Aryl Sulphonamide Modulators

• US 20080051441A1
• Filed: 12/23/2005
• Published: 02/28/2008
• Est. Priority Date: 12/28/2004
• Status: Abandoned Application

• Current Assignee: Astrazeneca AB (Astrazeneca PLC)
• Original Assignee: Astrazeneca AB (Astrazeneca PLC)
• Inventors: McLaren, Frances, Brown, Dean, Simpson, Thomas
• Application Number:
  US11/722,752
• Publication Number:
  US 20080051441A1
• Time in Patent Office: Days
• US Class Current: 514/364
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• 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 25/34 Tobacco-abuse
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 261/04 having one double bond between ring members or between a ring member and a non-ring member
• CPC Class Codes: C07D 271/06 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles

Abstract

Compounds of Formula I:
wherein R¹, R², R³, R⁴, R⁵ Ar¹ and X are as described in the specification, pharmaceutically-acceptable salts thereof, processes for preparing them, pharmaceutical compositions containing them and their use in therapy, especially for treatment of conditions associated with reductions in nicotinic transmission.

Claims

1. A compound of formula I:

wherein;

Ar¹ is selected from aryl or heteroaryl where aryl is selected from phenyl or naphthyl and heteroaryl is selected from furyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, pyridyl, pyrazinyl, pyrimidinyl or quinolinyl;

R³, R⁴ and R⁵ are at each occurrence independently selected from hydrogen, C_1-4alkyl and C_1-4alkoxy;

X is selected from moieties according to formula II, I, IV, V, VI or VII

R¹ and R² are independently selected at each occurrence from hydrogen, halogen, —

C_1-6alkyl, —

C_1-6alkoxy, —

C_2-6alkenyl, —

C_2-6alkynyl, C_3-8cycloalkyl, —

CN, —

NO₂, —

CF₃, —

CONR³R⁴, —

S(O)_nR³ where n is o, 1 or 2, —

NR³R⁴, —

CH₂NR³R⁴, —

OR³, —

CH₂OR³ or —

CO₂R³, where R³ and R⁴ at each occurrence are independently selected from hydrogen or C_1-4alkyl, and stereoisomers, enantiomers, in vivo-hydrolysable precursors and pharmaceutically-acceptable salts thereof.

2. A compound according to claim 1, wherein:

Ar¹ is phenyl or pyridyl;

R³, R⁴ and R⁵ are at each occurrence independently selected from hydrogen, C_1-4alkyl and C_1-4alkoxy;

X is selected from moieties according to formula II, III, IV, V, VI or VII

R¹ and R² are independently selected at each occurrence from hydrogen or halogen, and stereoisomers, enantiomers, in vivo-hydrolysable precursors and pharmaceutically-acceptable salts thereof.

3. A compound according to claim 1 selected from:

4-[3-(2,4,6-Trimethyl-phenyl)-4,5-dihydro-isoxazol-5-yl]-benzenesulfonamide;

2-Chloro-4-[3-(2,4,6-trimethyl-phenyl)-isoxazol-5-yl]-benzenesulfonamide;

3-Fluoro-4-[3-(2,4,6-trimethyl-phenyl)-isoxazol-5-yl]-benzenesulfonamide;

4-[3-(2,4,6-trimethyl-phenyl)-isoxazol-5-yl]-benzenesulfonamide;

2-Fluoro-4-[3-(2,4,6-trimethyl-phenyl)-isoxazol-5-yl]-benzenesulfonamide;

4-[3-(2,4,6-Trimethyl-phenyl)-[1,2,4]oxadiazol-5-yl]-benzenesulfonamide, and

4-[3-(4-Methoxy-2,3-dimethyl-phenyl)-4,5-dihydro-isoxazol-5-yl]-benzenesulfonamide.

4. A method of treatment or prophylaxis of a disease or condition in which modulation of the α

7 nicotinic receptor is beneficial which method comprises administering a therapeutically-effective amount of a compound according to claim 1 to a subject suffering from said disease or condition.

5. The method of claim 4, wherein said disease or condition is anxiety, schizophrenia, mania or manic depression.

6. A method of treatment or prophylaxis of neurological disorders, psychotic disorders or intellectual impairment disorders, which comprises administering a therapeutically effective amount of a compound according to claim 1.

7. The method of claim 6, wherein said disorder is Alzheimer'"'"'s disease, learning deficit, cognition deficit, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder, Parkinson'"'"'s disease, Huntington'"'"'s disease, Tourette'"'"'s syndrome, neurodegenerative disorders in which there is loss of cholinergic synapses, jetlag, nicotine addiction, craving, pain, or ulcerative colitis.

8. A method for inducing the cessation of smoking comprising administering an effective amount of a compound according to claim 1.

9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically-acceptable diluent, lubricant or carrier.

10. A method of treatment or prophylaxis of a disease or condition in which activation of the α

7 nicotinic receptor is beneficial which method comprises administering a therapeutically-effective amount of a pharmaceutical composition according to claim 9 to a subject suffering from said disease or condition.

11. The method of claim 10, wherein said disease or condition is anxiety, schizophrenia, mania or manic depression.

12. A method of treatment or prophylaxis of neurological disorders, psychotic disorders or intellectual impairment disorders, which comprises administering a therapeutically effective amount of a pharmaceutical composition according to claim 9.

13. The method of claim 12, wherein said disorder is Alzheimer'"'"'s disease, learning deficit, cognition deficit, attention deficit, memory loss, Attention Deficit Hyperactivity Disorder, Parkinson'"'"'s disease, Huntington'"'"'s disease, Tourette'"'"'s syndrome, neurodegenerative disorders in which there is loss of cholinergic synapses, jetlag, nicotine addiction, craving, pain, or ulcerative colitis.

14. A method for inducing the cessation of smoking comprising administering an effective amount of a pharmaceutical composition according to claim 9.

15-16. -16. (canceled)