2-oxo-1-pyrrolidine derivatives, processes for preparing them and their uses

• US 20030120080A1
• Filed: 08/20/2002
• Published: 06/26/2003
• Est. Priority Date: 02/23/2000
• Status: Active Grant

• Current Assignee: UCB Biopharma SRL (UCB SA)
• Original Assignee: UCB SA
• Inventors: Talaga, Patrice, Kenda, Benoit, Pasau, Patrick, Michel, Philippe, Differding, Edmond, Matagne, Alain, Lallemand, Benedicte
• Granted Patent: US 6,784,197 B2
• Time in Patent Office: Days
• US Class Current: 546/278.4
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/36 : Opioid-abuse
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 237/12 : having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups peptides C07K
• CPC Class Codes: C07D 207/26 : 2-Pyrrolidones
• CPC Class Codes: C07D 207/27 : with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 207/273 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
• CPC Class Codes: C07D 207/277 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 307/33 : in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 495/04 : Ortho-condensed systems

Abstract

The invention concerns 2-oxo-1-pyrrolidine derivatives of formula (I) wherein the substituents are as defined in the specification, as well as their use as pharmaceuticals. The compounds of the invention are particularly suited for treating neurological disorders such as epilepsy.

Claims

1. A compound having the formula I or a pharmaceutically acceptable salt thereof,

2. A compound according to claim 1 wherein X represents a substituent group selected from,

a) —

COO R⁷ or —

CONR⁵R⁶;

b) —

COO R⁷ or —

CONR⁵R⁶, wherein R⁵, R⁶ and R⁷ are hydrogen, C1-4-alkyl, phenyl or alkylphenyl;

c) carboxy or —

CONR⁵R⁶;

d) carboxy or —

CONR⁵R⁶ wherein R⁵ and R⁶ are preferably hydrogen, C1-4-alkyl, phenyl or alkylphenyl;

e) —

CONR⁵R⁶;

or

f) —

CONH₂.

3. A compound according to claim 1, wherein R¹ represents a substituent group selected from,

a) hydrogen, alkyl or aryl;

b) hydrogen, C1-12 alkyl or aryl;

c) hydrogen, lower alkyl or phenyl;

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

or

e) ethyl.

4. A compound according to claim 1, wherein R² and R^2a are independently a substituent group selected from,

a) hydrogen, halogen or alkyl;

b) hydrogen, halogen or lower alkyl;

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

5. A compound according to claim 4, wherein at least one of R² and R^2a is hydrogen or both are hydrogen.

6. A compound according to claim 1 wherein R^3a, R⁴ and R^4a are independently a substituent group selected from,

a) hydrogen, alkyl, aryl or aralkyl;

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

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

7. A compound according to claim 6, wherein at least one of R⁴ and R^4a is hydrogen or both are hydrogen.

8. A compound according to claim 6 or 7, wherein R^3a represents a substituent group selected from,

a) hydrogen or alkyl;

b) hydrogen or lower alkyl;

or

c) hydrogen.

9. A compound according to claim 1 wherein R³ is a substituent group selected from,

a) hydrogen, C1-12-alkyl each optionally substituted by 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 oxycarbonyl group and optionally, a C1-4-alkylene bridge;

C2-6-alkenyl or -alkynyl, each optionally substituted by one or more halogens;

azido;

cyano;

amido;

carboxy;

triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl and phenyl and attached to the ring either directly or via a carbonyl group or a C1-4-alkylene bridge;

naphthyl;

or phenyl, phenylalkyl or phenylalkenyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, C1-6-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 a C1-4-alkylene bridge;

b) as a) except that any alkyl is C1-6-alkyl and any C1-4 alkylene bridge is methylene;

c) C1-6-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanato, azido, alkoxy, alkylthio, phenylsulfonyl;

nitrooxy;

C2-3-alkenyl or -alkynyl each optionally substituted by one or more halogens or by acetyl;

tetrazolyl, pyridyl, furyl, pyrrolyl, thiazolyl or thienyl;

or phenyl or phenylalkyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, amino, azido, phenyl and nitro and each attached to the ring either directly or via a sulfonyloxy and, optionally, a C1-4-alkylene bridge, particularly methylene;

d) as c) except that any C1-4 alkylene bridge is methylene;

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

f) C1-4-alkyl optionally substituted by one or more substituents selected from halogen, thiocyanato or azido;

C2-5-alkenyl or -alkynyl, each optionally substituted by one or more halogens;

thienyl;

or phenyl optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl or azido;

or

g) C1-6-alkyl and C2-6-haloalkenyl.

10. A compound according to claim 1 wherein R⁵ and R⁶ are independently a substituent group selected from,

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

or

b) hydrogen or methyl.

11. A compound according to claim 10, wherein at least one of R⁵ and R⁶ ishydrogen or both are hydrogen.

12. A compound according to claim 1, wherein R⁷ is a substituent group selected from,

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

b) hydrogen, methyl or ethyl;

or

c) hydrogen.

13. A compound according to claim 1 wherein R⁸ is a substituent group selected from,

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

or

b) hydrogen or methyl.

14. A compound according to claim 1, wherein,

A2 is oxygen;

X is —

CONR⁵R⁶ or —

COOR⁷ or —

CO—

R⁸ or CN;

R¹ is hydrogen or alkyl, aryl, halogen, hydroxy, amino, nitro, cyano;

R², R³, R⁴, are the same or different and each is independently hydrogen or halogen, hydroxy, amino, nitro, cyano, acyl, acyloxy, a sulfonyl derivative, a sulfinyl derivative, an amino derivative, carboxy, ester, ether, amido, sulfonic acid, sulfonamide, alkoxycarbonyl, a thio derivative, alkyl, alkoxy, oxyester, oxyamido, aryl, an oxy derivative, heterocycle, vinyl and R³ may additionally represent C2-5 alkenyl, C2-5 alkynyl or azido each optionally substituted by one or more halogen, cyano, thiocyano, azido, cyclopropyl, acyl and/or phenyl;

or phenylsulfonyloxy whereby any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl;

R^2a, R^3a and R^4a are hydrogen;

R⁵, R⁶, R⁷ are the same or different and each is independently hydrogen, hydroxy, alkyl, aryl, heterocycle or oxy derivative; and

R⁸ is hydrogen, hydroxy, thiol, halogen, alkyl, aryl, heterocycle, alkylthio or thio derivative.

15. A compound according to claim 14, wherein

R¹ is methyl, ethyl, propyl, isopropyl, butyl or isobutyl;

R² and R⁴ are independently hydrogen or halogen or methyl, ethyl, propyl, isopropyl, butyl, isobutyl;

R³ is C1-5 alkyl, C2-5 alkenyl, C2-C5 alkynyl, cyclopropyl, azido, each optionally substituded by one or more halogen, cyano, thiocyano, azido, alkylthio, cyclopropyl, acyl and/or phenyl;

phenyl;

phenylsulfonyl;

phenylsulfonyloxy, tetrazole, thiazole, thienyl, furyl, pyrrole, pyridine, whereby any phenyl moiety may be substituted by one or more halogen, alkyl, haloalkyl, alkoxy, nitro, amino, and/or phenyl;

most preferably methyl, ethyl, propyl, isopropyl, butyl, or isobutyl.

X is —

COOH or —

COOMe or —

COOEt or —

COOtBu or —

CONH_2.

16. A compound according to claim 15, wherein

R¹ is methyl, ethyl or n-propyl;

R² and R⁴ are each hydrogen; and

X is —

CONH₂.

17. A compound according to claim 1, wherein

X is —

CA¹NH₂, —

CA¹NHCH₃ or —

CA¹N(CH₃)₂;

R¹ is alkyl or phenyl;

R³ is alkyl, alkenyl, alkynyl, cyano, isothiocyanato, ether, carboxyl, amido, aryl, heterocycle;

or

R³ is CH₂R¹⁰ wherein R¹⁰ is hydrogen, cycloalkyl, oxyester, oxyalkylsulfonyl, oxyarylsufonyl, aminoalkylsulfonyl, aminoarylsulfonyl, nitrooxy, cyano, isothiocyanato, azido, alkylthio, arylthio, alkylsulfinyl, alkylsulfonyl, heterocycle, aryloxy, alkoxy or trifluoroethyl;

R^3a is hydrogen, alkyl or aryl;

or

R³ and R^3a form a cycloalkyl;

and R², R^2a, R⁴ and R^4a are each hydrogen.

18. A compound according to claim 1, wherein

R¹ is alkyl;

R², R^2a, R^3a and R^4a are each hydrogen;

R³ is hydrogen;

C1-12-alkyl optionally substituted by 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 oxycarbonyl group and optionally a C1-4-alkylene bridge;

C2-6-alkenyl or -alkynyl, each optionally substituted by one or more halogens;

azido;

cyano;

amido;

carboxy;

triazolyl, tetrazolyl, pyrrolidinyl, pyridyl, 1-oxidopyridyl, thiomorpholinyl, benzodioxolyl, furyl, oxazolyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl or piperazinyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl and phenyl and attached to the ring either directly or via a carbonyl group or a C1-4-alkylene bridge;

naphthyl;

or phenyl, phenylalkyl or phenylalkenyl each optionally substituted by one or more substituents selected from halogen, C1-6-alkyl, C1-6 haloalkyl, C1-6-alkoxy, C1-6-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 additionally a C1-4-alkylene bridge;

R^3a is hydrogen or C1-4-alkyl;

R⁴ and R^4a are independently hydrogen, C1-4-alkyl, phenyl or benzyl.

19. A compound according to claim 18, wherein, R¹ is a substituent group selected from

a) C1-12-alkyl;

b) C1-6-alkyl;

or

c) ethyl;

and any C1-4-alkylene bridge present is methylene.

20. A compound according to claim 1, which is in racemic form and wherein when X is —

CONR⁵R⁶ and R¹ is hydrogen, methyl, ethyl or propyl, then substitution on the pyrrolidine ring is other than mono-, di-, or tri-methyl or mono-ethyl.

21. A compound according to claim 1, which is in racemic form and wherein when X is —

CONR⁵R⁶ and R¹ is hydrogen or C1-6-alkyl, C2-6-alkenyl or -alkynyl or cycloalkyl, each unsubstituted, then substitution in the ring is other than by alkyl, alkenyl or alkynyl, each unsubstituted.

22. A compound according to claim 1, wherein,

X is —

CA¹NH₂;

R¹ is hydrogen;

R³ is azidomethyl, iodomethyl, C2-6-alkyl optionally substituted by 1 to 5 halogen atoms, vinyl optionally subsituted by one or two methyls, and/or 1 to 3 halogen atoms, acetylene optionally substituted by C1-4-alkyl, phenyl or halogen;

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

R², R^2a, R⁴ and R^4a are each hydrogen;

as their racemates or in enantiomerically enriched form, preferably the pure enantiomers.

23. A compound according to claim 1, wherein

X is —

CA¹NH₂;

R¹ is H;

R³ is C1-6-alkyl, C2-6-alkenyl or C2-6-alkynyl optionally substituted by azido, oxynitro, 1 to 6 halogen atoms;

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

and R², R^2a, R⁴ and R^4a are each hydrogen;

as their racemates or in enantiomerically enriched form, preferably the pure enantiomers.

24. A compound according to claim 1, wherein

A¹ and A² are oxygen;

R¹ is ethyl;

X is —

CONH₂;

R³ is n-propyl or 2,2-difluorovinyl; and

all other substituents are hydrogen.

25. A compound of formula AA-II

26. A compound according to claim 25, wherein Q¹ is a substituent group selected from,

a) alkyl;

or

b) linear or branched C1-4-alkyl.

27. A compound according to any preceding claim as a pure enantiomer.

28. A compound according to any preceding claim, which, when the carbon atom to which R¹ is attached is asymmetric, is in the “

S”

-configuration.

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

33. The use of a compound according to any preceding claim for the manufacture of a medicament for the treatment of epilepsy, epileptogenesis, seizure disorders, convulsions and other neurological disorders including bipolar disorders, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, essential tremor and other movement disorders, neonatal cerebral haemorrhage, amyotrophic lateral 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 rhinoconjunctivitis.

34. A method for treating epilepsy, epileptogenesis, seizure disorders, convulsions and other neurological disorders including bipolar disorders, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, essential tremor and other movement disorders, neonatal cerebral haemorrhage, amyotrophic lateral 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 rhinoconjunctivitis, in a mammal in need of such treatment, comprising administering a therapeutic dose of at least one compound according to any preceding claim.

35. The use of a compound of formula I as illustrated in claim 1 or a pharmaceutically acceptable salt thereof, wherein the individual substituents are as defined in claim 1, with the provisos that at least one of as R², R³, R⁴, 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 —

CONR⁵R⁶, A² is oxygen and R¹ is hydrogen, methyl, ethyl or propyl then substitution on the pyrrolidine ring is other than mono-, di-, or tri-methyl or mono-ethyl, for the manufacture of a medicament for the treatment of epilepsy, epileptogenesis, seizure disorders, convulsions and other neurological disorders including bipolar disorders, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, essential tremor and other movement disorders, neonatal cerebral haemorrhage, amyotrophic lateral 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 rhinoconjunctivitis.

36. A method for treating epilepsy, epileptogenesis, seizure disorders, convulsions and other neurological disorders including bipolar disorders, mania, depression, anxiety, migraine, trigeminal and other neuralgia, chronic pain, neuropathic pain, cerebral ischemia, cardiac arrhythmia, myotonia, cocaine abuse, stroke, myoclonus, essential tremor and other movement disorders, neonatal cerebral haemorrhage, amyotrophic lateral 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 rhinoconjunctivitis, in a mammal in need of such treatment, comprising administering a therapeutic dose of at least onecompound of formula I as illustrated in claim 1 or a pharmaceutically acceptable salt thereof, wherein the individual substituents are as defined in claim 1, with the provisos that at least one of as R², R³, R⁴, 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 —

CONR⁵R⁶, A² is oxygen and R¹ is hydrogen, methyl, ethyl or propyl then substitution on the pyrollidine ring is other than mono-, di-, or tri-methyl or mono-ethyl.

39. The use according to claim 35 or 37 or the method according to claim 36 or 38, wherein the condition to be treated is epilepsy, neuropathic pain, bipolar disorder or migraine.

29. A compound selected from those hereinbefore numbered 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.

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 claim 36, wherein the compound of formula I is a compound according to any one of claims 29, 30 or 31.

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

31. The (4R) and (4S) diastereoisomers of (2S)-2-[2-oxo-4-propylpyrrolidinyl]butanamide or a pharmaceutically acceptable salt thereof.