Claims
- 1. A compound of formula I:
- 2. The compound of claim 1, wherein R5 is C1-5 alkyl, wherein the alkyl group is optionally substituted with —OH or 1 to 3 fluoro substituents.
- 3. The compound of claim 2, wherein R5 is C1-3 alkyl, wherein the alkyl group is optionally substituted with —OH or 1 to 3 fluoro substituents.
- 4. The compound of claim 2, wherein R5 is selected from methyl, ethyl, 2-hydroxyethyl, 2,2,2-trifluoroethyl, n-propyl, isopropyl, 1-hydroxyprop-2-yl, n-butyl and isobutyl.
- 5. The compound of claim 4, wherein R5 is methyl.
- 6. The compound of claim 1, wherein R5 is C3-5 cycloalkyl, wherein the cycloalkyl group is optionally substituted with —OH or 1 to 3 fluoro substituents.
- 7. The compound of claim 6, wherein R5 is selected from cyclopropyl, cyclobutyl and cyclopentyl.
- 8. The compound of claim 1, wherein R5 is selected from:
(a) —CH2—(C3-5 cycloalkyl), wherein the cycloalkyl group is optionally substituted with —OH or 1 to 3 fluoro substituents; and (b) —CH2-(phenyl), wherein the phenyl group is optionally substituted with 1 to 3 substituents independently selected from C1-4 alkyl, cyano, fluoro, chloro, —O(C1-4 alkyl), —S(C1-4 alkyl) and —S(O)2(C1-4 alkyl); where each alkyl group is optionally substituted with 1 to 3 fluoro substituent.
- 9. The compound of claim 8, wherein R5 is selected from cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, benzyl, 4-cyanobenzyl, 3-methylbenzyl, 4-methylbenzyl, 4-trifluoromethoxybenzyl, 3-fluorobenzyl and 4-fluorobenzyl.
- 10. The compound of claim 1, wherein each R4 is hydrogen.
- 11. The compound of claim 1, wherein a, b and c are 0.
- 12. The compound of claim 1, wherein d is 1.
- 13. The compound of claim 1, wherein d is 2.
- 14. The compound of claim 1, wherein e is 8.
- 15. The compound of claim 1, wherein e is 9.
- 16. A compound of formula II:
- 17. The compound of claim 16, wherein the stereochemistry at the 3-position of the pyrrolidine ring is (S).
- 18. The compound of claim 16, wherein the stereochemistry at the 3-position of the pyrrolidine ring is (R).
- 19. The compound of claim 17 or 18, wherein R5 is C1-3 alkyl wherein the alkyl group is optionally substituted with —OH or 1 to 3 fluoro substituents.
- 20. The compound of claim 17 or 18, wherein R5 is methyl.
- 21. A compound selected from:
2-[(S)-1-(8-methylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(8-isopropylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(8-prop-1-ylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(8-cyclopropylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(8-cyclobutylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(8-cyclopentylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(8-ethylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-{(S)-1-[8-(2-hydroxyethyl)aminooctyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(S)-1-[8-(R)-(1-hydroxyprop-2-yl)aminooctyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(S)-1-[8-(1-hydroxyprop-2-yl)aminooctyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(S)-1-[8-(S)-(1-hydroxyprop-2-yl)aminooctyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(S)-1-[8-(2,2,2-trifluoroethyl)aminooctyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-[(S)-1-(8-benzylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(8-methylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(8-isopropylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(8-prop-1-ylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(8-cyclopropylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(8-cyclobutylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(8-cyclopentylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(8-ethylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-{(R)-1-[8-(2-hydroxyethyl)aminooctyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(R)-1-[8-(R)-(1-hydroxyprop-2-yl)aminooctyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(R)-1-[8-(1-hydroxyprop-2-yl)aminooctyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(R)-1-[8-(S)-(1-hydroxyprop-2-yl)aminooctyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(R)-1-[8-(2,2,2-trifluoroethyl)aminooctyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-[(R)-1-(8-benzylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(9-methylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(9-isopropylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(9-prop-1-ylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(9-cyclopropylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(9-cyclobutylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(9-cyclopentylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(S)-1-(9-ethylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-{(S)-1-[9-(2-hydroxyethyl)aminononyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(S)-1-[9-(R)-(1-hydroxyprop-2-yl)aminononyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(S)-1-[9-(1-hydroxyprop-2-yl)aminononyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(S)-1-[9-(S)-(1-hydroxyprop-2-yl)aminononyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(S)-1-[9-(2,2,2-trifluoroethyl)aminononyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-[(S)-1-(9-benzylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(9-methylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(9-isopropylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(9-prop-1-ylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(9-cyclopropylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(9-cyclobutylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(9-cyclopentylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[(R)-1-(9-ethylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-{(R)-1-[9-(2-hydroxyethyl)aminononyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(R)-1-[9-(R)-(1-hydroxyprop-2-yl)aminononyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(R)-1-[9-(1-hydroxyprop-2-yl)aminononyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(R)-1-[9-(S)-(1-hydroxyprop-2-yl)aminononyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-{(R)-1-[9-(2,2,2-trifluoroethyl)aminononyl]pyrrolidin-3-yl}-2,2-diphenylacetamide; 2-[(R)-1-(9-benzylaminononyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[1-(8-methylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide; 2-[1-(8-isopropylaminooctyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-[1-(8-prop-1-ylaminooctyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-[1-(8-cyclopropylaminooctyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-[1-(8-cyclobutylaminooctyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-[1-(8-cyclopentylaminooctyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-[1-(8-ethylaminooctyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-{1-[8-(2-hydroxyethyl)aminooctyl]piperidin-4-yl}-2,2-diphenylacetamide; 2-{1-[8-(R)-(1-hydroxyprop-2-yl)aminooctyl]piperidin-4-yl}-2,2-diphenylacetamide; 2-{1-[8-(1-hydroxyprop-2-yl)aminooctyl]piperidin-4-yl}-2,2-diphenylacetamide; 2-{1-[8-(S)-(1-hydroxyprop-2-yl)aminooctyl]piperidin-4-yl}-2,2-diphenylacetamide; 2-{1-[8-(2,2,2-trifluoroethyl)aminooctyl]piperidin-4-yl}-2,2-diphenylacetamide; 2-[1-(8-benzylaminooctyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-[1-(9-methylaminononyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-[1-(9-isopropylaminononyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-[1-(9-prop-1-ylaminononyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-[1-(9-cyclopropylaminononyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-[1-(9-cyclobutylaminononyl)piperidin-4-yl]-2,2-diphenylacetamide: 2-[1-(9-cyclopentylaminononyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-[1-(9-ethylaminononyl)piperidin-4-yl]-2,2-diphenylacetamide; 2-{1-[9-(2-hydroxyethyl)aminononyl]piperidin-4-yl}-2,2-diphenylacetamide; 2-{1-[9-(R)-(1-hydroxyprop-2-yl)aminononyl]piperidin-4-yl}-2,2-diphenylacetamide; 2-{1-[9-(1-hydroxyprop-2-yl)aminononyl]piperidin-4-yl}-2,2-diphenylacetamide; 2-{1-[9-(S)-(1-hydroxyprop-2-yl)aminononyl]piperidin-4-yl}-2,2-diphenylacetamide; 2-{1-[9-(2,2,2-trifluoroethyl)aminononyl]piperidin-4-yl}-2,2-diphenylacetamide; and 2-[1-(9-benzylaminononyl)piperidin-4-yl]-2,2-diphenylacetamide; or a pharmaceutically-acceptable salt or solvate thereof
- 22. 2-[(S)-1-(8-Methylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide or a pharmaceutically-acceptable salt or solvate thereof.
- 23. 2-[(R)-1-(8-Methylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide or a pharmaceutically-acceptable salt or solvate thereof.
- 24. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1, 16, 21, 22 and 23.
- 25. The pharmaceutical composition of claim 24, wherein the composition is suitable for administration by inhalation.
- 26. The pharmaceutical composition of claim 24, wherein the composition further comprises a therapeutically effective amount of a β2-adrenoreceptor agonist.
- 27. The pharmaceutical composition of claim 24, wherein the composition further comprises a therapeutically effective amount of a steroidal anti-inflammatory agent.
- 28. The pharmaceutical composition of claim 24, wherein the composition further comprises a therapeutically effective amount of a phosphodiesterase-4 inhibitor.
- 29. A method for treating a mammal having a medical condition alleviated by treatment with a muscarinic receptor antagonist, the method comprising administering to the mammal a therapeutically effective amount of a compound of any one of claims 1, 16, 21, 22 and 23.
- 30. A method for treating a pulmonary disorder, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of any one of claims 1, 16, 21, 22 and 23.
- 31. A method of producing bronchodilation in a patient, the method comprising administering by inhalation to the patient a bronchodilation-producing amount of a compound of any one of claims 1, 16, 21, 22 and 23.
- 32. A method for treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient in need of treatment a therapeutically effective amount of a compound of any one of claims 1, 16, 21, 22 and 23.
- 33. A method of studying a biological system or sample comprising a muscarinic receptor, the method comprising:
(a) contacting the biological system or sample with a compound of claim 1; and (b) determining the effects caused by the compound on the biological system or sample.
- 34. A process for preparing a compound of formula I:
- 35. The process of claim 34, wherein the process further comprises the step of forming a pharmaceutically-acceptable salt of the compound of formula I.
- 36. A process for preparing a pharmaceutically-acceptable salt of a compound of formula I:
- 37. The product prepared by the process of any one of claims 34, 35 and 36.
- 38. A compound of formula X:
- 39. 2-[(S)-1-(8-N-Benzyl-N-methylaminooctyl)pyrrolidin-3-yl]-2,2-diphenylacetamide or a salt thereof.
- 40. 2-{(S)-1-[8-(N-tert-Butoxycarbonyl-N-methylamino)octy]pyrrolidin-3-yl}-2,2-diphenylacetamide or a salt thereof.
- 41. A compound of formula XI:
- 42. 8-(N-Benzyl-N-methylamino)octan-1-ol or a salt thereof.
- 43. 8-(N-tert-Butoxycarbonyl-N-methylamino)octan-1-ol.
- 44. Toluene-4-sulfonic acid 8-(N-tert-butoxycarbonyl-N-methylamino)octyl ester.
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 60/478,456, filed on Jun. 13, 2003; the entire disclosure of which is incorporated herein by reference in its entirety.
Provisional Applications (1)
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Number |
Date |
Country |
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60478456 |
Jun 2003 |
US |