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Claims for Patent: 6,878,721

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Claims for Patent: 6,878,721

Title: Beta2-adrenoceptor agonists
Abstract:Compounds of formula ##STR1## in free or salt or solvate form, where Ar is a group of formula ##STR2## Y is carbon or nitrogen and R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, X, n, p, q and r are as defined in the specification, their preparation and their use as pharmaceuticals, particularly for the treatment of obstructive or inflammatory airways diseases.
Inventor(s): Cuenoud; Bernard (Horsham, GB), Bruce; Ian (Horsham, GB), Fairhurst; Robin Alec (Horsham, GB), Beattie; David (Horsham, GB)
Assignee: Novartis AG (Basel, CH)
Application Number:10/009,008
Patent Claims: 1. A compound of formula ##STR17##

in free or salt or solvate form, where Ar is a group of formula ##STR18## R.sup.1 is hydrogen, hydroxy, or alkoxy; R.sup.2 and R.sup.3 are each independently hydrogen or alkyl; R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each independently hydrogen, halogen, cyano, hydroxy, alkoxy, aryl, alkyl, alkyl substituted by one or more halogen atoms or one or more hydroxy or alkoxy groups, interrupted C.sub.2 to C.sub.10 alkyl in which one or more pairs of carbon atoms are linked by --O--, --NR--, --S--, --S(.dbd.O)-- or --SO.sub.2 --, where R is hydrogen or C.sub.1 to C.sub.10 alkyl, alkenyl, trialkylsilyl, carboxy, alkoxycarbonyl, or --CONR.sup.11 R.sup.12, where R.sup.11 and R.sup.12 are each independently hydrogen or alkyl, or R.sup.4 and R.sup.5, R.sup.5 and R.sup.6, or R.sup.6 and R.sup.7 together with the carbon atoms to which they are attached denote a carbocyclic or a 5- or 6-membered O-heterocyclic ring containing one or two oxygen atoms; R.sup.8 is halogen, --OR.sup.13, --CH.sub.2 OR.sup.13 or --NHR.sup.13 where R.sup.13 is hydrogen, alkyl, alkyl interrupted by one or more hetero atoms, --COR.sup.14, where R.sup.14 is hydrogen, --N(R.sup.15)R.sup.16, alkyl or alkyl interrupted by one or more hetero atoms, or aryl and R.sup.15 and R.sup.16 are each independently hydrogen, alkyl or alkyl interrupted by one or more hetero atoms, or R.sup.13 is --C(.dbd.NH)R.sup.17, --SOR.sup.17 or --SO.sub.2 R.sup.17 where R.sup.17 is alkyl or alkyl interrupted by one or more hetero atoms, and R.sup.9 is hydrogen, or R.sup.8 is --NHR.sup.18 where --NHR.sup.18 and R.sup.9, together with the carbon atoms to which they are attached, denote a 5- or 6-membered heterocycle; R.sup.10 is --OR.sup.19 or --NHR.sup.19 where R.sup.19 is hydrogen, alkyl, alkyl interrupted by one or more hetero atoms, or --COR.sup.20, where R.sup.20 is --N(R.sup.21)R.sup.22, alkyl or alkyl interrupted by one or more hetero atoms, or aryl, and R.sup.21 and R.sup.22 are each independently hydrogen, alkyl or alkyl interrupted by one or more hetero atoms; X is halogen or halomethyl or alkyl; Y is carbon or nitrogen; n is 1 or 2; p is zero when Y is nitrogen or 1 when Y is carbon; q and r are each zero or 1, the sum of q+r is 1 or 2; and the carbon atom marked with an asterisk * has the R or S configuration, or a mixture thereof, when R.sup.1 is hydroxy or alkoxy.

2. A compound according to claim 1, in which Ar is a group of formula III: ##STR19##

in which R.sup.29, R.sup.30 and R.sup.31 are each independently hydrogen or C.sub.1 -C.sub.4 -alkyl; R.sup.1 is hydroxyl; R.sup.2 and R.sup.3 are hydrogen; R.sup.4 and R.sup.7 are identical and are each hydrogen, C.sub.1 -C.sub.4 -alkyl or C.sub.1 -C.sub.4 -alkoxy; and either R.sup.5 and R.sup.6 are identical and are each hydrogen, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy or C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.4 -alkyl, or R.sup.5 and R.sup.6 together denote --(CH.sub.2).sub.4 -- or --O(CH.sub.2).sub.2 O--.

3. A compound according to claim 2, in which the carbon atom in formula I marked with an asterisk * has the R configuration.

4. A compound according to claim 1, in which Ar is a group of formula ##STR20##

where R.sup.29, R.sup.30 and R.sup.31 are each independently hydrogen or C.sub.1 -C.sub.4 -alkyl.

5. A compound according to claim 1, in which R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each hydrogen or are such that the benzene ring to which they are attached is symmetrically substituted.

6. A compound according to claim 2, in which Ar is a group of formula III, R.sup.1 is hydroxy, R.sup.2 and R.sup.3 are hydrogen, R.sup.4 and R.sup.7 are identical and are each hydrogen, C.sub.1 -C.sub.4 -alkyl or C.sub.1 -C.sub.4 -alkoxy, and either R.sup.5 and R.sup.6 are identical and are each hydrogen, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy or C.sub.1 -C.sub.4 -alkoxy-C.sub.1 -C.sub.4 -alkyl, or R.sup.5 and R.sup.6 together denote --(CH.sub.2).sub.4 -- or --O(CH.sub.2).sub.2 O--, in free or salt or solvate form.

7. A compound according to claim 6, in which the carbon atom in formula I marked with an asterisk * has the R configuration.

8. A compound of formula ##STR21##

in free or salt or solvate form, (A) wherein Ar is a group of formula ##STR22## in which R.sup.29, R.sup.30 and R.sup.31 are each H, R.sup.1 is OH, R.sup.2 and R.sup.3 are each H and (i) n is 1, and R.sup.4 and R.sup.7 are each CH.sub.3 O-- and R.sup.5 and R.sup.6 are each H; or (ii) n is 1, and R.sup.4 and R.sup.7 are each H and R.sup.5 and R.sup.6 are each CH.sub.3 CH.sub.2 --; or (iii) n is 1, and R.sup.4 and R.sup.7 are each H and R.sup.5 and R.sup.6 are each CH.sub.3 --; or (iv) n is 1, and R.sup.4 and R.sup.7 are each CH.sub.3 CH.sub.2 -- and R.sup.5 and R.sup.6 are each H; or (v) n is 1, and R.sup.4 and R.sup.7 are each H and R.sup.5 and R.sup.6 together denote --(CH.sub.2).sub.4 --; or (vi) n is 1, and R.sup.4 and R.sup.7 are each H and R.sup.5 and R.sup.6 together denote --O(CH.sub.2).sub.2 O--; or (vii) n is 1, and R.sup.4 and R.sup.7 are each H and R.sup.5 and R.sup.6 are each CH.sub.3 (CH.sub.2).sub.3 --; or (viii) n is 1, and R.sup.4 and R.sup.7 are each H and R.sup.5 and R.sup.6 are each CH.sub.3 (CH.sub.2).sub.2 --; or (ix) n is 2, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are each H; or (x) n is 1, and R.sup.4 and R.sup.7 are each H and R.sup.5 and R.sup.6 are each CH.sub.3 OCH.sub.2 --; or (B) which is a compound selected from 8-hydroxy-5-[1-hydroxy-2-(indan-2-ylamino)-ethyl]-1H-quinolin-2-one; 5-[2-(5,6-dimethoxy-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin -2-one; 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-3-methyl-1H-q uinolin-2-one; 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-methoxymethoxy-6-meth yl-1H-quinolin-2-one; 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-6-methyl-1H-q uinolin-2-one; 8-hydroxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-3,4-dihydro-1 H-quinolin-2-one; 5-[(R)-2-(5,6-diethyl-2-methyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy- 1H-quinolin-2-one; (S)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinol in-2-one-hydrochloride; 5-[(R)-1-hydroxy-2-(6,7,8,9-tetrahydro-5H-benzocyclohepten-7-ylamino)-ethyl ]-8-hydroxy-1H-quinolin-2-one hydrochloride; (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinol in-2-one maleate; (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinol in-2-one hydrochloride; (R)-8-hydroxy-5-[(S)-1-hydroxy-2-(4,5,6,7-tetramethyl-indan-2-ylamino)-ethy l]-1H-quinolin-2-one; 8-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-indan-2-ylamino)-ethyl]-1H-quinolin- 2-one; 5-[2-(5,6-diethyl-indan-2-ylamino)-ethyl]-8-hydroxy-1H-quinolin-2-one; 8-hydroxy-5-[(R)-1-hydroxy-2-(2-methyl-2,3,5,6,7,8-hexahydro-1H-cyclopenta[ b]naphthalen-2-ylamino)-ethyl]-1H-quinolin-2-one; or 5-[(S)-2-(2,3,5,6,7,8-hexahydro-1H-cyclopenta[b]naphthalen-2-ylamino)-1-hyd roxy-ethyl]-8-hydroxy-1H-quinolin-2-one.

9. A pharmaceutical composition comprising a compound according to claim 1, together with a pharmaceutically acceptable carrier.

10. A pharmaceutical composition comprising a compound according to claim 7, together with a pharmaceutically acceptable carrier.

11. A method for the treatment of a condition selected from chronic or acute urticaria, psoriasis, allergic conjunctivitis, actinitis, hay fever and mastocytosis which comprises administering to a subject in need thereof an effective amount of a compound according to claim 1.

12. A method for the treatment of an obstructive or inflammatory airways disease which comprises administering to a subject in need thereof an effective amount of a compound according to claim 1.

13. A method for the treatment of obstructive or inflammatory airways disease which comprises administering to a subject in need thereof an effective amount of a compound according to claim 8.

14. A process for the preparation of a compound of formula I in free or salt or solvate form comprising: (a) for the preparation of a compound where R1 is hydroxy, either (i) reacting a compound of formula ##STR23## with a compound of formula ##STR24## where Ar.sup.1 is Ar as defined in claim 1 or a protected form thereof, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and n are as defined in claim 1 and R.sup.32 is hydrogen or an amine-protective group, or (ii) reducing a compound of formula ##STR25## where Ar.sup.1 is Ar as defined in claim 1 or a protected form thereof, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 are as defined in claim 1, to convert the indicated keto group into --CH(OH)--; or (b) for the preparation of a compound where R.sup.1 is hydrogen, reducing a corresponding compound of formula I where R.sup.1 is hydroxy; or (c) for the preparation of a compound of formula I where R.sup.1 is alkoxy, either (i) O-alkylating a corresponding compound of formula I where R.sup.1 is hydroxy or (ii) reacting a corresponding compound having a leaving moiety instead of R.sup.1 with an alcohol of formula R.sup.1 H where R.sup.1 is alkoxy; and, optionally, converting a resultant compound of formula I in protected form into a corresponding compound in unprotected form; and recovering the resultant compound of formula I in free or salt or solvate form.

15. A pharmaceutical composition comprising a compound according to claim 8, together with a pharmaceutically acceptable carrier.

16. A compound according to claim 1, in which Ar is a group of formula III ##STR26##

in which R.sup.29, R.sup.30 and R.sup.31 are each independently hydrogen or C.sub.1 -C.sub.4 -alkyl.

17. A compound according to claim 6, in which R.sup.4 and R.sup.7 are each hydrogen, and R.sup.5 and R.sup.6 are identical and are each C.sub.1 -C.sub.4 -alkyl.

18. A compound according to claim 7, in which R.sup.4 and R.sup.7 are each hydrogen, and R.sup.5 and R.sup.6 are identical and are each C.sub.1 -C.sub.4 -alkyl.

19. A method for the treatment of premature labour pain comprising administering to a subject in need thereof an effective amount of a compound according to claim 1.
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