Quinuclidine esters process and intermediate for their preparation and pharmaceutical compositions containing them

• US 5,543,419 A
• Filed: 07/05/1994
• Issued: 08/06/1996
• Est. Priority Date: 09/14/1991
• Status: Expired due to Fees

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Stobie, Alan, Cross, Peter E.
• Primary Examiner(s): Rotman, Alan L.
• Assistant Examiner(s): HUANG, EVELYN MEI
• Application Number:
  US08/204,260
• Time in Patent Office: 763 Days
• Field of Search: 514/305, 546/137
• US Class Current: 514/305
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: C07C 317/44 having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
• CPC Class Codes: C07C 323/56 the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07D 333/24 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems

Abstract

Compounds of formula (I) wherein X is either (a) a phenyl group optionally substituted by 1 or 2 substituents each independently selected from halo, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy and hydroxy or (b) a thienyl group; and Y is of formula (Ya) or (Yb) where A and B are 0, 1 or 2, D and E are 0 or 1, F is 0-3 and D+E+F=1-3, Z is 0, 1 or 2, R₁ and R₂ are H or alkyl or form a ring, and R₃ is C₁ -C₄ alkyl, C₃ -C₆ cycloalkyl or optionally substituted phenyl or benzyl, are antimuscarinic bronchodilators useful for treating chronic obstructive airways disease or asthma.

Claims

1. A compound of formula (I):

##STR128## or a pharmaceutically acceptable salt thereof, wherein X is either

(a) a phenyl group optionally substituted by 1 or 2 substituents each independently selected from halo, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy and hydroxy, or

(b) A thienyl group;

and Y is either (a) a group of formula (Ya) ##STR129## where A and B are independently 0, 1 or 2 or (b) a group of formula (Yb) ##STR130## where D and E are independently 0 or 1, F is 0, 1, 2 or 3 and D+E+F=1, 2 or 3;

Z is 0, 1 or 2,

R₁ and R₂ are independently H or C₁ -C₄ alkyl, or R₁ and R₂ are joined together to form, with the carbon atom to which they are attached, a 3- or 6-membered saturated or unsaturated carbocyclic ring, and R₃ is a C₁ -C₄ alkyl group, a C₃ -C₆ cycloalkyl group or a phenyl or benzyl group optionally substituted by up to 3 substituents each independently selected from halo, CF₃, C₁ -C₄ alkyl, C₁ -C₄ alkoxy and hydroxy.

2. A compound according to claim 1, in which X is an unsubstituted phenyl group.

3. A compound according to claim 2, in which Y is of formula (Ya) and R₁ and R₂ are both H.

4. A compound according to claim 2 in which Y is of formula (Ya), A is 1, B is 0 and R₁ and R₂ are independently H, methyl or ethyl.

5. A compound according to claim 4, in which R₃ is methyl.

6. A compound according to claim 5, of R-stereochemistry at the 3'"'"' position and S-stereochemistry at the 2 position having the formula (Ia):

##STR131##

7. A compound according to claim 6, in which Z is 1 and having R-stereochemistry at the sulphur atom of Y, the moiety containing the sulphur atom being of formula:

##STR132##

9. A pharmaceutical composition comprising a compound of formula (I) or (Ia) claim 1, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

10. A compound of formula (II):

##STR133## wherein X and Y are as claimed in claim 1.

11. A method of treatment of chronic obstructive airways disease or asthma, which comprises administering to a patient an effective amount of a compound according to claim 1.

8. (R)-3-Quinuclidinyl (2S,R_s)-2-hydroxymethyl-4-(methylsulphinyl)-2-phenylbutanoate.