR.sub.6 and --O--(CH.sub.2)p NR.sub.7 R.sub.8, in which p is an integer from 1-4. R.sub.3 and R.sub.4 are each independently represented by hydrogen or C.sub.1-6 alkyl; R.sub.5 and R.sub.6 are each independently represented by C.sub.1-6 alkyl, pehnyl, substitued phenyl, or a phenylaklyl substituent in which the phenyl ring may be optionally substituted; R.sub.7 and R.sub.6 are each independently represented by C.sub.1-6 represented by C.sub.1-6 alkyl or together with the adjacent nitrogen atom by piperidino, morpholino, or pyrrolidinyl group D is represented by hydrogen or C.sub.1--3 aklyl; and A is represented by: ##STR14## R is represented by 1 to 3 substituents in the case where the phenyl moiety is substituted and 1 and 2 substituents in the case where a thienyl moiety is substituted said substituents being selected from the group consisting of hydrogen, OH, halogen, CN, NO.sub.2, C.sub.1-6 alkyul, C.sub.1-6 alkoxy, CF.sub.3, OCF.sub.3, COOR.sub.3, and CONR.sub.3 R.sub.4 in which R.sub.3 and R.sub.4 are each independently as defined above; the pharmaceutically acceptable acid addition salts thereof and the pharmaceutically acceptable basic addition salts thereof.
- 2. A compound according to claim 1 wherein A is represented ##STR15##
- 3. A compound according to claim 1 wherein A is represented by: ##STR16##
- 4. A compound according to claim 1 wherein X is represented by O.
- 5. A compound according to claim 1 wherein X is represented by N.
- 6. A compound according to claim 1 wherein X is represented by S.
- 7. A compound according to claim 2 in which R is represented by either a 7-chloro substituent, or a 5,7-dichloro substituent or hydrogen.
- 8. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-2-quinolinecarboxylic acid.
- 9. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-6-methoxy-2-quinolinecarboxylic acid.
- 10. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-6-chloro-2-quinolinecarboxylic acid.
- 11. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-7-chloro-2-quinolinecarboxylic acid.
- 12. A compound according to claim 1 wherein said compound is n-propyl 4-(n-propyloxycarbonyl)methyloxy-2-quinoline-carboxylate.
- 13. A compound according to claim 1 wherein said compound is 4-(3-carboxypropyloxy)-2-quinolinecarboxylic acid.
- 14. A compound according to claim 1 wherein said compound is 4-(2-carboxyethyloxy)-2-quinolinecarboxylic acid.
- 15. A compound according to claim 1 wherein said compound is 4-(2-carboxyethyloxy)-2-quinolinecarboxylic acid.
- 16. A compound according to claim 1 wherein said compound is 4-carboxymethylthio-2-quinolinecarboxylic acid.
- 17. A compound according to claim 1 wherein said compound is 4-(2-carboxyethylthio)quinoline-2-carboxylic acid.
- 18. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-5,7-dichloro-2-quinolinecarboxylic acid.
- 19. A compound according to claim 1 wherein said compound is methyl 4-methoxycarbonylmethyloxy-7-cyano-2-quinoline-carboxylate.
- 20. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-5-cyano-2-quinolinecarboxylic acid.
- 21. A compound according to claim 1 wherein said compound is 7-carboxymethyloxythieno[2,3-b]pyridine-5-carboxylic acid.
- 22. A compound according to claim 1 wherein said compound is 4-carboxymethyloxythieno[2,3-b]pyridine-6-carboxylic acid.
- 23. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-5-chloro-b 2-quinolinecarboxylic acid.
- 24. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-7-methoxy-2-quinolinecarboxylic acid.
- 25. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-8-fluoro-2-quinolinecarboxylic acid.
- 26. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-8-chloro-2-quinolinecarboxylic acid.
- 27. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-5,7-difluoro-2-quinolinecarboxylic acid.
- 28. A compound according to claim 1 wherein said compound is 7-carboxymethyloxythieno[3,4-b]pyridine-3,5-dicarboxylic acid.
- 29. A compound according to claim 1 wherein said compound is 4-carboxamidomethyloxy-2-quinolinecarboxamide.
- 30. A compound according to claim 1 wherein said compound is pivaloyloxymethyl 4-carboxymethyloxy-5,6-dichloro-2-quinolinecarboxylate.
- 31. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-7-fluoro-2-quinolinecarboxylic acid.
- 32. A compound according to claim 1 wherein said compound is 4-carboxymethylamino-5,7-dichloro-2-quinolinecarboxylic acid.
- 33. A compound according to claim 1 wherein said compound is 2-(diethylamino)ethyl 5,7-dichloro-4-[2-(diethylamino)-ethyloxycarbnyl]methylamino-2-quinolinecarboxylate.
- 34. A compound according to claim 1 wherein said compound is 2-(dimethylamino)ethyl 5,7-dichloro-4-[2-(dimethyl-amino)ethyloxycarbonyl]methyloxy-2-quinolinecarboxylate .
- 35. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-6,7-trifluoromethyl-2-quinolinecarboxylic acid.
- 36. A compound according to claim 1 wherein said compound is 4-carboxymethyloxy-6,7-dichloro-2-quinolinecarboxylic acid.
- 37. A method for antagonizing the effects of excitatory amino acids upon the NMDA receptor complex comprising administering to a patient in need thereof an antagonistic amount of a compound according to claim 1.
- 38. A method for the treatment of epilepsy comprising administering to a patient in need thereof an anti-epileptic amount of a compound according to claim 1.
- 39. A method for the treatment of neurodegenerative diseases comprising administering to a patient in need thereof an effective amount of a compound according to claim 1.
- 40. A method for preventing ischemic/hypoxic damage to cerebral tissue comprising administering to a patient in need thereof an effective amount of a compound according to claim 1.
- 41. A method for the treatment of anxiety comprising administering to a patient in need thereof an anxiolytic amount of a compound according to claim 1.
- 42. A method for producing an analgesic effect comprising administering to a patient in need thereof an analgesic amount of a compound according to claim 1.
- 43. A pharmaceutical composition according to claim 1 comprising a compound according to claim 1 present in an effective amount sufficient to inhibit the effect which the excitatory amino acids have upon the NMDA receptor complex in admixture with a pharmaceutically acceptable carrier.
Parent Case Info
This application is a continuation-in-part of Ser. No. 352,423, filed on May 16, 1989, now abandoned.
The present invention is directed to a new class of excitatory amino acid antagonists. Another aspect of the invention is directed to methods for the treatment of epilepsy, neurodegenerative diseases such as Huntington's disease, and for preventing ischemic/hypoxic damage to nervous tissues contained within the central nervous system.
In accordance with the present invention, a new class of excitatory amino acid antagonists which act at the NMDA receptor complex have been discovered. These compounds can be represented by the following formulae: ##STR1## in which X is represented by a substituent selected from the group consisting of O, S, or NH; n is represented by an integer from 0 to 6; R.sub.1 and R.sub.2 are each independently represented by a substituent selected from the group consisting of --NR.sub.3 R.sub.4, --OH, --OR.sub.5, and --OCH.sub.2 OCOR.sub.6 and, --O--(CH.sub.2).sub.p NR.sub.7 R.sub.8 in which p is an integer from 1-4; R.sub.3 and R.sub.4 are each independently represented by hydrogen or a C.sub.1-6 alkykl; R.sub.5 and R.sub.6 are each independently represented by a C.sub.1-6 aklyl, a phenyl ring, a substituted phenyl ring, or a phenylakly substituent in which the phenyl ring may be optionally substituted; R.sub.7 and R.sub.8 are independently represented by a C.sub.1-6 alkyl or together with the adjacent nitrogen atom for a piperidino, morpholino, or pyrrolidinyl group; D is represented by hydrogen or a C.sub.1-3 alkyl; and A is represented by: ##STR2## R is represented by a substituent selected from the group consisting of hydrogen, OH, halogen, CN, NO.sub.2, C.sub.1-6 aklyl, C.sub.1-6 alkoxy, OCF.sub.3, OCF.sub.3, COOR.sub.3, and CONR.sub.3 R.sub.4 in which R.sub.3 and R.sub.4 are each independently as defined above; the pharmaceutically acceptable acid addition salts thereof, and the pharmaceutically acceptable basic addition salts thereof.
As used in this application:
The expression "pharmaceutically acceptable acid addition salts" is intended to apply to any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formulae I-IV or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di-, and tricarboxylic acids. Illustrative of such acids are for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic, salicyclic, 2-phenoxy-benzoic, p-toluenesulfonic acid, and sulfonic acids such as methane sulfonic acid and 2-hydroxyethane sulfonic acid. Such salts can exist in either a hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are soluble in water and various hydrophilic organic solvents, and which in comparison to their free base forms, generally demonstrate higher melting points.
The expression "pharmaceutically acceptable basic addition salts" is intended to apply to any non-toxic organic or inorganic basic addition salts of the compounds represented by Formulae I-IV or any of its intermediates. Illustrative bases which form suitable salts include alkali metal or alkaline-earth metal hydroxides such as sodium, potassium, calciu, magnesium, or barium hydroxides; ammonia, and aliphatic, alicyclic, or armoatic organic amines such as methylamine, dimethylamine, trimethylamine, and picoline. Either the mono- or di-basic salts can be formed with those compounds.
Some of the compounds of Formulae I-IV exist as optical isomers. Any reference in this application to one of the compounds represented by Formulae I-IV is meant to encompass either a specific optical isomer or a mixture of optical isomers. The specific optical isomers can be separated and recovered by techniques known in the art such as chromatography on chiral stationary phases or resolution via chiral salt formation and subsequent separation by selective crystallization.
The compounds of Formulae II, III, and IV may exist in the following tautomeric forms: ##STR3## Any reference to the compounds of Formulae II, III, or IV should be considered as encompassing either of the tautomers.
In the compounds of Formula I, A can be represented by a phenyl ring bearing the substituent R. When R is other than a hydrogen atom, there can be up to 3 such substituents occurring on the indicated pheny ring. These substituents can be the same or can differ. These substitutents can be located at any of the ortho, meta, or para positions. Likewise in the compounds of Formulae I-IV, R.sub.5 and R.sub.6 can be represented by either substituted phenyl rings or an phenylalkyl substituent in which the phenyl ring is substituted. These substituted phenyl rings may also be substituted with up to 3 substituents. These substituents may be the same or different and may be located at any of the meta, para, or ortho positions.
The thiophene derivatives of Formulae I-IV may contain substituents on their thiophene ring as represented by R. There may be up to 2 substituents appearing on the thiophene ring and these substituents may be the same or different. These substituents may appear at any of the free positions of the thiophene ring other than the position bearing the S atom. As used in this application, the term "free position" refers to a carbon atom in a cyclic structure that is substituted with only a hydrogen atom.
Illustrative examples of compounds encompassed by the present invention include:
The preferred compounds of the present invention are those of Formula I in which X is represented by O, or NH and A forms a phenyl ring which is either unsubstituted, monosubstituted at the 7-position with a chlorine atom, or is disubstituted with chlorine atoms at positions 5 and 7. It is preferred for R.sub.1 and R.sub.2 to be represented by either a hydroxyl or an ester function.
The compounds of Formula I can be prepared by methods which are analogously known in the art. For example those compounds of Formula I in which X is represented by either O or S and n is represented by the integer 0 or 2-6, can be produced by conducting an alkylation reaction between a condensed carbocyclic or heterocyclic 4-substituted pyridine 2-carboxylate derivative (hereinafter "annulated pyridine") as described by Formula V and a .omega.-substituted alkanoic acid (hereinafter ".omega.-alkanoic acid") derivative as described by Formula VI below: ##STR4##
In Formula V, X is represented by O or S, and A, and R.sub.1 are as defined in Formula I. It is preferred that the nonreacting substituents of the annulated pyridine of Formula V, correspond to those appearing in the final product with the exception of R.sub.1. If R.sub.1 is to be represented by --OH in the final product, then it should be protected during the alkylation with a suitable protecting group such as a C.sub.1-6 alkyl. For those compounds in which R.sub.1 is to be represented by either an ester derivative or an amide derivative, then the desired amide or ester can be added to the core structure of Formula V prior to the alkylation reaction or it can be added to the core structure of Formula I after the alkylation reaction has been completed utilizing techniques well known in the art.
In Formula VI, Z is a leaving group such as a halogen, --OSO.sub.2 CH.sub.3, or --O--SO.sub.2 --C.sub.6 H.sub.5 --CH.sub.3 and R.sub.2, D, and n are as defined in Formula I. It is also preferred that the non-reacting substituents of the .omega.-alkanoic acid derivative other than R.sub.2 correspond to those appearing in the final product. If R.sub.2 is to be represented by OH in the final product, then it should be protected during the alkylation with a suitable protecting group such as a C.sub.1-6 alkyl. For those compounds in which R.sub.2 is to be represented by either an ester or amide derivative, an .omega.-alkanoic acid derivative may be utilized in which R.sub.2 is represented by the desired ester or amide derivative or the desired ester or amide derivative can be added to the core structure of Formula I upon completion of the alkylation reaction by techniques well known in the art.
As noted above, ester and amide derivatives can be added to the R.sub.1 and R.sub.2 positions of the core structure of Formula I by methods well known in the art. One suitable contact a compound of Formula I in which R.sub.1 and R.sub.2 are represented by OH with a base such as diethylisopropylamine in a polar inert solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile, acetone or tetrahydrofuran, thereby forming a bis carboxylate salt. The bis carboxylate salt is then contacted with 2 to 5 equivalents, preferably about 2.5 equivalents, of an alkylhalide corresponding to the desired ester, and allowed to react at a temperature of about 25.degree. C. for a period of time ranging from 16-24 hours. The reaction mixture is then quenched with dilute aqueous acid and extractive work-up as is known in the art affords the diester compounds of Formula I, which can be purified by standard methods such as chromatography, recrystallization, or distillation.
Amides can also be easily added to the compounds of Formula I by taking a compound of Formula I in which R.sub.1 and R.sub.2 are each represented by ester functions and contacting it with an excess of ammonia or a mono- or dialkylamine at a temperature of from 0.degree.-100.degree. C. for a period of time ranging from 1-48 hours in an alcoholic solvent such as methanol or ethanol. The resulting amide derivatives of Formula I can then be isolated and purified by techniques known in the art.
Another method for producing amides or esters comprises contacting a compound of Formula I in which R.sub.1 and R.sub.2 are represented by --OH with a halogenating agent such as thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentachloride, etc. The resulting diacid halides are then contacted with an excess of ammonia, monoalkylamines, dialkylamines, aliphatic alcohols, aromatic alcohols or a dialkylamino alkyl alcohol such as dimethylaminoethanol, diethylaminoethanol, optionally in the presence of a base such as a tertiary alkylamine, in an inert solvent such as ether, dioxane, tetrahydrofuran, etc. at a temperature of from 0.degree.-25.degree. C. for a period of time ranging from 5-16 hours. The resulting amides or esters can be isolated and purified by methods known in the art.
The alkylation reaction between the annulated pyridine of Formula V and the .omega.-alkanoic acid derivative of Formula VI is conducted according to techniques known in the art. Typically, the annulated pyridine of Formula V is first contacted with from about 1 to about 5 equivalents of a base and more preferably from about 1 to about 2.5 equivalents. The base and the annulated pyridine are stirred together at a temperature range of from about 0.degree. C. to about 25.degree. C. for a period of time ranging from about 5 minutes to about 60 minutes in a solvent. Suitable bases include alkali metal carbonates and bicarbonates such as potassium carbonate, alkali metal hydroxides such as sodium hydroxide, alkali metal hydrides such as sodium hydride, or tertiary alkylamines such as triethyl amine. Suitable solvents include diethyl ether, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, sulfolane, N-methyl-2-pyrollidone, benzene, toluene, acetone, butanone, methanol, ethanol, water or mixtures of water and water miscible solvents. Dimethylformamide is typically utilized.
An approximately equimolar amount of the .omega.-alkanoic acid derivative of Formula VI is then added to the reaction mixture and the reactants are stirred together for a period of time ranging from about 2 to about 48 hours and more preferably from 5 to 24 hours. The alkylation reaction is conducted at a temperature range of from about -40.degree. C. to about 100.degree. C. and more preferably from 25.degree. C. to 50.degree. C.
The completed reaction is quenched into water, saturated ammonium chloride, or dilute aqueous acid. The product can then be recovered and purified by techniques well known in the art. For example the product can be recovered by either extraction with an organic solvent, or concentration and filtration of the resulting solid. The crude product can then be purified by chromatographic techniques such as silica gel chromatography or by recrystallization from a solvent system such as ethyl acetate/hexane or methanol/water.
The .omega.-alkanoic acid derivatives of Formula VI are known in the art as are methods for their preparation. Many of these derivatives are commercially available.
Methods for producing the annulated pyridines of Formula V are known in the art. The starting materials for the annulated pyridines of Formula V in which X is either O or S, is an acetylinic dicarboxylic ester as described by Formula VII and an aromatic amino compound as described by Formula VIII: ##STR5## In Formula VII, B is represented by an alkyl residue such as methyl or ethyl. In Formula VIII, Ar is represented by one of the following aromatic rings: ##STR6## As is apparent to those skilled in the art, the particular aromatic amino compound that is utilized should be structurally analogous to the residue which is represented by A in the desired compound of Formula I.
A Michael condensation is conducted with the acetylinic dicarboxylic ester of Formula VII and the aromatic amine of Formula VIII thereby producing a Michael adduct as described by Formula IX in which Ar and B are as defined above: ##STR7##
The Michael condensation is conducted according to techniques known in the art. Typically, one equivalent of the aromatic amine of Formula VIII is contacted with about 1 to about 2 equivalents, and more preferably from about 1.1 to about 1.5 equivalents of the acetylinic dicarboxylic ester of Formula VII. The reaction is typically conducted at a temperature range of from about 25.degree. C. to about 200.degree. C., and more preferably from about 40.degree. C. to about 110.degree. C. for a period of time ranging from about 2 to about 48 hours and more preferably from about 5 to about 24 hours. The reaction can be conducted either neat or in a solvent such as methanol, ethanol, benzene, toluene, chloroform, tetrahydrofuran. Methanol is preferred.
After the reaction is completed, the solvent is evaporated and the resulting oil can be utilized directly in the next step of the synthesis. If desired, the crude amino adduct can be purified by conventional techniques known in the art such as silica gel chromatography.
The next step in the synthesis of the annulated pyridines of Formula V is the cyclization of the Michael adduct of Formula IX thereby producing an annulated pyridine of Formula V in which X is represented by O.
The cyclization is accomplished by heating the adduct of Formula IX to a temperature range of from about 150 to about 300.degree. C., (preferably from 200.degree.-270.degree. C.) in a solvent such as diphenyl ether, nujol, or polyphosphoric acid for a period of time ranging from about 0.1 to about 3 hours and more preferably from 25 minutes to 60 minutes. The reaction mixture is then cooled to about 25.degree. C. and the resulting precipitated product is collected by filtration. If desired, a hydrocarbon solvent such as hexane may be added to the reaction mixture to speed the precipitation of the solid. If a solid is not formed during this cooling period, then the bulk of the high boiling solvent is removed under vacuum and the product is then isolated by techniques known in the art. After the product is collected, it is washed in a hydrocarbon solvent and air dried. The crude annulated pyridine in which X is represented by O may be utilized in the alkylation reaction with the .omega.-alkanoic acid derivative or it may be utilized to produce an annulated pyridine of Formula V in which X is represented by S.
As is evident from structure IX, Michael adducts which would be formed from certain unsymmetrical aromatic amines could produce mixtures of positional isomers in the cyclization reaction which forms the annulated pyridines of Formula V. These mixtures may be separated by methods well known in the art such as fractional crystallization or column chromatography. For example, condensation of 3-chloroaniline with dimethyl acetylenedicarboxylate and subsequent cyclization of the obtained Michael adduct affords a mixture of methyl 5-chloro-4-hydroxy-2-quinolinecarboxylate and methyl 7-chloro-4-hydroxy-2-quinolinecarboxylate, which can be separated by fractional crystallization from acetic acid as outlined by Heindel, et.al., J. Med. Chem, 11, p. 1218 (1968).
Alternatively mixtures of isomers which are not separated at the Formula V stage may be converted to mixtures of Formula I and then separated by methods known in the art such as fractional crystallization or column chromatography. For example, a mixture of methyl 5-cyano-4-hydroxy-2-quinolinecarboxylate and methyl 7-cyano-4-hydroxy-2-quinolinecarboxylate can be alkylated as described above with methyl bromoacetate and the resulting mixture of 5- and 7-cyano positional isomers of the product can be separated by flash column chromatography on silica gel using ethyl acetate/hexane as eluant.
The annulated pyridines of Formula V produced by the cyclization reaction can be optionally purified by techniques known in the art such as silica gel chromatography or recrystallization from a solvent such as methanol, methanol/water, or DMF/water prior to its conversion into one of the compounds of Formula I.
The annulated pyridines of Formula V in which X is represented by 0 can be utilized to produce the annulated pyridines of Formula V in which X is represented by S in the following manner. Typically about 1 equivalent of the annulated pyridine of Formula V in which X is represented by O will be contacted with about 0.5 to about 1.0 equivalents of a thiocarbonylating reagent, such as, for example, Lawesson's reagent, P.sub.2 S.sub.5 /pyridine, etc. The reactants are typically stirred together at a temperature range of from about 0.degree. C. to about 110.degree. C., and more preferably from about 25.degree. C. to about 60.degree. C., for a period of time ranging from about 0.5 hours to about 24 hours. The reaction is typically conducted in a dry solvent, typically an ether such as, dimethoxyethane or THF. After the reaction is completed, it is typically quenched in ice water and the product is recovered directly by filtration or by extraction with an organic solvent. The resulting organic phase is then separated, dried, and evaporated at reduced pressures, thereby producing the desired annulated pyridine in which X is represented by S. This crude product can be utilized or it can be further purified by techniques known in the art such as recrystallization or column chromatography.
The method disclosed above for synthesizing the annulated pyridines of Formula V, produces a compound in which R.sub.1 will be represented by an alkoxy residue such as methoxy or ethoxy. This annulated pyridine may be utilized directly in the alkylation reaction with the .omega.-alkanoic acid derivative and the appropriate carboxylic acid derivative may be added after the completion of the alkylation reaction. Alternatively, the methyl or ethyl residue may be removed by conducting a basic hydrolysis and the appropriate carboxylic acid derivative may be added to the annulated pyridine by techniques known in the art prior to conducting the alkylation reaction.
The compounds of the present invention which can be described by Formulae II, III, and IV can also be produced utilizing the same synthetic method as that taught for producing the annulated pyridines of Formula V. As is readily apparent, those compounds of Formula V in which X is O and A is a thiophene residue are the subject of Formulae II, III, and IV. Thus the description of the appropriate starting materials, reaction conditions, and means of purifications discussed immediately above is equally applicable to either the annulated pyridines of Formula V or the compounds of Formulae II, III, or IV.
The compounds of Formula I in which X is represented by O and n is represented by l can be made in the following manner. Initially an annulated pyridine as previously described by Formula V in which X is represented by O, is subjected to an addition reaction with a propargylic ester as described by Formula X in which B is represented by a protecting group such as a C.sub.1-6 alkyl or a phenyl ring and D is as in Formula I: ##STR8##
This addition reaction produces an intermediate as described by Formula XI: ##STR9## in which X is O, R.sub.1, D, and A are as defined in Formula I and B is as described above. The intermediate of Formula XI is then subjected to a reductive hydrogenation thereby producing the desired compound of Formula I.
As is apparent to those skilled in the art, it is preferred that the nonreacting substituents of the annulated pyridine correspond to those appearing in the desired product. When R.sub.1 is to be represented by either an ester, or amide derivative, then the appropriate carboxylic derivative can be placed on the annulated pyridine starting material or it can be added after the hydrogenation reaction is completed. Likewise, if R.sub.1 is to be represented by --OH in the final product, then it should be protected with a suitable protecting group suCh as a C.sub.1-6 alkyl during the reaction with the propargylic ester. Likewise, if the protecting group of the propargylic ester is not identical to the R.sub.2 substituent in the desired product, then the appropriate R.sub.2 substituent can be added to the core structure of Formula I using methods known in the art after the hydrogenation reaction is completed.
The addition reaction between the annulated pyridine of Formula V and the propargylic ester of Formula X can be accomplished according to techniques known in the art. Typically the annulated pyridine is contacted with 1 to 2 equivalents of a base and from about 1 to about 2 equivalents of the propargylic ester of Formula X. The reactants are heated to a temperature range of from about 60.degree. C. to about 90.degree. C. for a period of time ranging from about 1 hour to about 48 hours. Suitable bases include trialkyl amines such as triethyl amine, alkali metal alcoholates such as sodium methoxide, alkali metal carbonates, and bicarbonates such as sodium bicarbonate and potassium carbonate. The reaction is also typically conducted in a solvent such as diethylether, tetrahydrofuran, dioxane, methanol, ethanol, tert-butanol, isopropanol, t-amyl alcohol, benzene, etc. Alcohols are currently preferred; t-butanol is most preferred.
Upon completion of the addition reaction, the product is typically recovered by evaporating the solvent under a vacuum. The resulting oil is typically redissolved in one of the non-water soluble solvents described above, or in a halogenated solvent such as CHCl.sub.3 or CH.sub.2 Cl.sub.2, and is then washed in succession with a dilute aqueous mineral acid, a dilute aqueous base, water, and a saturated solution of sodium chloride. The resulting organic layer is then dried over standard drying agents, and evaporated under a vacuum to afford the crude intermediate of Formula XI. This crude intermediate may be hydrogenated without further purification. If desired, it may be purified by either recrystallization or chromatography on silica gel.
The reductive hydrogenation of the intermediate of Formula XI is accomplished in the following manner. The intermediate is dissolved in an organic solvent such as a lower aklyl alcohol, acetic acid, ethyl acetate, or tetrahydrofuran and contacted with from 1-10 weight percent of a transistion metal catalyst such as, for example, palladium on charcoal. The hydrogenation is conducted under 1-4 atmospheres, preferably 2-3 atmospheres, of H.sub.2 gas at a temperature range of 20.degree.-30.degree. C. The reaction is stopped when one equivalent of hydrogen is consumed. The catalyst is removed by filtration and the desired compound of Formula I is recovered by techniques known in the art such as extraction. It can also be purified by techniques known in the art such as chromatography on silica gel or recrystallization from a solvent system such as ethylacetate/hexane.
Those compounds of Formula I in which X is represented by S and n is represented by l can be made in the following manner. Typically they are produced by carrying out an alkylation reaction between an annulated pyridine as previously described by Formula V in which X is represented by S and an acrylic acid derivative as described by Formula XII: ##STR10## in which R.sub.2 and D are as defined in Formula I or R.sub.2 is represented by a suitable protecting group such as a C.sub.1-6 alkyl.
This alkylation reaction is conducted in a manner similar to the alkylation reaction between the annulated pyridine of Formula V and the .omega.-alkanoic acid derivative of Formula VI which was discussed above. As in that alkylation reaction, when R.sub.1 and R.sub.2 are to be represented by either amide or ester derivatives, these can be added to the core structure of Formula I by techniques well known in the art or the alkylation can be conducted with reactants having the appropriate R.sub.1 and R.sub.2 substituents. The desired compound of Formula I can be recovered and purified by methods similar to those taught above.
The compounds of Formula I in which X is represented by NH and n is the integer O or 2-6 can be produced utilizing techniques known in the art. For example they can be produced by conducting an alkylation reaction between a .omega.-alkanoic acid derivative as previously described by Formula VI and an activated annulated pyridine as described by Formula XIII: ##STR11## in which Y is represented by --SO.sub.2 --C.sub.6 H.sub.6, --SO.sub.2 --C.sub.6 H.sub.5 --CH.sub.3, --SO.sub.2 --O 13 C.sub.6 H.sub.5 --Cl, --CO--CCl.sub.3, or --CO--CF.sub.3 and both R.sub.1 and R are as defined in Formula I.
The alkylation reaction between the activated annulated pyridine of Formula XIII and the .omega.-alkanoic acid derivative of Formula VI is conducted in a manner similar to that described for the alkylation reaction between the annulated pyridine of Formula V and the .omega.-alkanoic acid derivative of Formula VI. Thus the discussion concerning the proper criterion for the reactants, the proper reaction conditions as well as suitable methods of isolation, and purification of the product produced thereby are equally applicable to this reaction as well.
This alkylation reaction produces an intermediate which can be described by Formula XIV in which Y is as defined above and R.sub.1, R.sub.2, A, D, and n are as defined in Formula I: ##STR12##
The desired compound of Formula I can be produced from the intermediate of Formula XIV by subjecting the intermediate to a hydrolysis reaction thereby removing the activating group Y. This hydrolysis can be conducted utilizing techniques well known in the art. For example, the intermediate is typically contacted with from about 3 to about 10 equivalents of a strong mineral acid such as concentrated or 90% sulfuric acid. The intermediate is typically stirred in the presence of the acid for a period of time ranging from 0.5 hours to about 3 hours at a temperature range of from 0.degree. C. to about 25.degree. C.. The hydrolysis can be conducted in neat acid. Upon completion of the hydrolysis, the desired compound of Formula I can be recovered by techniques well known in the art such as quenching into water and extraction with an organic solvent. It can also be purified by techniques known in the art such as recrystallization from a solvent system such as methanol/DMF, chromatography on silica gel, or ion-exchange chromatography.
If desired, the groups Y and R.sub.1 and R.sub.2 can be removed sequentially, that is, conditions can be found such that the group Y can be hydrolyzed as described but R.sub.1 and R.sub.2 are left intact. The ester function can then be removed as described earlier (hydrolysis methods known in the art). Conversely, R.sub.1 and R.sub.2 can be removed preferentially by methods known in the art, leaving the Y group intact which then can be removed as above.
The activated annulated pyridines of Formula XIII can be produced using techniques well known in the art. Typically an annulated pyridine as described by Formula V in which X is represented by O is contacted with an activated isocyanate of the formula:
Alternatively, the activated annulated pyridines of Formula XIII can be produced by contacting an annulated pyridine of Formula V in which X is represented by NH with an acylating agent such as trifuluroacetic anhydride or trichloroacetyl chloride. The resulting product can be isolated and purified by techniques known in the art.
The annulated pyridines of Formula V in which X is represented by NH are known in the art as are their methods of preparation. Wright, Synthesis, pg. 1058 (1984).
The annulated pyridines of Formula I in which X is represented by NH and n is represented by 1 can be produced by methods known in the art. An alkylation reaction is conducted between an annulated pyridine as previously described by Formula V in which X is represented by NH and an acrylic acid derivative as previously described by Formula XII. This alkylation produces the desired compound of Formula I in which X is represented by NH, n is 1, and D, R.sub.1, R.sub.2, and A are as defined in Formula I. The alkylation reaction can be conducted in a manner analogous to the alkylation reaction between the annulated pyridine of Formula V and the .omega.-alkanoic acid derivatives of Formula VI which was previously discussed. Likewise the compounds can be isolated and purified in the same manner as that taught above. As in the other reaction schemes, if either R.sub.1 or R.sub.2 is not the desired ester or amide derivative, then the appropriate ester or amide derivative can be added to the molecule using techniques well known in the art.
The compounds of Formulae I-IV are excitatory amino acid antagonists. They antagonize the effects which excitatory amino acids have upon the NMDA receptor complex. They preferentially bind to the strychnine-insensitive glycerin binding site located on the NMDA receptor complex. They are useful in the treatment of a number of disease states.
Ischemia, hypoglycemia, and trauma have been shown to raise extracellular concentrations of glutamate and aspartate to potentially neurotoxic levels. These antagonists will be neuroprotective in these and potentially other syndromes characterized by elevated glutamate and or aspartate concentrations.
The compounds exhibit anti-convulsant properties and are useful in the treatment of epilepsy. They are useful in the treatment of grand mal seizures, petit mal seizures, psychomotor seizures, and autonomic seizures. One method of demonstrating their anti-epileptic properties is by the compounds ability to inhibit audiogenic convulsions in DBA/2 mice. This test can be conducted in the following manner.
Typically one group of from 6-8 male DBA/2J audiogenic susceptible mice are administered from about 0.01 .mu.g to about 100 .mu.g of the test compound. The test compound is administered intracerebrally into the lateral ventricle of the brain. A second group of mice are administered an equal volume of a saline control by the same route. Five minutes later the mice are placed individually in glass jars and are exposed to a sound stimulus of 110 decibels for 30 seconds. Each mouse is observed during the sound exposure for signs of seizure activity. The control group will have a statistically higher incidence of seizures than the group which receives the test compound.
The compounds of Formulae I-IV are useful for preventing or minimizing the damage which nervous tissues contained within the CNS suffer upon exposure to either ischemic, hypoxic, or hypoglycemic conditions. Representative examples of such ischemic, hypoxic, or hypoglycemic conditions include strokes or cerebrovascular accidents, carbon monoxide poisoning, hyperinsulinemia, cardiac arrest, drownings, suffocation, reduction of neuronal damage following trauma to the brain or spinal cord, and neonatal anoxic trauma. The compounds should be administered to the patient within 24 hours of the onset of the hypoxic, ischemic, or hypoglycemic condition in order for the compounds to effectively minimize the CNS damage which the patient will experience.
The compounds are also useful in the treatment of neurodegenerative diseases such as Huntington's disease, Alzheimer's disease, senile dementia, glutaric acidaemia type I, multi-infarct dementia, and neuronal damage associated with uncontrolled seizures. The administration of these compounds to a patient experiencing such a condition will serve to either prevent the patient from experiencing further neurodegeneration or it will decrease the rate at which the neurodegeneration occurs.
As is apparent to those skilled in the art, the compounds will not correct any CNS damage that has already occurred as the result of either disease or a lack of oxygen or sugar. As used in this application, the term "treat" refers to the ability of the compounds to prevent further damage or delay the rate at which any further damage occurs.
The compounds exhibit an anxiolytic effect and are thus useful in the treatment of anxiety. These anxiolytic properties can be demonstrated by their ability to block distress vocalizations in rat pups. This test is based upon the phenomenon that when a rat pup is removed from its litter, it will emit an ultrasonic vocalization. It was discovered that anxiolytic agents block these vocalizations. The testing methods have been described by Gardner, C. R., Distress vocalization in rat pups: a simple screening method for anxiolytic drugs. J. Pharmacol. Methods, 14:181-187 (1885) and Insel et.al. Rat pup ultrasonic isolation calls: Possible mediation by the benzodiapine receptor complex. Pharmacol. Biochem. Behav., 24: 1263-1267 (1967).
The compounds also exhibit an analgesic effect and are useful in controlling pain.
In order to exhibit these therapeutic properties, the compounds need to be administered in a quantity sufficient to inhibit the effect which the excitatory amino acids have upon the NMDA receptor complex. The dosage range at which these compounds exhibit this antagonistic effect can vary widely depending upon the particular disease being treated, the severity of the patient's disease, the patient, the particular compound being administered, the route of administration, and the presence of other underlying disease states within the patient, etc. Typically the compounds exhibit their therapeutic effect at a dosage range of from about 0.1 mg/kg/day to about 50 mg/kg/day for any of the diseases or conditions listed above. Repetitive daily administration may be desirable and will vary according to the conditions outlined above.
The compounds of the present invention may be administered by a variety of routes. They are effective if administered orally. The compounds may also be administered parenterally (i.e. subcutaneously, intravenously, intramuscularly, intraperitoneally, or intrathecally).
Pharmaceutical compositions can be manufactured utilizing techniques known in the art. Typically an antagonistic amount of the compound will be admixed with a pharmaceutically acceptable carrier.
For oral administration, the compounds can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions, or emulsions. Solid unit dosage forms can be capsules of the ordinary gelatin type containing, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, and cornstarch or they can be sustained release preparations. In another embodiment, the compounds of Formula I can be tableted with conventional tablet bases such as lactose, sucrose, and cornstarch in combination with binders, such as acacia, cornstarch, or gelatin, disintegrating agents such as potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. Liquid preparations are prepared by dissolving the active ingredient in an aqueous or non-aqueous pharmaceutically acceptable solvent which may also contain suspending agents, sweetening agents, flavoring agents, and preservative agents as are known in the art.
For parenteral administration the compounds may be dissolved in a physiologically acceptable pharmaceutical carrier and administered as either a solution or a suspension. Illustrative of suitable pharmaceutical carriers are water, saline, dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative, or synthetic origin. The pharmaceutical carrier may also contain preservatives, buffers, etc., as are known in the art. When the compounds are being administered intrathecally, they may also be dissolved in cerebrospinal fluid as is known in the art.
As used in this application:
The compounds may also be admixed with any inert carrier and utilized in laboratory assays in order to determine the concentration of the compounds within the serum, urine, etc., of the patient as is known in the art.
Neurodegenerative diseases are typically associated with a loss of NMDA receptors. Thus, the compounds of Formula I-IV may be utilized in diagnostic procedures to aid physicians with the diagnosis of neurodegenerative diseases. The compounds may be labeled with isotopic agents by techniques known in the art and utilized as imaging agents. They may then be administered to a patient in order to determine whether the patient is exhibiting a decreased number of NMDA receptors and the rate at which that loss is occurring.
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Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
352423 |
May 1989 |
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Patent Grant
5026700
