Cyclic sulfonamides for inhibition of gamma-secretase

1. A compound of formula I:

wherein the bonds indicated by wavy lines are mutually cis with respect to the cyclohexane ring;

R 3 represents H or a hydrocarbon group of up to 10 carbon atoms, optionally substituted with CF 3 , CHF 2 , halogen, CN, OR 5 , COR 5 , CO 2 R 5 , OCOR 6 , N(R 5 ) 2 , CON(R 5 ) 2 or NR 5 COR 6 ;

R 5 represents H or C 1-4 alkyl;

R 6 represents C 1-4 alkyl; and

Ar 1 and Ar 2 independently represent phenyl or heteroaryl, either of which bears 0-3 substituents independently selected from halogen, CN, NO 2 , CF 3 , CHF 2 , OH, OCF 3 , CHO, CH═NOH, C 1-4 alkoxy, C 1-4 alkoxycarbonyl, C 2-6 acyl, C 2-6 alkenyl and C 1-4 alkyl which optionally bears a substituent selected from halogen, CN, NO 2 , CF 3 , OH and C 1-4 alkoxy;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein Ar 1 is selected from 6-(trifluoromethyl)-3-pyridyl and phenyl which is optionally substituted in the 4-position with halogen, CN, vinyl, allyl, acetyl, methyl or mono-, di- or trifluoromethyl;

and Ar 2 is selected from phenyl groups bearing halogen substituents in the 2- and 5-positions, the 2- and 6-positions, or in the 2-, 3- and 6-positions.

3. A compound according to claim 2 wherein Ar 1 is 4-chlorophenyl or 4-trifluoromethylphenyl and Ar 2 is 2,5-difluorophenyl.

4. A compound according to any previous claim wherein R 3 represents H or a non-aromatic hydrocarbon group of up to 6 carbon atoms which is unsubstituted.

5. A compound according to claim 4 wherein R 3 represents H, methyl, ethyl, n-propyl, isopropyl or allyl.

6. A compound according to claim 5 selected from

(4aRS,6RS,8aSR)-6-(2,5-difluorophenyl)-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine 2,2-dioxide;

(3S,4aR,6R,8aS)-6-(2,5-difluorophenyl)-3-ethyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine 2,2-dioxide;

(3R,4aR,6R,8aS)-6-(2,5-difluorophenyl)-3-ethyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine 2,2-dioxide;

(3RS,4aRS,6RS,8aSR)-6-(2,5-difluorophenyl)-3-isopropyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine 2,2-dioxide;

(3SR,4aRS,6RS,8aSR)-6-(2,5-difluorophenyl)-3-isopropyl-6-{[4-(trifluoromethyl)phenyl]sulfonyl}octahydro-1H-2,1-benzothiazine 2,2-dioxide; and

(3S,4aR,6R,8aS)-6-[(4-chlorophenyl)sulfonyl]-6-(2,5-difluorophenyl)-3-ethyloctahydro-1H-2,1-benzothiazine 2,2-dioxide;

and the pharmaceutically acceptable salts thereof.

7. A pharmaceutical composition comprising a compound according to any previous claim and a pharmaceutically acceptable carrier.

8. A process for preparing a compound of formula I as defined in claim 1 comprising the steps of:

(a) cyclising a compound of formula (2):

by treatment with strong base in an aprotic solvent to form a compound of formula (1):

(b) optionally alkylating the compound of formula (1) with R 3a —L; and

(c) removing the N-protecting group;

where Prt is a protecting group, L is a leaving group, R 3a is R 3 that is other than H, R a is C 1-6 alkyl which optionally bears up to 3 halogen substituents, or phenyl which optionally bears up to 3 substituents selected from halogen and C 1-4 alkyl, and Ar 1 , Ar 2 and R 3 are as defined in claim 1 .

9. A compound of claim 1 or a pharmaceutically acceptable salt thereof wherein Ar 1 represents 4-trifluoromethylphenyl, Ar 2 represents 2,5-difluorophenyl, and R 3 represents ethyl.

10. A compound of claim 1 which is in the homochiral form of formula (IA)

or a pharmaceutically acceptable salt thereof.

11. A compound of claim 1 which is in the homochiral form of formula (IB)

or a pharmaceutically acceptable salt thereof.

12. A compound of claim 9 which is in the homochiral form of formula (IA)

or a pharmaceutically acceptable salt thereof.

13. A compound of claim 10 which is in the homochiral form of formula (IB)

or a pharmaceutically acceptable salt thereof.