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US 8,133,905 B2Granted
Biphenyl compounds useful as muscarinic receptor antagonists
AssigneeTheravance, Inc.
InventorsYongQi Mu, YuHua Ji, Mathai Mammen, Viengkham Malathong
Life of this patent
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Abstract
The invention provides compounds of formula I: wherein a, b, c, m, n, q, r, W, Z1, Ar1, Z2, Y, R1, R2, and R3 are as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.
Claims20
A compound of formula Ic:
- wherein:
- a is 0 or 1;
- Rl is halo;
- b is 0 or 1;
- R2 is halo;
- m is 0 or 1;
- Z1 is selected from —C(O)N(R4)— and —N(R4)C(O)—, where R4 is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;
- n is 0 or 1;
- Ar1 represents a phenylene group substituted with (R5)p where p is 0 or an integer from 1 to 4 and each R5 is independently selected from halo, hydroxy, (1-4C)alkyl, and (1-4C)alkoxy;
- q is 0 or 1;
- Z2 is selected from —C(O)N(R6)— and —N(R6)C(O)—, where R6 is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;
- r is 0, 1 or 2;
- Y′ is selected from
- where:
- t is 0 or an integer from 1 to 3;
- v is 0 or an integer from 1 to 4;
- each R10 independently represents fluoro or (1-4C)alkyl;
- R11 is selected from hydrogen, —OH, -(1-4C)alkyleneOH, —C(O)NR11aR11b, and —CH2C(O)NR11aR11b, where R11a and R11b are independently selected from hydrogen, (1-4C)alkyl, hydroxy, (1-4C)alkoxy, (1-4C)alkyleneOR11c, (3-6C)cycloalkyl, phenyl optionally substituted with hydroxy, and (1-4C)alkyleneC(O)NR11dR11e, where said (3-6C)cycloalkyl is unsubstituted or substituted with 1 or 2 (1-6C)alkyl or —NR11dR11e groups, and where each of R11c, R11d and R11e is independently hydrogen or (1-4C)alkyl;
- or R11a is taken together with R11b to form a 3-7 membered ring, optionally substituted with hydroxyl;
- R12 and R13 are taken together to form a ring selected from piperazinone, morpholine, and piperazine;
- and said piperazine is substituted with (R13c)w where w is 0 or an integer from 1 to 3 and each R13c is independently selected from (1-4C)alkyl, phenyl, and benzyl, optionally substituted with 1 to 5 fluoro substituents, or two R13c groups are joined to form (1-3C)alkylene;
- wherein each alkyl and alkoxy group in R5 is optionally substituted with 1 to 5 fluoro substituents;
- or a pharmaceutically acceptable salt or stereoisomer thereof.
20 more elements
A compound of formula Ic:
- or a pharmaceutically acceptable salt or stereoisomer thereof, prepared by the process comprising:
- (a) reacting a compound of formula II:
- or a salt thereof, with a compound of formula III:
- wherein L1 represents a leaving group;
- or
- (b) coupling a compound of formula IVa:
- with a compound of formula Va:
- or (b′) coupling a compound of formula IVb:
- with a compound of formula Vb:
- or
- (c) coupling a compound of formula VIa:
- with a compound of formula VIIa:
- or (c′) coupling a compound of formula VIb:
- with a compound of formula VIIb:
- or
- (d) reacting a compound of formula VIII:
- wherein L2 represents a leaving group, with a compound of formula IX:
- H—Y IX
- or
- (e) reacting a compound of formula II with a compound of formula X:
- in the presence of a reducing agent;
- or
- (f) reacting a compound of formula XI:
- with a compound of formula IX in the presence of a reducing agent;
- and then
- (g) removing any protecting groups that may be present to provide a compound of formula Ic;
- and
- (h) optionally forming a pharmaceutically acceptable salt of the compound of formula Ic;
- wherein:
- a is 0 or 1;
- Rl is halo;
- b is 0 or 1;
- R2 is halo;
- m is 0 or 1;
- Z1 is selected from —C(O)N(R4)— and —N(R4)C(O)—, where R4 is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;
- n is 0 or 1;
- Ar1 represents a phenylene group substituted with (R5)p where p is 0 or an integer from 1 to 4 and each R5 is independently selected from halo, hydroxy, (1-4C)alkyl, and (1-4C)alkoxy;
- q is 0 or 1;
- Z2 is selected from —C(O)N(R6)— and —N(R6)C(O)—, where R6 is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;
- r is 0, 1 or 2;
- Y′ is selected from
- t is 0 or an integer from 1 to 3;
- v is 0 or an integer from 1 to 4;
- each R10 independently represents fluoro or (1-4C)alkyl;
- R11 is selected from hydrogen, —OH, -(1-4C)alkyleneOH, —C(O)NR11aR11b, and —CH2C(O)NR11aR11b, where R11a and R11b are independently selected from hydrogen, (1-4C)alkyl, hydroxy, (1-4C)alkoxy, (1-4C)alkyleneOR11c, (3-6C)cycloalkyl, phenyl optionally substituted with hydroxy, and (1-4C)alkyleneC(O)NR11dR11e, where said (3-6C)cycloalkyl is unsubstituted or substituted with 1 or 2 (1-6C)alkyl or —NR11dR11e groups, and where each of R11c, R11d and R11e is independently hydrogen or (1-4C)alkyl;
- or R11a is taken together with R11b to form a 3-7 membered ring, optionally substituted with hydroxyl;
- R12 and R13 are taken together to form a ring selected from piperazinone, morpholine, and piperazine;
- and said piperazine is substituted with (R13c), where w is 0 or an integer from 1 to 3 and each R13c is independently selected from (1-4C)alkyl, phenyl or benzyl, optionally substituted with 1 to 5 fluoro substituents, or two R13c groups are joined to form (1-3C)alkylene;
- and
- wherein each alkyl and alkoxy group in R5 is optionally substituted with 1 to 5 fluoro substituents.
47 more elements
Dependencies are inferred from the claim text.