Pyrazolone Compounds As Metabotropic Glutamate Receptor Agonists For The Treatment Of Neurological And Psychiatric Disorders

• US 20090069340A1
• Filed: 12/22/2005
• Published: 03/12/2009
• Est. Priority Date: 12/27/2004
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: Ma, Fupeng, Bunting, Heather, Sun, Guang-Ri, Sundar, Babu, Chen, Deborah, Frey, Jennifer, Forst, Janet, Ukkiramapandian, Radhakrishnan, Slassi, Abdelmalik, Egle, Ian, Urbanek, Rebecca, Walsh, Sally, Isaac, Methvin, Steelman, Gary, Nugiel, David, Balestra, Michael
• Application Number:
  US11/793,050
• Publication Number:
  US 20090069340A1
• Time in Patent Office: Days
• US Class Current: 514/254.50
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 25/18 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 25/28 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 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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: C07D 211/62 attached in position 4
• CPC Class Codes: C07D 231/22 : with aryl radicals attached to ring nitrogen atoms
• CPC Class Codes: C07D 401/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/08 : Bridged systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems

Abstract

Compounds of Formula (I), wherein R¹, R², R³, R⁴, R⁵, R⁶, X, and n are as defined for Formula (I) in the description, processes for the preparation of the compounds and new intermediates employed in the preparation, pharmaceutical compositions containing the compounds, and the use of the compounds in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction.

Claims

1. A compound according to Formula I:

2. A compound according to claim 1, wherein

3. A compound according to claim 2, wherein

4. A compound according to claim 3, wherein

5. A compound according to claim 3, wherein X is selected from the group consisting of Br, Cl, and OC_1-6-alkyl.

6. A compound according to claim 5, wherein X is Br or Cl.

7. A compound according to claim 1, wherein R¹ is selected from the group consisting of aryl, C_3-8-cycloalkyl, C_1-6-alkyl-aryl, and C_1-6-alkyl-C_3-8-cycloalkyl, wherein R¹ may be substituted by one or more A.

8. A compound according to claim 7, wherein R¹ is selected from aryl and C_3-8-cycloalkyl, wherein R¹ may be substituted by one or more A.

9. A compound according to claim 8, wherein R¹ is aryl that may be substituted by one or more A.

10. A compound according to claim 9, wherein R¹ is phenyl that may be substituted by one or more A.

11. A compound according to claim 8, wherein R¹ is C_3-8-cycloalkyl that maybe substituted by one or more A.

12. A compound according to claim 11, wherein R¹ is cyclohexyl that may be substituted by one or more A.

13. A compound according to claim 1, wherein R² is selected from the group consisting of H and C_1-6-alkyl.

14. A compound according to claim 13, wherein R² is C_1-6-alkyl.

15. A compound according to claim 14, wherein R² is selected from methyl and ethyl.

16. A compound according to claim 1, wherein R⁵ and R⁶, when one or both are present, are independently selected from the group consisting of H, aryl, and C_3-8-cycloalkyl, wherein R⁵ and R⁶ may be substituted by one or more A.

17. A compound according to claim 1, wherein Q is C.

18. A compound according to claim 17, wherein R⁵ and R⁶ are both present.

19. A compound according to claim 18, wherein R⁵, R⁶, and Q combine to form a 5- to 7-membered ring containing atoms independently selected from the group consisting of C, N, O and S.

20. A compound according to claim 19, wherein the ring is

21. A compound according to claim 20, wherein the ring is

22. A compound according to claim 20, wherein the ring is

23. A compound according to claim 20, wherein R^3′

and R^4′

are independently selected from the group consisting of H, C_1-6-alkyl, C_1-6-alkyl-aryl, aryl, and heteroaryl, wherein R³ and R⁴ may be substituted by one or more A.

24. A compound according to claim 23, wherein R^4′

is aryl that may be substituted by one or more A.

25. A compound according to claim 24, wherein R^4′

is phenyl that may be substituted by one or more A.

26. A compound according to claim 20, wherein the ring is

27. A compound according to claim 1, wherein

X is selected from the group consisting of Cl, Br, and OC_1-6-alkyl;

31. A pharmaceutical composition comprising a compound according to claim 1 or 28 and a pharmaceutically acceptable carrier or excipient.

32. A method for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction in an animal in need of such treatment, comprising the step of administering to said animal a therapeutically effective amount of a compound according to claim 1 or 28.

33. A method for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction in an animal in need of such treatment, comprising the step of administering to said animal a therapeutically effective amount of a pharmaceutical composition according to claim 31.

34. The method according to claim 32 wherein the neurological and psychiatric disorders are selected from the group consisting of cerebral deficit subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, AIDS-induced dementia, Alzheimer'"'"'s disease, Huntington'"'"'s Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson'"'"'s disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine, urinary incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, mood disorders, circadian rhythm disorders, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, tardive dyskinesia, sleep disorders, attention deficit/hyperactivity disorder, and conduct disorder.

37. The method according to claim 33 wherein the neurological and psychiatric disorders are selected from the group consisting of cerebral deficit subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemia neuronal damage, dementia, AIDS-induced dementia, Alzheimer'"'"'s disease, Huntington'"'"'s chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson'"'"'s disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine, urinary incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, mood disorders, circadian rhythm disorders, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, tardive dyskinesia, sleep disorders, attention deficit/hyperactivity disorder, and conduct disorder.

28. A compound according to Formula II:

29. A compound selected from those shown in the following table:

30. A compound according to claim 29, wherein the compound is selected from the group consisting of:

35. The use of a compound according to Formula I or Formula II, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of cerebral deficit subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, AIDS-induced dementia, Alzheimer'"'"'s disease, Huntington'"'"'s Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson'"'"'s disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine, urinary incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, mood disorders, circadian rhythm disorders, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, tardive dyskinesia, sleep disorders, attention deficit/hyperactivity disorder, and conduct disorder.

36. A compound of Formula I or Formula II, or a pharmaceutically acceptable salt or solvate thereof, for use in therapy of cerebral deficit subsequent to cardiac bypass surgery and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, dementia, AIDS-induced dementia, Alzheimer'"'"'s disease, Huntington'"'"'s Chorea, amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson'"'"'s disease, muscular spasms and disorders associated with muscular spasticity including tremors, epilepsy, convulsions, migraine, urinary incontinence, substance tolerance, substance withdrawal, psychosis, schizophrenia, anxiety, mood disorders, circadian rhythm disorders, trigeminal neuralgia, hearing loss, tinnitus, macular degeneration of the eye, emesis, brain edema, pain, tardive dyskinesia, sleep disorders, attention deficit/hyperactivity disorder, and conduct disorder.