US 6,878,721 B1Granted

Beta2-adrenoceptor agonists

AssigneeNovartis AG

InventorsBernard Cuenoud, Ian Bruce, Robin Alec Fairhurst, David Beattie

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Abstract

Compounds of formula in free or salt or solvate form, where Ar is a group of formula Y is carbon or nitrogen and R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, 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.

Claims19

Dependent claims

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.

12 more elements

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.

38 more elements

Dependencies are inferred from the claim text.

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Abstract

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.

12 more elements