Heterocyclic carboxamides

• US 20030232841A1
• Filed: 06/20/2003
• Published: 12/18/2003
• Est. Priority Date: 04/15/1998
• Status: Abandoned Application

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Howard, Harry R.
• Application Number:
  US10/601,209
• Publication Number:
  US 20030232841A1
• Time in Patent Office: Days
• US Class Current: 514/255.06
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• 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 9/12 Antihypertensives
• CPC Class Codes: C07D 207/34 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 207/416 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 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

A compound of the formula

wherein X, Y, Z, R² and R³ are as defined above, useful in treating or preventing migraine, depression and other disorders for which a 5-HT₁, agonist or antagonist is indicated.

Claims

1. A compound of the formula

2. A compound according to claim 1, wherein Z is oxygen, S(O)_m wherein m is zero;

or NH.

3. A compound according to claim 1, wherein Y is a group of the formula

4. A compound according to claim 1, wherein R² is hydrogen or (C₁-C₄)alkyl and X² is hydrogen, fluoro or chloro.

5. A compound according to claim 1, wherein R³ is —

(CH₂)_tB wherein t is zero or one and B is phenyl or naphthyl wherein the phenyl and naphthyl groups may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C₁-C₆)alkyl, (C₁-C₆)alkoxy, (C₁-C₆) alkoxy-(C₁-C₆)alkyl-, trifluoromethyl, trifluoromethoxy, cyano, hydroxy, COOH and (C₁-C₆)alkylS(O)_h wherein h is 0, 1 or 2.

6. A compound according to claim 1, wherein Z is oxygen, S(O)_m wherein m is zero;

or NH;

Y is a group of the formula

7. A compound of claim 1, wherein the compound is selected from the group consisting of:

5-[2-(4-methylpiperazin-1-yl)-phenyl]-furan-2-carboxylic acid 4-chlorobenzylamide;

5-[2-(4-methylpiperazin-1-yl)-phenyl]-furan-2-carboxylic acid 4-chlorophenylamide;

5-[2-(4-methylpiperazin-1-yl)-phenyl]-thiophene-2-carboxylic acid 4-chlorophenylamide;

5-[2-(4-methylpiperazin-1-yl)-phenyl]-thiophene-2-carboxylic acid 4-chlorobenzyl-amide;

5-[2-(4-methylpiperazin-1-yl)-phenyl]-furan-2-carboxylic acid [2-(4-chlorophenyl )ethyl]-amide;

4-[2-(4-methylpiperazin-1-yl)-phenyl]-furan-2-carboxylic acid 4-chlorobenzylamide;

5-[2-(4-methylpiperazin-1-yl)-phenyl]-thiophene-2-carboxylic acid benzylamide;

5-[2-(4-methylpiperazin-1-yl)-phenyl]-thiophene-2-carboxylic acid 4-fluorobenzylamide;

5-[2-(4-methylpiperazin-1-yl)-phenyl]-thiophene-2-carboxylic acid 4-methoxybenzylamide;

5-[2-(4-methylpiperazin-1-yl)-phenyl]-thiophene-2-carboxylic acid [2-(4-chlorophenyl)ethyl]-amide;

3-methyl-5-[2-(4-methylpiperazin-1-yl)-phenyl]-thiophene-2-carboxylic acid 4-chlorobenzylamide;

5-[5-fluoro-2-(4-methylpiperazin-1-yl)-phenyl]-thiophene-2-carboxylic acid 4-chlorobenzylamide; and

5-[2-(4-methylpiperazin-1-yl)-phenyl]-1H-pyrrole-2-carboxylic acid 4-chlorobenzylamide.

8. A pharmaceutical composition for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer'"'"'s disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson'"'"'s diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, cancer, chronic paroxysmal hemicrania and headache in a mammal, comprising an amount of a compound according to claim 1 that is effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, comprising an amount of a compound according to claim 1 that is effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier.

10. A method for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer'"'"'s disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson'"'"'s diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, cancer, chronic paroxysmal hemicrania and headache in a mammal, comprising administering to a mammal in need of such treatment or prevention an amount of a compound according to claim 1 that is effective in treating or preventing such disorder or condition.

11. A method for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, comprising administering to a mammal in need of such treatment or prevention an amount of a compound according to claim 1 that is effective in treating or preventing such disorder or condition.

12. A pharmaceutical composition for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer'"'"'s disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson'"'"'s diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, cancer, chronic paroxysmal hemicrania and headache in a mammal, comprising a serotonin receptor antagonizing or agonizing effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, comprising a serotonin receptor antagonizing or agonizing effective amount of a compound of according to claim 1 and a pharmaceutically acceptable carrier.

14. A method for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer'"'"'s disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson'"'"'s diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, cancer, chronic paroxysmal hemicrania and headache in a mammal, comprising administering to a mammal requiring such treatment or prevention a serotonin receptor antagonizing or agonizing effective amount of a compound according to claim 1.

15. A method for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, comprising administering to a mammal requiring such treatment or prevention a serotonin receptor antagonizing or agonizing effective amount of a compound according to claim 1.

16. A pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, comprising:

a) a pharmaceutically acceptable carrier;

b) a compound of according to claim 1;

and

c) a 5-HT re-uptake inhibitor or a pharmaceutically acceptable salt thereof;

wherein the amount of the active compounds are such that the combination is effective in treating or preventing such disorder or condition.

17. A method for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, comprising administering to a mammal requiring such treatment or prevention:

a) a compound according to claim 1;

and

b) a 5-HT re-uptake inhibitor or a pharmaceutically acceptable salt thereof;

wherein the amounts of the active compounds are such that the combination is effective in treating or preventing such disorder or condition.

18. A pharmaceutical composition according to claim 20, wherein the 5-HT re-uptake inhibitor is sertraline or a pharmaceutically acceptable salt thereof.

19. A method according to claim 21, wherein the 5-HT re-uptake inhibitor is sertraline or a pharmaceutically acceptable salt thereof.

20. A method for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine pain, Alzheimer'"'"'s disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson'"'"'s diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, cancer, chronic paroxysmal hemicrania and headache in a mammal, comprising administering to a mammal requiring such treatment or prevention:

a) a compound according to claim 1;

and

b) a 5-HT re-uptake inhibitor or a pharmaceutically acceptable salt thereof;

wherein the amounts of the active compounds are such that the combination is effective in treating or preventing such disorder or condition.

21. A method for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, comprising administering to said mammal requiring such treatment or prevention:

a) a 5-HT_1A antagonist or a pharmaceutically acceptable salt thereof; and

b) a 5-HT_1D antagonist compound according to claim 1 or a pharmaceutically acceptable salt thereof;

wherein the amounts of the active compounds are such that the combination is effective in treating or preventing such disorder or condition.

22. A method for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer'"'"'s disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson'"'"'s diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, cancer, chronic paroxysmal hemicrania and headache in a mammal, comprising administering to a mammal requiring such treatment or prevention:

a) a 5-HT_1A antagonist or a pharmaceutically acceptable salt thereof; and

b) a 5-HT_1D antagonist compound according to claim 1 or a pharmaceutically acceptable salt thereof;

wherein the amounts of the active compounds are such that the combination is effective in treating or preventing such disorder or condition.

23. A pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, comprising:

a) a 5-HT_1A antagonist or a pharmaceutically acceptable salt thereof; and

b) a 5-HT_1D antagonist compound according to claim 1 or a pharmaceutically acceptable salt thereof;

wherein the amounts of the active compounds are such that the combination is effective in treating or preventing such disorder or condition.

24. A pharmaceutical composition for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer'"'"'s disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson'"'"'s diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, cancer, chronic paroxysmal hemicrania and headache in a mammal, comprising:

a) a 5-HT_1A antagonist or a pharmaceutically acceptable salt thereof; and

b) a 5-HT_1D antagonist compound according to claim 1 or a pharmaceutically acceptable salt thereof;

wherein the amounts of the active compounds are such that the combination is effective in treating or preventing such disorder or condition.