RU2002124522A

RU2002124522A - 2-OXO-1-pyrrolidine derivatives, method for their preparation and use

Info

Publication number: RU2002124522A
Application number: RU2002124522/04A
Authority: RU
Inventors: Эдмон ДИФФЕРДЭН; Бенуа Кенда; Бенедикт ЛЯЛЛЕМЭН; Ален МАТАНЬ; Филипп Мишель; Патрик ПАЗО; Патрис ТАЛАГА
Original assignee: ЮСиБи, С.А.
Priority date: 2000-02-23
Filing date: 2001-02-21
Publication date: 2004-04-20

Claims

1. The compound of formula I or its pharmaceutically acceptable salt,

where X represents –CA ¹ NR ⁵ R ⁶ or –CA ¹ —OR ⁷ or –CA'-R ⁸ or CN;

A ¹ and A ² independently represent oxygen, sulfur, or —NR ⁹ ;

R ¹ represents hydrogen, alkyl, aryl or —CH ₂ —R ^1a , where R ^1a is aryl, heterocycle, halogen, hydroxy, amino, nitro or cyano;

R ² -, R ³ and R ⁴ are the same or different and each independently represents hydrogen, halogen, hydroxy, thiol, amino, nitro, nitrooxy, cyano, azido, carboxy, amido, sulfonic acid, sulfonamide, alkyl, alkenyl, alkynyl , ester, ether, aryl, heterocycle, or hydroxy derivative, thio derivative, amino derivative, acyl derivative, sulfonyl derivative or sulfinyl derivative;

R ^2a , R ^3a and R ^4a are the same or different and each independently represents hydrogen, halogen, alkyl, alkenyl, alkynyl or aryl;

R ⁵ , R ⁶ , R ⁷ and R ⁹ are the same or different and each independently represents hydrogen, hydroxy, alkyl, aryl, heterocycle or hydroxy derivative; and

R ⁸ represents hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle or thio derivative;

with the proviso that at least one of R ² , R ³ , R ⁴ , R ^2a , R ^3a and R ^4a is other than hydrogen; and that when the compound is a mixture of all possible isomers, X is - CONR ⁵ R ⁶ , A is oxygen and R ¹ is hydrogen, methyl, ethyl or propyl, then the substitution on the pyrrolidine ring is different from mono-, di- or trimethyl or monoethyl; and that when R ¹ , R ² , R ⁴ , R ^2a , R ^3a and R ^{4a are} each hydrogen, A ² is oxygen and X is —CONR ⁵ R ⁶ , then R ³ is different from carboxy, ester, amido , substituted oxopyrrolidine, hydroxy, hydroxy derivative, amino, amino derivatives, methyl, naphthyl, phenyl optionally substituted by hydroxy derivative or in the para position by a halogen atom.

2. The compound according to claim 1, where X represents a group of a Deputy selected from,

a) –COOR ⁷ or –CONR ⁵ R ⁶ ;

b) —COOR ⁷ or —CONR ⁵ R ⁶ , where R ⁵ , R ⁶ and R ⁷ are hydrogen, C _1-4 alkyl, phenyl or alkyl phenyl;

c) carboxy or-CONR ⁵ R ⁶ ;

d) carboxy or —CONR ⁵ R ⁶ , wherein R ⁵ and R ⁶ are preferably hydrogen, C _1-4 alkyl, phenyl or alkyl phenyl;

e) -CONR ⁵ R ⁶ or

f) -CONH ₂ .

3. The compound according to claim 1, where R ¹ represents a group of a substituent selected from,

a) hydrogen, alkyl or aryl;

b) hydrogen, C _1-12 alkyl or aryl;

c) hydrogen, lower alkyl or phenyl;

d) methyl, ethyl, propyl, isopropyl, butyl, iso- or tert-butyl, 2,2,2-trimethylethyl, each optionally attached via a methylene bridge or from the same groups substituted by at least one halogen atom; or

e) ethyl.

4. The compound according to claim 1, where R ² and R ^2a independently represent a group of a substituent selected from,

a) hydrogen, halogen or alkyl;

b) hydrogen, halogen or lower alkyl;

c) hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or tert-butyl, 2,2,2-trimethylethyl or the same groups substituted by at least one halogen atom.

5. The compound according to claim 4, in which at least one of R ² and R ^2a is hydrogen, or both are hydrogen.

6. The compound according to claim 1, where R ^3a , R ⁴ and R ^4a independently represent a group of a substituent selected from,

a) hydrogen, alkyl, aryl or aralkyl;

b) hydrogen, methyl, ethyl, phenyl or benzyl;

7. The compound according to claim 6, in which at least one of R ⁴ and R ^4A is hydrogen or both are hydrogen.

8. The compound according to claim 6 or 7, in which R ^3a represents a group of a substituent selected from,

a) hydrogen or alkyl;

b) hydrogen or lower alkyl; or

c) hydrogen.

9. The compound according to claim 1, in which R ³ represents a group of a substituent selected from such groups as:

a) hydrogen, C _{1 -12} alkyl, each optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy and attached to the ring, either directly or via a thio, sulfinyl, sulfonyl, carbonyl or hydroxycarbonyl group, and optionally a C _1-4 alkylene bridge; C _2-6 alkenyl or alkynyl, each optionally substituted with one or more halogens; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxide pyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl, each optionally substituted with one or more substituents selected from _1-6 and phenyl and attached to the ring, either directly or through a carbonyl group or a C _1-4 alkylene bridge; naphthyl; or phenyl, phenylalkyl or phenylalkenyl each optionally substituted with one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, amino, azido, phenyl and nitro and each attached to the ring, either directly or through an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and, optionally, a C _1-4 alkylene bridge;

b) as a), except that any alkyl is C _1-6 alkyl and any C _1-4 alkylene bridge is methylene;

c) C _1-6 alkyl optionally substituted with one or more substituents selected from halogen, thiocyanato, azido, alkoxy, alkylthio, phenylsulfonyl; nitrooxy; C _2-3 -alkenyl or -alkynyl each optionally substituted with one or more halogens or acetyl;

tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl; or phenyl or phenylalkyl, each optionally substituted with one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy, amino, azido, phenyl and nitro, and each attached to a ring, either directly or via sulfonyloxy and, optionally, a C _1-4 alkylene bridge, in particular methylene;

d) as c), with the exception that any C _1-4 alkylene bridge is methylene;

e) hydrogen, halogen or methyl, ethyl, propyl, isopropyl, butyl, iso or tert-butyl, 2,2,2-trimethylethyl or the same groups substituted by at least one halogen atom;

f) C _1-4 alkyl optionally substituted with one or more substituents selected from halogen, thiocyanato or azido; C _2-5 alkenyl or alkynyl, each optionally substituted with one or more halogens; thienyl; or phenyl optionally substituted with one or more substituents selected from halogen, C _1-6 alkyl, C _1-6 haloalkyl or azido; or

d) C _1-6 alkyl and C _2-6 haloalkenyl.

10. The compound according to claim 1, in which R ⁵ and R ⁶ independently represent a group of a substituent selected from:

a) hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or tert-butyl, 2,2,2-trimethylethyl; or

b) hydrogen or methyl.

11. The compound of claim 10, wherein at least one of R ⁵ and R ⁶ is hydrogen, or both are hydrogen.

12. The compound according to claim 1, in which R ⁷ represents a group of a substituent selected from:

a) hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or tert-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or the same groups substituted by at least one halogen atom;

b) hydrogen, methyl or ethyl; or

c) hydrogen.

13. The compound according to claim 1, in which R ⁸ represents a group of a substituent selected from:

a) hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso or tert-butyl, 2,2,2-trimethylethyl, phenyl, benzyl or the same groups substituted by at least one halogen atom; or

b) hydrogen or methyl.

14. The compound according to claim 1, where A ² represents oxygen;

X represents —CONR ⁵ R ⁶ or COOR ⁷ or CO R ⁸ or CN;

R ¹ represents hydrogen or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano;

R ² , R ³ , R ⁴ are the same or different and each independently represents hydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, sulfonyl derivative, sulfinyl derivative, amino derivative, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, thio derivative, alkyl, alkoxy, hydroxy ether, oxyamido, aryl, hydroxy derivative, heterocycle, vinyl and R ³ may additionally be C _2-5 alkenyl, C _2-5 alkynyl or azido, each optionally substituted with one or more halogen, cyan , Thiocyano, azido, cyclopropyl, acyl and / or phenyl; or phenylsulfonyloxy, wherein any phenyl moiety may be substituted with one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and / or phenyl;

R ^2a R ^3a and R ^4a represents hydrogen;

R ⁵ , R ⁶ , R ⁷ are the same or different and each independently represents hydrogen, hydroxy, alkyl, aryl, heterocycle or hydroxy derivative; and

R ⁸ represents hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle, alkylthio or thio derivative.

15. The compound of claim 14, wherein:

R ¹ represents methyl, ethyl, propyl, isopropyl, butyl or isobutyl;

R ² and R ⁴ independently represent hydrogen, or halogen, or methyl, ethyl, propyl, isopropyl, butyl, isobutyl;

R ³ is C _1-5 alkyl, C _2-5 alkenyl, C ₂ -C5 alkynyl, cyclopropyl, azido, each optionally substituted with one or more halogen, cyano, thiociano, azido, alkylthio, cyclopropyl, acyl and / or phenyl; phenyl; phenylsulfonyl; phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl, pyrrole, pyridine, where any phenyl moiety may be substituted with one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and / or phenyl; most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl,

X represents —COOH, or —COOMe, or —COOEt, or —COOtBu, or —CONH ₂ .

16. The compound according to clause 15, in which R ¹ represents methyl, ethyl or n - propyl;

R ² and R ^{4 are} each hydrogen;

and X represents —CONH ₂ .

17. The compound according to claim 1,

where X represents — CA ¹ NH ₂ , —CA ¹ NCH _3, or —CA ¹ N (CH ₃ ) ₂ ;

R ¹ represents alkyl or phenyl;

R ³ represents alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl, amido, aryl, heterocycle; or R ³ represents CH ₂ R ¹⁰ where R ¹⁰ represents hydrogen, cycloalkyl, hydroxyether, hydroxyalkylsulfonyl, hydroxyarylsulfonyl,

aminoalkylsulfonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy or trifluoroethyl;

R ^3a represents hydrogen, alkyl or aryl; or

R ³ and R ^3a form cycloalkyl;

and R ² , R ^2a R ⁴ and R ^{4a are} each hydrogen.

18. The compound according to claim 1, in which:

R ¹ represents alkyl;

R ² , R ^2a , R ^3a and R ^{4a are} each hydrogen;

R ³ represents hydrogen; C _1-12 alkyl optionally substituted with one or more substituents selected from hydroxy, halogen, cyano, thiocyanato or alkoxy, and attached to the ring, either directly or through a thio, sulfinyl, sulfonyl, carbonyl or hydroxycarbonyl group and optionally C _1-4 alkylene bridge; C _2-6 alkenyl or alkynyl, each optionally substituted with one or more halogen; azido; cyano; amido; carboxy; triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl, each optionally substituted with one or more C ₆ -alkyl substituents and phenyl, and attached to the ring, either directly or through a carbonyl group or a C _1-4 alkylene bridge; naphthyl; or phenyl, phenylalkyl or phenylalkenyl, each optionally substituted with one or more substituents selected from halo, C _l-6 -alkyl, C _1-6 -haloalkyl, C _1-6 -alkoxy, C _1-6 -alkylthio, amino, azido , phenyl and nitro, and each attached to the ring, either directly or via an oxy, sulfonyl, sulfonyloxy, carbonyl or carbonyloxy group and optionally an additional C _1-4 alkylene bridge;

R ^3a represents hydrogen or C _1-4 alkyl;

R ⁴ and R ^4a independently represent hydrogen, C _1-4 alkyl, phenyl or benzyl.

19. The compound of claim 18, wherein R ¹ is a substituent group selected from:

a) C _l-12 alkyl;

b) C _1-6 alkyl; or

c) ethyl;

and any C _1-4 alkylene bridge present is methylene.

20. The compound according to claim 1, which is in racemic form and in which, when X is —CONR ⁵ R ⁶ and R ¹ is hydrogen, methyl, ethyl or propyl, then the substitution on the pyrrolidine ring is different from mono, di- or trimethyl or monoethyl.

21. The compound according to claim 1, which is in racemic form and, in which, when X is —CONR ⁵ R ⁶ and R ¹ is hydrogen or C _1-6 alkyl, C _2-6 alkenyl or alkynyl or cycloalkyl, each unsubstituted, then the substitution in the ring is different from alkyl, alkenyl or alkynyl, each unsubstituted.

22. The compound according to claim 1, in which X represents-CA ¹ NH ₂

R ¹ represents hydrogen;

R ³ is azidomethyl, iodomethyl, C _2-6 alkyl optionally substituted with 1 to 5 halogen atoms, vinyl optionally substituted with one or two methyls and / or 1 to 3 halogen atoms, acetylene optionally substituted with C _{1 -4-} alkyl, phenyl or halogen;

R ^3a represents hydrogen or halogen, preferably fluorine; and

R ² , R ^2a , R ⁴ and R ⁴ a are each hydrogen; as well as its racemates or enantiomerically enriched form, preferably PURE enantiomers.

23. The compound according to claim 1, in which X represents-CA ¹ NH ₂ ;

R ¹ represents H;

R ³ represents C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, optionally substituted with azido, oxynitro, from 1 to 6 halogen atoms;

R ^3a represents hydrogen or halogen, preferably fluorine;

and R ² , R ^2a R ⁴ and R ^{4a are} each hydrogen;

as well as its racemates or enantiomerically enriched form, preferably PURE enantiomers.

24. The compound according to claim 1, in which:

A ¹ and A ² are oxygen;

R ¹ represents ethyl;

X represents —CONH ₂ ;

R ³ represents n-propyl or 2,2-difluorovinyl; and all other substituents are hydrogen.

25. The compound of formula AA-II

where X, R ¹ a R ² , R ³ , R ⁴ , R ^2a , R ^3a and R ^{4a are} defined in claim 1 and Q ¹ together with the oxygen to which it is attached, represents a leaving group.

26. The compound of claim 25, wherein Q ¹ is a substituent group selected from:

a) alkyl; or

b) linear or branched C _1-4 alkyl.

27. The compound according to any preceding paragraph as a pure enantiomer.

28. The compound according to any preceding paragraph, which, when the carbon atom to which R ^{1 is} attached, is asymmetric, is in the "S" - configuration.

29. A compound selected from those that have in the description of the invention the numbers 8.9, 10, 22, 23, 27, 30, 31, 32, 33, 38, 40, 41, 43, 46, 47.49, 64, 71, 72, 73, 75, 81, 83, 86, 87, 88, 92, 93, 95, 96, 98, 100, 103, 105, 110, 119, 127, 142, 146, 149, 151, 152, 156,157, 158, 159,162, 163, 164, 165, 166, 169,170, 171, 173, 174, 175, 176, 180, 181, 185,187, 188, 195, 196, 197, 198, 200, 201, 204, 205, 207, 209, 211, 212, 213, 214, 215, 219, 221, 222, 223, 224, 225, 226, 228, 229, 234, 250, 251 ,. 252, 264, 265, 267, 304, 306, 350, 351, AA 1, AA 2, AA 3, AA 4 and AA 5, or a pharmaceutically acceptable salt thereof.

30. (2S) -2 - [(4S) -4- (2,2-difluorovinyl) -2-oxopyrrolidinyl] butanamide or a pharmaceutically acceptable salt thereof.

31. (4R) and (4S) diastereosomers of (2S) -2- [2-oxo-4-propyrrolidinyl] butanamide or their pharmaceutically acceptable salts.

32. A pharmaceutical composition comprising an effective amount of a compound according to any preceding paragraph in combination with a pharmaceutically acceptable diluent or carrier.

33. The use of a compound according to any one of claims 1 to 31 for the manufacture of preparations for the treatment of epilepsy, epileptogenesis, stroke and convulsions, other neurological diseases, including bipolar diseases, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine dependence, paralysis, myoclonia, significant concussion and other movement disorders, neonatal cerebral palsy, amyotrophic lat -sectoral sclerosis, spasticity, Parkinson's disease and other degenerative diseases, bronchial asthma, asthmatic status and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rinokonyuktivita.

34. A method of treating epilepsy, epileptogenesis, stroke and convulsions, other neurological diseases, including bipolar diseases, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, to , paralysis, myoclonia, significant concussion and other movement disorders, neonatal cerebral palsy, amyotrophic lateral sclerosis, spasticity, Parkinson's disease and other degenerative diseases, bronchial asthma, asthmatic state and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis, in a mammal in need of such treatment, comprising administering a therapeutic dose of a compound according to any one of claims 1- 32.

35. The use of the compounds of formula I according to claim 1 or a pharmaceutically acceptable salt thereof, provided that at least one of R ² , R ³ , R ⁴ , R ^2a R ^3a and R ^4a is other than hydrogen, and that when the compound represents a mixture of all possible isomers, X represents —CONR ⁵ R ⁶ , A ² represents oxygen and R ¹ represents hydrogen, methyl, ethyl or propyl, then the substitution on the pyrrolidine ring is different from mono-, di-, or trimethyl or monoethyl, for the production of drugs for the treatment of epilepsy, epileptogenesis, apoplexy stroke and convulsions other neurological diseases, including bipolar diseases, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine dependence, paralysis, myoclonia, significant concussion and other movement disorders neonatal cerebral palsy, amyotrophic lateral sclerosis, spasticity, Parkinson's disease and other degenerative diseases, bronchial asthma, asthmatic state and allergic bronchitis, asthmatic syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis.

36. A method of treating epilepsy, epileptogenesis, stroke and convulsions, other neurological diseases, including bipolar diseases, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, to , paralysis, myoclonia, significant concussion and other movement disorders, neonatal cerebral palsy, amyotrophic lateral sclerosis, spasticity, Parkinson's disease and other degenerative diseases, bronchial asthma, asthma and allergic bronchitis, asthma syndrome, bronchial hyperreactivity and bronchospastic syndromes as well as allergic and vasomotor rhinitis and rhinoconjunctivitis, in a mammal in need of such treatment, comprising administering a therapeutic dose of at least one compound of formula I according to 1 or a pharmaceutically acceptable salt thereof, provided that at least one of R ² , R ³ , R ⁴ , R ^2a and R ^4a is other than hydrogen, and that when the compound is are a mixture of all possible isomers, X is —CONR ⁵ R ⁶ , A ² is oxygen and R ¹ is hydrogen, methyl, ethyl or propyl, then the substitution on the pyrrolidine ring is different from mono-, di-, or trimethyl or monoethyl.

37. The use according to claim 35, wherein the compound of formula I is a compound according to any one of claims 29, 30, or 31.

38. The method according to clause 36, wherein the compound of formula I is a compound according to any one of clauses 29, 30 or 31.

39. The use according to clause 35 or 37, or the method according to clause 36 or 38, wherein the diseases to be treated are epilepsy, neuropathy, pain, bipolar disease or migraine.