IP Library › Patent Application 10979794

Patent Application

App. No. 10/979,794

Synthesis of COX-2 and FAAH inhibitors

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Patent No.: US None
App. No.: 10/979,794

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Abstract

Methods for preparing indoles that are useful COX-2 inhibitors and intermediates useful in such methods are described.

Claims (228)

1 . A method for preparing a compound having the formula:

wherein:

each R is, independently, H; a C 1 to C 6 alkyl, optionally independently substituted with one or more —OH, —NH 2 , or halogen; or a C 1 to C 6 alkenyl optionally independently substituted with one or more —OH, —NH 2 or halogen;

m is 1, 2, 3 or 4;

R 1 is H or a halogen;

R 2 is H; a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen;

wherein each R 2A is independently: H, a C 1 to C 6 alkyl, a C 1 to C 6 alkenyl, a C 1 to C 6 alkynyl, a C 6 to C 10 aryl, a C 3 to C 10 cycloalkyl, or a C 7 to C 20 arylalkyl optionally independently substituted with one or more halogen, —OH, —C(O)OH, or —NH 2 ;

R 3 is H or a halogen;

A is

wherein each R 4 is independently H, a halogen, —CN, —SH; —OH; a C 1 to C 3 alkyl, optionally, independently substituted with one or more halogen; —OR 4A ; —SR 4A ; SOR 4A ; —S(O) 2 R 4A , wherein R 4A is a C 1 to C 3 alkyl, optionally independently substituted with one or more halogen;

X is S, O, NH or NR 5 , wherein R 5 is a C 1 to C 10 alkyl;

n=1,2,3, 4 or 5 when A is

n=1, 2, 3 or 4 when A is;

and Z is O or S,

the method comprising,

reacting a compound having the formula:

wherein A, R, R 1 , R 2 , R 3 and Z are as defined above and B is a C 1 to C 6 alkyl, a C 1 to C 6 alkenyl, a C 1 to C 6 alkynyl, a C 6 to C 10 aryl, a C 3 to C 10 cycloalkyl, or a C 7 to C 20 arylalkyl wherein one carbon is optionally replaced by Si(CH 3 ) 3 and wherein B is optionally independently substituted with one or more halogen, —OH, —C(O)OH, or —NH 2 ,

with an organic acid or an inorganic acid in the presence of an organic solvent to prepare a compound having the formula:

2 . The method of claim 1 wherein A is

3 . The method of claim 1 wherein Z is 0.

4 . The method of claim 1 wherein m is 1.

5 . The method of claim 1 wherein R is H.

6 . The method of claim 1 wherein R is H and m is 1.

7 . The method of claim 1 wherein B is —CH 2 CH 2 Si(CH 3 ) 3 .

8 . The method of claim 1 wherein R 4 is halogen.

9 . The method of claim 8 wherein R 4 is Cl.

10 . The method of claim 1 wherein n is 1.

11 . The method of claim 1 wherein R 1 is H.

12 . The method of claim 1 wherein A is

13 . A method for preparing a compound having the formula:

wherein:

m is 1,2, 3 or 4;

R 1 is H or a halogen;

R 2 is H; a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen;

R 3 is H or a halogen; A is

wherein each R 4 is independently H, a halogen, —CN, —SH; —OH; a C 1 to C 3 alkyl, optionally, independently substituted with one or more halogen; —OR 4A ; —SR 4A ; —SOR 4A ; —S(O) 2 R 4A , wherein R 4A is a C 1 to C 3 alkyl, optionally independently substituted with one or more halogen;

X is S, O, NH or NR 5 , wherein R 5 is a C 1 to C 10 alkyl;

n=1,2,3, 4 or 5 when A is

n=1,2, 3 or 4 when A is

and Z is O or S;

the method comprising:

(a) reacting a compound having the formula:

wherein m, R, R 1 , R 2 , and R 3 are as defined above, and B is a C 1 to C 6 alkyl, a C 1 to C 6 alkenyl, a C 1 to C 6 alkynyl, a C 6 to C 10 aryl, a C 3 to C 10 cycloalkyl, or a C 7 to C 20 arylalkyl wherein one carbon is optionally replaced by Si(CH 3 ) 3 and wherein B is optionally independently substituted with one or more halogen, —OH, —C(O)OH, or —NH 2 with a strong base in an organic solvent;

(b) treating with a compound of the formula

wherein R 4 , n and X are described above and Y is a suitable leaving group to generate a compound having the formula

formula:

14 . The method of claim 13 wherein A is

15 . The method of claim 13 wherein Z is O.

16 . The method of claim 13 wherein m is 1.

17 . The method of claim 13 wherein R is H.

18 . The method of claim 13 wherein R is H and m is 1.

19 . The method of claim 13 wherein B is —CH 2 CH 2 Si(CH 3 ) 3 .

20 . The method of claim 13 wherein R 4 is halogen.

21 . The method of claim 20 wherein R 4 is Cl.

22 . The method of claim 13 wherein n is 1.

23 . The method of claim 13 wherein R 1 is H.

24 . The method of claim 13 wherein A is R 4

25 . The method of claim 13 wherein Y is a halogen.

26 . The method of claim 13 wherein

27 . A compound having the formula:

wherein, each R is, independently, H; a C 1 to C 6 alkyl, optionally independently substituted with one or more —OH, —NH 2 , or halogen; or a C 1 to C 6 alkenyl optionally independently substituted with one or more —OH, —NH 2 or halogen;

m is 1, 2, 3 or 4;

R 1 is H or a halogen;

R 2 is H; a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen;

wherein each R 2A is independently: H, a C 1 to C 6 alkyl, a C 6 to C 10 alkenyl, a C 6 to C 10 alkynyl, a C 6 to C 10 aryl, a C 3 to C 10 cycloalkyl, or a C 7 to C 20 arylalkyl optionally independently substituted with one or more halogen, —OH, —C(O)OH, or —NH 2 ;

R 3 is H or a halogen; and

B is a C 1 to C 6 alkyl, a C 1 to C 6 alkenyl, a C 1 to C 6 alkynyl, aryl, cycloalkyl, or arylalkyl wherein one carbon is optionally replaced by Si(CH 3 ) 3 and wherein B is optionally independently substituted with one or more halogen, —OH, —C(O)OH, or —NH 2 .

28 . The compound of claim 27 wherein R is H; m is 1; R 1 is H or a halogen;

R 2 is H; a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen;

R 3 is H or a halogen; and

B is a C 1 to C 6 alkyl, a C 1 to C 6 alkenyl, a C 1 to C 6 alkynyl, a C 6 to C 10 aryl, a C 3 to C 10 cycloalkyl, or a C 7 to C 20 arylalkyl wherein one carbon is optionally replaced by Si(CH 3 ) 3 .

29 . The compound of claim 27 or claim 28 wherein R 2 is H; a C 1 to C 3 alkyl, optionally independently substituted with one or more halogen.

30 . The compound of claim 27 or claim 28 wherein B is —CH 2 CH 3 , —CH 3 , —CH 2 C 6 H 5 , —CH 2 CH═CH 2 , or —C(CH 3 ) 3 , optionally substituted with one or more halogen.

31 . The compound of claim 27 or claim 28 wherein B is —CH 2 CH 2 Si(CH 3 ) 3 .

32 . A compound having the formula

wherein R 1B is H or a halogen; R 2B is H or a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen; R 3B is H or a halogen; and R 4B is H or a halogen.

33 . The compound of claim 32 wherein RIB is H, Cl or F; R 3B is H, Cl or F; and R 4B is H, Cl or F.

34 . The compound of claim 32 or claim 33 wherein R 2B is H or a C 1 to C 3 alkyl.

35 . A compound having the formula:

wherein R 2C is H or a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen; R 1C and R 3C are independently H or a halogen; and R 6 is a C 1 to C 10 alkyl, a C 6 to C 20 arylalkyl or a C 2 to C 20 alkenyl group

36 . The compound of claim 35 wherein R 2C is methyl or ethyl.

37 . The compound of claim 35 or claim 36 wherein R 1C and R 3C are independently Cl or F.

38 . The compound of claim 35 or claim 36 wherein R 1C and/or R 3C are Cl.

39 . The compound of claim 35 or claim 36 wherein R 1C and/or R 3C are F.

40 . The compound of claim 35 wherein R 6 is a C 1 to C 10 alkyl, optionally substituted with a phenyl.

41 . A method for preparing a compound having the formula:

wherein:

B is a C 1 to C 6 alkyl, a C 1 to C 6 alkenyl, a C 1 to C 6 alkynyl, a C 6 to C 10 aryl, a C 3 to C 10 cycloalkyl, or a C 7 to C 20 arylalkyl wherein B is optionally independently substituted with one or more halogen, —OH, —C(O)OH, or —NH 2 ;

R is, independently, H; a C 1 to C 6 alkyl, optionally independently substituted with one or more —OH, —NH 2 , or halogen; or a C 1 to C 6 alkenyl optionally independently substituted with one or more —OH, —NH 2 or halogen;

m is 1,2, 3 or 4;

R 1 is H or a halogen;

R 2 is H; a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen;

R 3 is H or a halogen;

A is

wherein each R 4 is independently H, a halogen, —CN, —SH; —OH; a C 1 -C 3 alkyl, optionally, independently substituted with one or more halogen; —OR 4A ; —SR 4A ; —SOR 4A ; —S(O) 2 R 4A , wherein R 4A is a C 1 to C 3 alkyl, optionally independently substituted with one or more halogen;

X is S, O, NH or NR 5 , wherein R 5 is a C 1 to C 10 alkyl;

n=1, 2,3, 4 or 5 when A is

n=1, 2, 3 or 4 when A is

and Z is O or S:

the method comprising:

(a) reacting a compound having the formula:

wherein m, R, R 1 , R 2 , B and R 3 are as defined above with a strong base in an organic solvent;

(b) adding

wherein R 4 , n and X are described above and Y is a suitable leaving group to prepare a compound having the formula:

42 . The method of claim 41 wherein A is

43 . The method of claim 41 wherein Z is O.

44 . The method of claim 41 wherein m is 1.

45 . The method of claim 41 wherein R is H.

46 . The method of claim 41 wherein R is H and m is 1.

47 . The method of claim 13 or claim 41 wherein

in which B is a C 1 to C 6 alkyl, a C 1 to C 6 alkenyl, a C 1 to C 6 alkynyl, a C 6 to C 10 aryl, a C 3 to C 10 cycloalkyl, or a C 7 to C 20 arylalkyl wherein one carbon is optionally replaced by Si(CH 3 ) 3 and wherein B is optionally independently substituted with one or more halogen, —OH, —C(O)OH, or —NH 2 ;

m is 1, 2, 3 or 4;

R 1 is H or a halogen;

R 2 is H; a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen;

R 3 is H or a halogen, is provided by reacting:

with BOH, wherein B is as defined above.

48 . The method of claim 1 wherein

is provided by:

(a) treating

wherein A, Z, m, R, R 1 , R 2 , R 3 and B are as defined in claim 1 with a strong base in an organic solvent; and

(b) adding

wherein R 4 , n and X are as defined in claim 1 and Y is a suitable leaving group.

49 . A method for preparing a compound having the formula:

wherein:

m is 1, 2, 3 or 4;

R 1 is H or a halogen;

R 2 is H; a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen;

R 3 is H or a halogen;

A is

wherein each R 4 is independently H, a halogen, —CN, —SH; —OH; a C 1 to C 3 alkyl, optionally, independently substituted with one or more halogen; —OR 4A ; —SR 4A ; —SOR 4A , —S(O) 2 R 4A , wherein R 4A is a C 1 to C 3 alkyl, optionally independently substituted with one or more halogen;

X is S, O, NH or NR 5 , wherein R 5 is a C 1 to C 10 alkyl;

n=1, 2, 3, 4 or 5 when A is

n=1, 2, 3 or 4 when A is

and Z is O or S:

the method comprising:

(a) reacting

wherein R 1 , R 2 and R 3 are as defined above and R 6 is a C 1 to C 10 alkyl, alkenyl or alkynl with

wherein R 4 , n and X are described above and Y is a suitable leaving group;

(b) treating with an acid in an alcohol and then neutralizing the acid to yield

to produce a compound having the formula:

50 . A method for preparing a compound having the formula:

wherein:

B is a C 1 to C 6 alkyl, a C 1 to C 6 alkenyl, a C 1 to C 6 alkynyl, a C 6 to C 10 aryl, a C 3 to C 10 cycloalkyl, or a C 7 to C 20 arylalkyl wherein one carbon is optionally replaced by Si(CH 3 ) 3 and wherein B is optionally independently substituted with one or more halogen, —OH, —C(O)OH, or —NH 2 ;

Each R is, independently, H; a C 1 to C 6 alkyl, optionally independently substituted with one or more —OH, —NH 2 , or halogen; or a C 1 to C 6 alkenyl optionally independently substituted with one or more —OH, —NH 2 or halogen;

m is 1, 2, 3 or 4;

R 1 is H or a halogen;

R 2 is H; a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen;

wherein each R is independently: H, a C 1 to C 6 alkyl, a C 1 to C 6 alkenyl, a C 1 to C 6 alkynyl, a C 6 to C 10 aryl, a C 3 to C 10 cycloalkyl, or a C 7 to C 20 arylalkyl optionally independently substituted with one or more halogen, —OH, —C(O)OH, or —NH 2 ;

R 3 is H or a halogen;

A is

X is S, O, NH or NR 5 , wherein R 5 is a C 1 to C 10 alkyl;

n=1,2,3, 4 or 5 when A is

n==2, 3 or 4 when A is

and Z is O or S:

the method comprising:

(a) reacting

wherein R 1 , R 2 and R 3 are as defined above and R 6 is a C 1 to C 10 alkyl, alkenyl or alkynl with

wherein R 4 n and X are described above and Y is a suitable leaving group;

(b) treating with an acid in an alcohol and then neutralizing the acid to yield

wherein B is a C 1 to C 6 alkyl, a C 1 to C 6 alkenyl, a C 1 to C 6 alkynyl, a C 6 to C 10 aryl, a C 3 to C 10 cycloalkyl, or a C 7 to C 20 arylalkyl wherein B is optionally independently substituted with one or more halogen, —OH, —C(O)OH, or —NH 2 to produce a compound having the formula:

51 . A method for preparing a compound having the formula:

wherein:

m is 1, 2, 3 or 4;

R 1 is H or a halogen;

R 2 is H; a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen;

R 3 is H or a halogen;

A is

X is S, O, NH or NR 5 , R 5 is a C 1 to C 10 alkyl;

n=1, 2, 3, 4 or 5 when A is

n=1, 2, 3 or 4 when A is

and Z is O or S:

the method comprising:

(a) reacting

wherein R 1 , R 2 and R 3 are as defined above and R 6 is a C 1 to C 10 alkyl, alkenyl or alkynl with

wherein R 4 , n and X are described above and Y is a suitable leaving group;

(b) treating with an acid in an alcohol and then neutralizing the acid to yield

to produce a compound having the formula:

and treating with an organic or inorganic acid to generate a compound having the formula:

52 . A compound having the formula:

wherein each R is, independently, H; a C 1 to C 6 alkyl, optionally independently substituted with one or more —OH, —NH 2 , or halogen; or a C 1 to C 6 alkenyl optionally independently substituted with one or more —OH, —NH 2 or halogen;

m is 1,2, 3 or 4;

R 1 is H or a halogen;

R 2 is H; a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen;

R 3 is H or a halogen;

A is

X is S, O, NH or NR 5 , wherein R 5 is a C 1 to C 10 alkyl; n=1, 2, 3, 4 or 5 when A is

n=1,2, 3 or 4 when A is

Z is O or S;

and B is a C 1 to C 6 alkyl, a C 1 to C 6 alkenyl, a C 1 to C 6 alkynyl, a C 6 to C 10 aryl, a C 3 to C 10 cycloalkyl, or a C 7 to C 20 arylalkyl wherein one carbon is optionally replaced by Si(CH 3 ) 3 and wherein B is optionally independently substituted with one or more halogen, —OH, —C(O)OH, or —NH 2 .

53 . A compound having the formula:

m is 1, 2, 3 or 4;

R 1 is H or a halogen;

R 2 is H; a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen;

R 3 is H or a halogen;

A is

X is S, O, NH or NR 5 , wherein R 5 is a C 1 to C 10 alkyl;

n=1, 2, 3, 4 or 5 when A is

n=1, 2, 3 or 4 when A is

Z is O or S.

54 . A compound having the formula:

m is 1,2, 3 or 4;

R 1 is H or a halogen;

R 2 is H; a C 1 to C 6 alkyl, optionally independently substituted with one or more halogen;

R 3 is H or a halogen.

Assignments (2)

CHANGE OF NAME Recorded Apr 17, 2008

From: MICROBIA, INC.

To: IRONWOOD PHARMACEUTICALS, INC.

Reel/Frame 020828/0232 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 4, 2005

From: BARTOLINI, WILMIN; CALI, BRIAN M.; CHEN, BARBARA; CHIEN, YUEH-TYNG; CURRIE, MARK G.; MILNE, G. TODD; PEARSON, JAMES PHILIP; TALLEY, JOHN JEFFREY; ZIMMERMAN, CRAIG

To: MICROBIA, INC.

Reel/Frame 016000/0357 →