Novel Tetrazole Derivatives as Positive Allosteric Modulators of Metabotropic Glutamate

• US 20070299110A1
• Filed: 11/02/2005
• Published: 12/27/2007
• Est. Priority Date: 11/04/2004
• Status: Abandoned Application

• Current Assignee: Addex Pharma S.A.
• Original Assignee: Addex Pharma S.A.
• Inventors: Gagliardi, Stefania, Rocher, Jean-Philippe, Palombi, Giovanni
• Application Number:
  US11/667,096
• Publication Number:
  US 20070299110A1
• Time in Patent Office: Days
• US Class Current: 514/318
• 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 25/22 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 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

The present invention relates to new tetrazole compounds of formula I wherein B, P, Q, W, R₁ and R₂ are defined in the description: invention compounds are useful for the treatment or prevention of central nervous system disorders as well as other disorders modulated by mGluR5 receptors.

Claims

1. A compound which conforms to the general formula I:

2. A compound according to claim 1 having the formula I-A

3. A compound according to claim 1 having the formula I-B

Wherein

P and Q are each independently selected and denote a cycloalkyl, a heterocycloalkyl, an aryl or heteroaryl group of formula

R₃, R₄, R₅, R₆, and R₇ independently are hydrogen, halogen, —

NO₂, —

(C₁-C₆)alkyl, —

(C₃-C₆)cycloalkyl, —

(C₃-C₇)cycloalkylalkyl, —

(C₂-C₆)alkenyl, —

(C₂-C₆)alkynyl, halo-(C₁-C₆)alkyl, heteroaryl, heteroarylalkyl, arylalkyl, aryl, —

OR₈, —

NR₈R₉, —

C(═

NR₁₀)NR₈R₉, N(═

NR₁₀)NR₈R₉, —

NR₈COR₉, NR₈CO₂R₉, NR₈SO₂R₉, —

NR₁₀CO NR₈R₉, —

SR₈, —

S(═

O)R₈, —

S(═

O)₂R₈, —

S(═

O)₂NR₈R₉, —

C(═

O)R₈, —

C(═

O)—

O—

R₈, —

C(═

O)NR₈R₉, —

C(═

NR₈)R₉, or C(═

NOR₈)R₉ substituents;

wherein optionally two substituents are combined to the intervening atoms to form a bicyclic heterocycloalkyl, aryl or heteroaryl ring;

wherein each ring is optionally further substituted with 1-5 independent halogen, —

CN, —

(C₁-C₆)alkyl, —

O—

(C₀-C₆)alkyl, —

O—

(C₃-C₇)cycloalkylalkyl, —

O(aryl), —

O(heteroaryl), —

O—

(—

C₁-C₃)alkylaryl, —

O—

(C₁-C₃)alkylheteroaryl, N((—

C₀-C₆)alkyl)((C₀-C₃)alkylaryl) or —

N((C₀-C₆)alkyl)((C₀-C₃-) alkylheteroaryl) groups;

R₈, R₉, R₁₀ each independently is hydrogen, (C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₇)cycloalkylalkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halo-(C₁-C₆)alkyl, heterocycloalkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl;

any of which is optionally substituted with 1-5 independent halogen, —

CN, —

C₁-C₆)alkyl, —

O—

(C₀-C₆)alkyl, —

O—

(C₃-C₇)cycloalkylalkyl, —

O(aryl), —

O(heteroaryl), —

N—

(C₀-C₆)alkyl)₂, —

N((C₀-C₆)alkyl)((C₀-C₃-)alkylheteroaryl) groups;

D, E, F, G and H represent independently —

C(R₃)═

, —

C(R₃)═

C(R₄)—

, —

C(═

O)—

, —

C(═

S)—

, —

O—

, —

N═

, —

N(R₃)—

or —

S—

;

J represents —

C(R₁₁, R₁₂), —

O—

, —

N(R₁₁)—

or —

S—

;

R₁₁, R₁₂ independently are hydrogen, —

(C₁-C₆)alkyl, —

(C₃-C₆)cycloalkyl, —

(C₃-C₇)cycloalkylalkyl, —

(C₂-C₆)alkenyl, (C₂-C₆)alkynyl, halo(C₁-C₆)alkyl, heteroaryl, heteroarylalkyl, arylalkyl or aryl;

any of which is optionally substituted with 1-5 independent halogen, —

CN, —

(C₁-C₆)alkyl, —

O(C₀-C₆)alkyl, —

O(C₃-C₇)cycloalkylalkyl, —

O(aryl), —

O(heteroaryl), —

N((C₀-C₆)alkyl)((C₀-C₆)alkyl), —

N((C₀-C₆)alkyl)((C₃-C₇)cycloalkyl) or —

N((C₀-C₆)alkyl)(aryl) substituents;

any N may be an N-oxide;

or pharmaceutically acceptable salts, hydrates or solvates of such compounds.

4. A compound according to claim 1, which can exist as optical isomers, wherein said compound is either the racemic mixture or an individual optical isomer.

5. A compound according to claim 1, wherein the compound is selected from:

(4-Fluoro-phenyl)-{(S)-3-[5-(4-fluoro-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-methanone;

(4-Fluoro-phenyl)-{3-[5-(4-fluoro-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-methanone;

(4-Fluoro-phenyl)-{3-[5-(2-fluoro-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-methanone;

(4-Fluoro-phenyl)-[(S)-3-(5-phenyl-tetrazol-2-yl)-piperidin-1-yl]-methanone;

(4-Fluoro-phenyl)-[(R)-3-(5-phenyl-tetrazol-2-yl)-piperidin-1-yl]-methanone;

{(S)-3-[5-(4-Chloro-phenyl)-tetrazol-2-yl]-piperidin-1-yl) -(4-fluoro-phenyl)-methanone;

(4-Fluoro-phenyl)-{(S)-3-[5-(4-methoxy-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-methanone;

(4-Fluoro-phenyl)-{(S)-3-[5-(2-fluoro-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-methanone;

{(S)-3-[5-(2-Chloro-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-(4-fluoro-phenyl)-methanone;

(4-Fluoro-phenyl)-{(R)-3-[5-(4-fluoro-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-methanone;

(4-Fluoro-phenyl)-[(S)-3-(5-pyridin-4-yl-tetrazol-2-yl)-piperidin-1-yl]-methanone;

(4-Fluoro-phenyl)-[(S)-3-(5-pyridin-3-yl-tetrazol-2-yl)-piperidin-1-yl]-methanone;

(4-Fluoro-phenyl)-[(S)-3-(5-pyridin-2-yl-tetrazol-2-yl)-piperidin-1-yl]-methanone;

(4-Fluoro-phenyl)-{(S)-3-[5-(2-methoxy-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-methanone;

(4-Fluoro-phenyl)-[(S)-3-(5-p-tolyl-tetrazol-2-yl)-piperidin-1-yl]-methanone;

(4-Fluoro-phenyl)-[(S)-3-(5-m-tolyl-tetrazol-2-yl)-piperidin-1-yl]-methanone;

(4-Fluoro-phenyl)-{(S)-3-[5-(3-fluoro-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-methanone;

{(S)-3-[5-(4-Fluoro-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-(5-methyl-isoxazol-4-yl)-methanone;

(6-Fluoro-pyridin-3-yl)- [(S)-3-(5-phenyl-tetrazol-2-yl)-piperidin-1-yl]-methanone;

(3,4-Difluoro-phenyl)-[(S)-3-(5-phenyl-tetrazol-2-yl)-piperidin-1-yl]-methanone;

{(S)-3-[5-(4-Fluoro-phenyl)-tetrazol-2-yl] -piperidin-1-yl}-(6-fluoro-pyridin-3-yl)-methanone;

(4-Fluoro-2-methyl-phenyl)-[(S)-3-(5-phenyl-tetrazol-2-yl)-piperidin-1-yl]-methanone;

(4-Fluoro-2-methyl-phenyl)-{(S)-3-[5-(4-fluoro-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-methanone;

(3,4-Difluoro-phenyl)-{(S)-3-[5-(4-fluoro-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-methanone;

(2,4-Difluoro-phenyl)-{(S)-3-[5-(4-fluoro-phenyl)-tetrazol-2-yl]-piperidin-1-yl}-methanone;

(2,4-Difluoro-phenyl)-[(S)-3-(5-phenyl-tetrazol-2-yl)-piperidin-1-yl]-methanone;

(4-Fluoro-phenyl)-{3-[5-phenyl-tetrazol-2-yl]-piperidin-l-yl}-methanone; and

(5-Methyl-isoxazol-4-yl)-[(S)-3-(5-phenyl-tetrazol-2-yl)-piperidin-1-yl]-methanone.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier and/or excipient.

7. A method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR5 allosteric modulators, comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound/composition according to claim 1.

8. A method of treating or preventing a condition in a mammal, including a human, the treatment or prevention of which is affected or facilitated by the neuromodulatory effect of mGluR5 positive allosteric modulators (enhancer), comprising administering to a mammal in need of such treatment or prevention, an effective amount of a compound/composition according to claim 1.

9. A method useful for treating or preventing central nervous system disorders selected from the group consisting of anxiety disorders:

Agoraphobia, Generalized Anxiety Disorder (GAD), Obsessive-Compulsive Disorder (OCD), Panic Disorder, Posttraumatic Stress Disorder (PTSD), Social Phobia, Other Phobias, Substance-Induced Anxiety Disorder, comprising administering an effective amount of a compound/composition according to claim 1.

10. A method useful for treating or preventing central nervous system disorders selected from the group consisting of childhood disorders:

Attention-Deficit/Hyperactivity Disorder), comprising administering an effective amount of a compound/composition according to claim 1.

11. A method useful for treating or preventing central nervous system disorders selected from the group consisting of eating Disorders (Anorexia Nervosa, Bulimia Nervosa), comprising administering an effective amount of a compound/composition according to claim 1.

12. A method useful for treating or preventing central nervous system disorders selected from the group consisting of mood disorders:

Bipolar Disorders (I &

II), Cyclothymic Disorder, Depression, Dysthymic Disorder, Major Depressive Disorder, Substance-Induced Mood Disorder, comprising administering an effective amount of a compound/composition according to claim 1.

13. A method useful for treating or preventing central nervous system disorders selected from the group consisting of psychotic disorders:

Schizophrenia, Delusional Disorder, Schizoaffective Disorder, Schizophreniform Disorder, Substance-Induced Psychotic Disorder, comprising administering an effective amount of a compound/composition according to claim 1.

14. A method useful for treating or preventing central nervous system disorders selected from the group consisting of cognitive disorders:

Delirium, Substance-Induced Persisting Delirium, Dementia, Dementia Due to HIV Disease, Dementia Due to Huntington'"'"'s Disease, Dementia Due to Parkinson'"'"'s Disease, Dementia of the Alzheimer'"'"'s Type, Substance-Induced Persisting Dementia, Mild Cognitive Impairment, comprising administering an effective amount of a compound/composition according to claim 1.

15. A method useful for treating or preventing central nervous system disorders selected from the group consisting of personality disorders:

Obsessive-Compulsive Personality Disorder, Schizoid, Schizotypal disorder, comprising administering an effective amount of a compound/composition according to claim 1.

16. A method useful for treating or preventing central nervous system disorders selected from the group consisting of substance-related disorders:

Alcohol abuse, Alcohol dependence, Alcohol withdrawal, Alcohol withdrawal delirium, Alcohol-induced psychotic disorder, Amphetamine dependence, Amphetamine withdrawal, Cocaine dependence, Cocaine withdrawal, Nicotine dependence, Nicotine withdrawal, Opioid dependence, Opioid withdrawal, comprising administering an effective amount of a compound/composition according to claim 1.

19. A method for preparing a tracer for imaging metabotropic glutamate receptors, comprising using or more compounds of claim 1 to prepare the tracer.

17-18. -18. (canceled)