Claims for Patent: 6,878,721

Summary for Patent: 6,878,721

Title:	Beta2-adrenoceptor agonists
Abstract:	Compounds of formulain free or salt or solvate form, whereAr is a group of formulaY is carbon or nitrogen and R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8>, R<9>, R<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):	Bernard Cuenoud, Ian Bruce, Robin Alec Fairhurst, David Beattie
Assignee:	Novartis AG
Application Number:	US10/009,008
Patent Claims:	1. A compound of formula in free or salt or solvate form, where Ar is a group of formula R1 is hydrogen, hydroxy, or alkoxy; R2 and R3 are each independently hydrogen or alkyl; R4, R5, R6 and R7 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 C2 to C10 alkyl in which one or more pairs of carbon atoms are linked by —O—, —NR—, —S—, —S(═O)— or —SO2—, where R is hydrogen or C1 to C10 alkyl, alkenyl, trialkylsilyl, carboxy, alkoxycarbonyl, or —CONR11R12, where R11 and R12 are each independently hydrogen or alkyl, or R4 and R5, R5 and R6, or R6 and R7 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; R8 is halogen, —OR13, —CH2OR13 or —NHR13 where R13 is hydrogen, alkyl, alkyl interrupted by one or more hetero atoms, —COR14, where R14 is hydrogen, —N(R15)R16, alkyl or alkyl interrupted by one or more hetero atoms, or aryl and R15 and R16 are each independently hydrogen, alkyl or alkyl interrupted by one or more hetero atoms, or R13 is —C(═NH)R17, —SOR17 or —SO2R17 where R17 is alkyl or alkyl interrupted by one or more hetero atoms, and R9 is hydrogen, or R8 is —NHR18 where —NHR18 and R9, together with the carbon atoms to which they are attached, denote a 5- or 6-membered heterocycle; R10 is —OR19 or —NHR19 where R19 is hydrogen, alkyl, alkyl interrupted by one or more hetero atoms, or —COR20, where R20 is —N(R21)R22, alkyl or alkyl interrupted by one or more hetero atoms, or aryl, and R21 and R22 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 R1 is hydroxy or alkoxy. 2. A compound according to claim 1, in which Ar is a group of formula III: in which R29, R30 and R31 are each independently hydrogen or C1-C4-alkyl; R1 is hydroxyl; R2 and R3 are hydrogen; R4 and R7 are identical and are each hydrogen, C1-C4-alkyl or C1-C4-alkoxy; and either R5 and R6 are identical and are each hydrogen, C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkoxy-C1-C4-alkyl, or R5 and R6 together denote —(CH2)4— or —O(CH2)2O—. 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 where R29, R30 and R31 are each independently hydrogen or C1-C4-alkyl. 5. A compound according to claim 1, in which R4, R5, R6 and R7 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, R1 is hydroxy, R2 and R3 are hydrogen, R4 and R7 are identical and are each hydrogen, C1-C4-alkyl or C1-C4-alkoxy, and either R5 and R6 are identical and are each hydrogen, C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkoxy-C1-C4-alkyl, or R5 and R6 together denote —(CH2)4— or —O(CH2)2O—, 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 in free or salt or solvate form, (A) wherein Ar is a group of formula in which R29, R30 and R31 are each H, R1 is OH, R2 and R3 are each H and (i) n is 1, and R4 and R7 are each CH3O— and R5 and R6 are each H; or (ii) n is 1, and R4 and R7 are each H and R5 and R6 are each CH3CH2—; or (iii) n is 1, and R4 and R7 are each H and R5 and R6 are each CH3—; or (iv) n is 1, and R4 and R7 are each CH3CH2— and R5 and R6 are each H; or (v) n is 1, and R4 and R7 are each H and R5 and R6 together denote —(CH2)4—; or (vi) n is 1, and R4 and R7 are each H and R5 and R6 together denote —O(CH2)2O—; or (vii) n is 1, and R4 and R7 are each H and R5 and R6 are each CH3(CH2)3—; or (viii) n is 1, and R4 and R7 are each H and R5 and R6 are each CH3(CH2)2—; or (ix) n is 2, R4, R5, R6 and R7 are each H; or (x) n is 1, and R4 and R7 are each H and R5 and R6 are each CH3OCH2—; 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-quinolin-2-one; 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-methoxymethoxy-6-methyl-1H-quinolin-2-one; 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-6-methyl-1H-quinolin-2-one; 8-hydroxy-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-3,4-dihydro-1H-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-quinolin-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-quinolin-2-one maleate; (R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one hydrochloride; (R)-8-hydroxy-5-[(S)-1-hydroxy-2-(4,5,6,7-tetramethyl-indan-2-ylamino)-ethyl]-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-hydroxy-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 with a compound of formula where Ar1 is Ar as defined in claim 1 or a protected form thereof, R2, R3, R4, R5, R6, R7 and n are as defined in claim 1 and R32 is hydrogen or an amine-protective group, or (ii) reducing a compound of formula where Ar1 is Ar as defined in claim 1 or a protected form thereof, R2, R3, R4, R5, R6, R7 are as defined in claim 1, to convert the indicated keto group into —CH(OH)—; or (b) for the preparation of a compound where R1 is hydrogen, reducing a corresponding compound of formula I where R1 is hydroxy; or (c) for the preparation of a compound of formula I where R1 is alkoxy, either (i) O-alkylating a corresponding compound of formula I where R1 is hydroxy or (ii) reacting a corresponding compound having a leaving moiety instead of R1 with an alcohol of formula R1H where R1 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 in which R29, R30 and R31 are each independently hydrogen or C1-C4-alkyl. 17. A compound according to claim 6, in which R4 and R7 are each hydrogen, and R5 and R6 are identical and are each C1-C4-alkyl. 18. A compound according to claim 7, in which R4 and R7 are each hydrogen, and R5 and R6 are identical and are each C1-C4-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.