Therapeutic carbamates

• US 20040029919A1
• Filed: 12/07/2000
• Published: 02/12/2004
• Est. Priority Date: 12/07/1999
• Status: Active Grant

• Current Assignee: Theravance Biopharma R&D IP, LLC (Theravance Biopharma, Inc.)
• Original Assignee: Theravance, Inc
• Inventors: Mammen, Mathai, Oare, David
• Granted Patent: US 7,238,709 B2
• Time in Patent Office: Days
• US Class Current: 514/327
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 211/48 having an acyclic carbon atom attached in position 4
• CPC Class Codes: C07D 211/52 having an aryl radical as the second substituent in position 4
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 471/08 Bridged systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 471/14 : Ortho-condensed systems
• CPC Class Codes: C07D 495/08 : Bridged systems

Abstract

This invention relates to hindered carbamate derivatives that are muscarinic receptor antagonists, pharmaceutical compositions comprising such compounds, and methods of preparing these compounds.

Claims

1. A compound of Formula (I):

L₁—

X—

L₂ 

 

(I)

wherein;

L₁ is a group of formula (a);

wherein;

A is an aryl or a heteroaryl ring;

B″

is —

O—

;

R^x is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyl, acylamino, aminoacyloxy, aryl, carboxyalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutes cycloalkenyl, heteroaryl, heteroaralkyl, alkylsulfonyl, or alkylsulfinyl;

R¹ is hydrogen or alkyl;

R² is Het, or is selected from a group consisting of formula (i), (ii), and (iii);

wherein;

----- is an optional double bond;

n₁ is an integer of from 1 to 4;

n₂ is an integer of from 1 to 3;

V is —

CH—

, —

O—

, —

S(O)n₃—

(where n₃ is an integer of from 0 to

     2), or —

NR⁴—

(wherein R⁴ is hydrogen, alkyl, substituted alkyl, aryl, or heteroaryl);

“

Het”

is a heteroaryl ring which optionally attaches (a) to a linker;

R³ is hydrogen, alkyl, halo, amino, substituted amino, —

OR^a (where R^a is hydrogen, alkyl, or acyl), or a covalent bond attaching (a) to a linker;

R⁵ is hydrogen, alkyl, halo, amino, substituted amino, —

OR^b (where R^b is hydrogen or alkyl), aryl, aralkyl, heteroaralkyl, or a covalent bond attaching (a) to a linker;

R⁶, R⁷, and R⁸ are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching (a) to a linker;

K is a bond or an alkylene group;

K″

is a bond, —

C(O)—

, —

S(O)_n4—

(where n₄ is an integer of from 0 to

     2), or an alkylene group optionally substituted with a hydroxyl group; and

B is heterocycloamino or heteroarylamino, which optionally attaches (a) to a linker;

provided that at least one of the R⁵, R⁶, R⁷, R⁸, “

Het”

, heterocycloamino or heteroarylamino groups attaches (a) to a linker;

X is a linker; and

L₂ is an organic group comprising at least one primary, secondary or tertiary amine;

or a pharmaceutically acceptable salt;

or prodrug thereof.

2. The compound of claim 1 wherein L₂ is a group selected from a group consisting of:

(i) a group of formula (b);

wherein;

D″

is alkylene;

D is —

NR³¹R³², —

N⁺(R³³R³⁴R³⁵) or —

OR³² where R³¹, R³³, and R³⁴ are, independently of each other, hydrogen, alkyl, or aralkyl; and

R³² and R³⁵ represent a covalent bond attaching (b) to a linker;

R²⁷ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R²⁸ is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R²⁹ and R³⁰ are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino;

or

one of R²⁷, R²⁸, R²⁹, or R³⁰ together with the adjacent group forms a methylenedioxy or ethylenedioxy group;

(ii) a group of formula (c);

wherein;

n₁₁ is an integer of from 1 to 7;

n₁₂is 0 to 7;

F is —

NR⁴⁰—

, —

O—

, —

S—

, or —

CHR⁴¹—

(wherein R⁴⁰ and R⁴¹ are, independently of each other, hydrogen, alkyl, or substituted alkyl);

F″

is a covalent bond, —

OR⁴³, —

NR⁴²R⁴³, or —

N⁺R⁴³R⁴⁴R⁴⁵ wherein R⁴² is hydrogen or alkyl, R⁴⁴ and R⁴⁵ are alkyl, and R⁴³ is hydrogen, alkyl, or a covalent bond attaching (c) to a linker;

R³⁶ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;

R³⁷ is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryl, heteraryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; and

R³⁸ is hydrogen, alkyl, halo, hydroxy, alkoxy, or a covalent bond attaching the ligand to a linker provided that at least one of R³⁸ and R⁴³ attaches (c) to a linker;

R³⁹ is hydrogen, alkyl, halo, hydroxy, alkoxy, or substituted alkyl; and

(iii) a group of formula (d) or (e);

wherein;

R⁴⁶ is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, or heterocycle;

R⁴⁷ is alkyl, substituted alkyl, aryl, acyl, heterocycle, or —

COOR⁵⁰ where R⁵⁰ is alkyl;

or

R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form heterocycle, which heterocycle, in addition to optionally bearing the optional substituents defined hereinbelow for a heterocycle, can also optionally be substituted with one or more (e.g. 1, 2, 3, or

     4) alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.

R⁴⁸ is a covalent bond that attaches the (d) to a linker; and

R⁴⁹ is alkyl;

or a pharmaceutically acceptable salt;

or prodrug thereof.

3. The compound of claim 1 or 2 wherein A is phenyl or pyridyl.

4. The compound of claim 1 or 2 wherein R¹ is hydrogen, methyl, or ethyl.

5. The compound of claim 1 or 2 wherein R² is pyrrolyl, pyridinyl, or imidazolyl.

6. The compound of claim 1 or 2 wherein R² is phenyl.

7. The compound of claim 1 or 2 wherein K is a bond or a methylene group.

8. The compound of claim 1 or 2 wherein K″

is a bond.

9. The compound of claim 1 or 2 wherein R^x is alkyl, alkenyl, or alkynyl, each optionally substituted with 1 to 5 alkoxy or fluoro substituents.

10. The compound of claim 1 or 2 wherein R^x is (C₁-C₆)alkyl, (C₂-C₆)alkenyl,

(C₂-C₆)alkynyl, each optionally substituted with 1 to 3 methoxy, ethoxy or fluoro substituents.

11. The compound of claim 1 or 2 wherein R^x is (C₁-C₆)alkyl optionally substituted with 1 to 3 methoxy, ethoxy, or fluoro substituents.

12. The compound of claim 1 wherein R^x is methyl, ethyl, propyl, isopropyl, butyl, isobutyl or secbutyl, optionally substituted with methoxy or ethoxy or with 1 to 3 or fluoro substituents.

13. The compound of claim 1 wherein R^x is methyl, ethyl, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, fluoromethyl, difluoromethyl trifluoromethyl, trifluoromethoxymethyl, formyl, or acetyl.

14. The compound of claim 1 or 2 wherein R^x is methyl, ethyl, methoxymethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

15. The compound of claim 1 or 2 wherein B is a heterocycloamino group which attaches (a) to a linker.

16. The compound of claim 1 or 2 wherein B is pyrrolidine, piperidine, or hexahydroazepine attaching (a) to a linker.

17. The compound of claim 1 or 2 wherein B is piperidine wherein the nitrogen atom of said piperidine attaches (a) to a linker.

18. The compound of claim 1 or 2 wherein B is piperidin-3-yl or piperidin-4-yl wherein the nitrogen at the 1 position optionally attaches (a) to a linker.

19. The compound of claim 1 wherein B taken together with R^x is 4-methylpiperidine-1,4-diyl.

20. The compound of claim 2 wherein L₂ is a group of formula (d) or (e).

21. The compound of claim 20 wherein:

R⁴⁶ is alkyl or substituted alkyl;

R⁴⁷ is alkyl, substituted alkyl, or heterocycle;

or R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form heterocycle.

22. The compound of claim 1 or 2 wherein L₂ has any one of the formula A1-A590 shown hereinabove.

23. The compound of claim 1 or 2 wherein L₁ is:

24. The compound of claim 23 wherein L₁ is:

25. The compound of claim 24 wherein the piperidino nitrogen of L₁ is bonded to X.

26. The compound of claim 1 or 2 wherein X is alkylene optionally substituted with one, two, or three hydroxy groups, alkylene wherein one, two or three carbon atoms have been replaced by an oxygen atom, -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fluoro groups.

27. The compound of claim 1 or 2 wherein X is a group of formula:

—

X¹—

Z—

(Y^a—

Z)_m—

Y^b—

Z—

Z^a—

wherein

m is an integer of from 0 to 20;

X^a at each separate occurrence is selected from the group consisting of —

O—

, —

S—

, —

NR—

, —

C(O)—

, —

C(O)O—

, —

C(O)NR—

, —

C(S)—

, —

C(S)O—

, —

C(S)NR—

or a covalent bond where R is as defined below;

Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;

Y^a and Y^b at each separate occurrence are selected from the group consisting of —

O—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

NR—

, —

S(O)_n—

, —

C(O)NR′

—

, —

NR′

C(O)—

, —

NR′

C(O)NR′

—

, —

NR′

C(S)NR′

—

, —

C(═

NR′

)—

NR′

—

, —

NR′

—

C(═

NR′

)—

, —

OC(O)—

NR′

—

, —

NR′

—

C(O)—

O—

, —

N═

C(X^a)—

NR′

—

, —

NR′

C(X^a)═

N—

, —

P(O)(OR′

)—

O—

, —

O—

P(O)(OR′

)—

, —

S(O)_nCR′

R″

—

, —

S(O)_n—

NR′

—

, —

NR′

—

S(O)—

, —

S—

S—

, and a covalent bond;

where n is 0, 1 or 2; and

R, R′ and

R″

at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;

provided at least one of X^a, Y^a, Y^b or Z is not a covalent bond.

28. The compound of claim 1 or 2 wherein X is an alkylene group having from 3 to 20 carbon atoms;

wherein one or more carbon atoms in the alkylene group is optionally replaced with —

O—

; and

wherein the chain is optionally substituted on carbon with one or more hydroxyl.

29. The compound of claim 1 or 2 wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.

30. The compound of claim 1 or 2 wherein X has the following formula:

31. The compound of claim 1 or 2 wherein X has one of the following the formula:

32. The compound of claim 2 which is a compound of Formula (Ia):

33. The compound of claim 1 or 2 wherein L₂ is a group of formula A234, A363, A364, A153, A28, A324, A329, A562, A87, or A239 as described herein.

34. The compound of claim 1 which is a compound of formula (III):

35. The compound of claim 34 wherein X is a group of formula:

—

X^a—

Z—

(Y^a—

Z)_m—

Y^b—

Z—

X^a—

wherein

m is an integer of from 0 to 20;

X^a at each separate occurrence is selected from the group consisting of —

O—

, —

S—

, —

NR—

, —

C(O)—

, —

C(O)O—

, —

C(O)NR—

, —

C(S)—

, —

C(S)O—

, —

C(S)NR—

or a covalent bond where R is as defined below;

Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;

Y^a and Y^b at each separate occurrence are selected from the group consisting of —

O—

, —

C(O)—

, —

OC(O)—

, —

C(O)O—

, —

NR—

, —

S(O)_n—

, —

C(O)NR′

—

, —

NR′

C(O)—

, —

NR′

C(O)NR′

—

, —

NR′

C(S)NR′

—

, —

C(═

NR′

)—

NR′

—

, —

NR′

—

C(═

NR′

)—

, —

OC(O)—

NR′

—

, —

NR′

—

C(O)—

O—

, —

N═

C(X^a)—

NR′

—

, —

NR′

—

C(X^a)═

N—

, —

P(O)(OR′

)—

O—

, —

O—

P(O)(OR′

)—

, —

S(O)_nCR′

R″

—

, —

S(O)_n—

NR′

—

, —

NR′

—

S(O)_n—

, —

S—

S—

, and a covalent bond;

where n is 0, 1 or 2; and

R, R′ and

R″

at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;

provided at least one of X^a, Y^a, Y^b or Z is not a covalent bond.

36. The compound of claim 34 wherein X is an alkylene group having from 3 to 20 carbon atoms;

wherein one or more carbon atoms in the alkylene group is optionally replaced with —

O—

; and

wherein the chain is optionally substituted on carbon with one or more hydroxyl.

37. The compound of claim 34 wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane-1,3-diyl, 2-hydroxypropane-1,3-diyl, or 5-oxa-nonane-1,9-diyl.

38. The compound of claim 34 wherein X has the following formula:

39. The compound of claim 34 wherein X has one of the following the formula:

40. The compound of claim 2 wherein L₂ is a group of formula (d) wherein R⁴⁶ is a heterocycle, optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;

and R⁴⁷ is alkyl, substituted alkyl, acyl, or —

COOR⁵⁰.

41. The compound of claim 2 wherein wherein L₂ is a group of formula (d) wherein R⁴⁶ is alkyl that is optionally substituted with from 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, NR^aR^b, wherein R^a and R^b may be the same or different and are chosen from hydrogen, alkyl, substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, and heterocyclic.

42. The compound of claim 2 wherein L₂ is a group of formula (d) wherein R⁴⁶ is 3-piperidinyl, 4-piperidinyl, or 3-pyrrolidinyl, which R⁴⁶ is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.

43. The compound of claim 2 wherein R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring which ring is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.

44. The compound of claim 2 wherein R⁴⁶ and R⁴⁷ together with the nitrogen atom to which they are attached form a heterocycle that is an aza-crown ether.

45. The compound of claim 44 wherein the aza-crown ether is 1-aza-12-crown-4, 1-aza-15-crown-5, or 1-aza-18-crown-6.

47. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 or 2.

48. A method of treating a disease mediated by a muscarinic receptor in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of claim 1 or 2.

49. The method of claim 48 wherein the disease is urinary incontinence chronic pulmonary obstructive disease, asthma, hyper salivation a cognitive disorder, blurred vision, or irritable bowel syndrome.

50. A compound of formula L₁—

H wherein L₁, has the values defined in claim 1;

or a salt thereof.

51. The compound of claim 50 which is a compound of formula (V):

52. A compound of formula R_a—

X—

L₂ wherein X, and L₂ have the values defined in claim 2;

and R_a is a suitable leaving group.

46. Compound number 1-146 as described in Table A and Table B herein;

or a pharmaceutically acceptable salt or prodrug thereof.