Modulators of CRTH2, COX-2 and FAAH
Certain substituted indoles that are modulators of one or more or of CRTH2, COX-2 AND FAAH are described. The compounds are useful for treatment of pain and/or inflammation as well as other disorders.
1 . A compound having the formula:
wherein:
R 1 is: H or a halogen;
R 2 is: H, a halogen, or R 2B O— wherein
R 2B is selected from:
(a) H;
(b) C 1 to C 6 alkyl or a C 2 to C 6 alkenyl that is optionally independently substituted with one or more halogen; —OH, —NH 2 , —C(O)OH;
wherein each R 2A is independently: H, a C 1 to C 6 alkyl, a C 2 to C 6 alkenyl, a C 2 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;
X 1 is —O—, —S—, —N(H)— or —N(H)S(O 2 )—;
Z is
or C;
R 4 is H; a C 1 to C 10 alkyl; a C 2 -C 10 alkenyl; a C 2 -C 10 alkynyl; a C 3 to C 8 cycloalkyl; a C 1 to C 6 hydroxyalkyl; a hydroxyl substituted C 6 to C 8 aryl; a primary, secondary or tertiary C 1 to C 6 alkylamino; primary, secondary or tertiary C 6 to C 8 arylamino; C 2 to C 6 alkylcarboxylic acid; a C 1 to C 6 alkylester; a C 6 to C 8 aryl; a C 6 to C 8 arylcarboxylic acid; a C 6 to C 8 arylester; a C 6 to C 8 aryl substituted C, to C 6 alkyl; a 4 to 8 membered heterocyclic alkyl or heteroaryl wherein the heteroatoms are selected from O, S, S(O) 2 , N, and S(O); an alkyl-substituted or aryl-substituted a 4 to 8 membered heterocyclic alkyl or heteroaryl wherein the heteroatoms are selected from O, S, S(O) 2 , N, and S(O), wherein one or more H within R 4 can be substituted by a halogen, —OH, or —C(O)OH, —NH 2 ;
n is 1, 2, 3, 4 or 5;
Each R 5 is independently: H, an optionally substituted C 1 -C 4 alkyl, wherein the substituents are independently selected from a halogen and —OH;
represents a C 3 -C 6 saturated carbocycle, a C 6 aryl, C 3 -C 6 non-saturated, non-aromatic carbocycle, a 6-membered heteroaryl having 1, 2, 3, 4 or 5 heteroatoms independently selected from O, S, S(O) 2 , N, S(O) and N(R 7 ) or a 3- to 7-membered saturated or non-saturated heterocycle having 1, 2, 3, 4 or 5 heteroatoms independently selected from O, S, S(O) 2 , N, S(O) and N(R 7 );
each R 6 is independently H, a halogen, —CH 3 , —CN, —OCH 3 , —SCH 3 , —SCF 3 , —OCH 2 CF 3 or —CH 2 CH 3 wherein one or more H can be replaced by a halogen;
m=1, 2, 3, 4, or 5;
R 7 is: H, a halogen, —CH 3 , —CN, —OCH 3 , —SCH 3 , or —CH 2 CH 3 wherein one or more H can be replaced by a halogen; and
R 8 is: H, a halogen or —CH 3 , wherein one or more H can be replaced by a halogen.
2 . The compound of claim 1 wherein
represents a C 3 -C 6 saturated carbocycle.
3 . The compound of claim 2 wherein the C 3 -C 6 saturated carbocycle is selected from cyclohexyl, cyclopentyl, cyclobutyl and cyclopropyl.
4 . The compound of claim 1 wherein
represents a C 3 -C 6 non-saturated, non-aromatic carbocycle.
5 . The compound of claim 4 wherein the C 3 -C 6 non-saturated, non-aromatic carbocycle is selected from a cyclohexenyl, a cyclopentenyl, a cyclobutenyl.
6 . The compound of claim 1 wherein
represents a 6-membered heteroaryl.
7 . The compound of claim 6 wherein the 6-membered heteroaryl is selected from pyrazine, pyridazine, triazine, tetrazine, and pentazine.
8 . The compound of claim 1 wherein
represents a 3- to 7-membered saturated heterocycle.
9 . The compound of claim 8 wherein the 6-membered saturated heterocycle is selected from piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine sulfoxide, thiomorpholine sulfone, tetrahydropyran, tetrahydrothiopyran, and dioxane.
10 . The compound of claim 1 wherein
represents a 3- to 7-membered non-saturated heterocycle.
11 . The compound of claim 10 wherein the 3- to 7-membered non-saturated heterocycle is selected from: thiphene, furan, pyrrole, thaizole, oxazole, imidizole, isothazole, isoxazole pyrazole, triazole, tetrazole, oxadiazole, oxatriazole and thiadiazole.
12 . The compound of claim 1 wherein R 1 is H.
13 . The compound of claim 1 wherein R 1 is a halogen.
14 . The compound of claim 13 wherein R 1 is F or Cl.
15 . The compound of claim 1 wherein R 2B is a substituted C 1 to C 6 alkyl or a substituted C 2 to C 6 alkenyl.
16 . The compound of claim 1 wherein R 2B is not substituted.
17 . The compound of claim 1 wherein R 2B is a C 1 to C 6 alkyl or a C 2 to C 6 alkenyl optionally substituted with one or more halogen.
18 . The compound of claim 1 wherein R 2B is a C 1 to C 3 alkyl or alkenyl.
19 . The compound of claim 18 wherein R 2B is a C 1 to C 3 alkyl.
20 . The compound of claim 19 wherein R 2B is a methyl group or an ethyl group.
21 . The compound of claim 1 wherein R 2B is substituted only with a halogen.
22 . The compound of claim 1 wherein R 2 is H.
23 . The compound of claim 1 wherein R 3 is a halogen.
24 . The compound of claim 23 wherein R 3 is Cl.
25 . The compound of claim 23 wherein R 3 is F.
26 . The compound of claim 1 wherein X 1 is —O—.
27 . The compound of claim 1 wherein X 1 is —S—.
28 . The compound of claim 1 wherein X 1 is —N(H)—
29 . The compound of claim 1 wherein X 1 is —N(H)S(O) 2 —.
30 . The compound of claim 1 wherein Z is
31 . The compound of claim 1 wherein Z is
or C.
32 . The compound of claim 1 wherein R 6 is selected from: —CH 3 , —CF 2 H, —CH 2 F, —CF 3 , —CN, —OCF 2 H, —OCH 3 , —SCF 3 , —SCF 2 H, —SCH 3 , —CH 2 CH 3 and —OCF 3 .
33 . The compound of claim 1 wherein R 7 is selected from: —CH 3 , —CF 2 H, —CH 2 F, —CF 3 , —CN, —OCF 2 H, —OCH 3 , —SCF 3 , —SCF 2 H, —SCH 3 , —CH 2 CH 3 and —OCF 3 .
34 . The compound of claim 1 wherein n is 1 or 2.
35 . The compound of claim 1 wherein m is 1 or 2.
36 . The compound of claim 1 wherein R 5 is H.
37 . The compound of claim 1 wherein R 5 is a methyl group or an ethyl group.
38 . The compound of claim 1 wherein R 5 is an unsubstituted methyl group or an unsubstituted ethyl group.
39 . The compound of claim 1 wherein R 4 is H.
40 . The compound of claim 1 wherein X 1 is O and R 4 is H.
41 . The compound of claim 1 wherein X 1 is O and R 4 is other than H.
42 . The compound of claim 1 wherein R 4 is an optionally independently substituted C 3 to C 10 branched alkyl.
43 . The compound of claim 1 wherein R 4 is a C 1 to C 10 alkyl.
44 . The compound of claim 43 wherein R 4 is a C 4 to C 8 cycloalkyl.
45 . The compound of claim 1 wherein R 4 is a C 1 to C 6 hydroxy substituted alkyl.
46 . The compound of claim 45 wherein R 4 is a hydroxyl substituted C 4 to C 8 aryl.
47 . The compound of claim 1 wherein R 4 is a primary, secondary or tertiary C 1 to C 6 alkylamino.
48 . The compound of claim 1 wherein R 4 is a primary, secondary or tertiary C 4 to C 8 arylamino.
49 . The compound of claim 1 wherein R 4 is a C 2 to C 6 alkylcarboxylic acid.
50 . The compound of claim 1 wherein R 4 is a C 1 to C 6 alkylester.
51 . The compound of claim 50 wherein R 4 is a branched C 1 to C 6 alkylester.
52 . The compound of claim 1 wherein R 4 is a C 4 to C 8 aryl.
53 . The compound of claim 1 wherein R 4 is a C 4 to C 8 arylcarboxylic acid.
54 . The compound of claim 1 wherein R 4 is a C 4 to C 8 arylester.
55 . The compound claim 1 wherein R 4 is C 4 to C 8 aryl substituted C 1 to C 6 alkyl.
56 . The compound of claim 1 wherein R 4 is a C 4 to C8 heterocyclic alkyl or aryl.
57 . The compound of claim 1 wherein R 4 is an alkyl-substituted or aryl-substituted C 4 to C 8 heterocyclic alkyl or aryl.
58 . The compound of claim 1 wherein R 4 is substituted.
59 . The compound of claim 1 wherein R 4 is unsubstituted.
60 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
61 . A method for treating inflammation comprising administering a composition comprising the compound of claim 1 .
62 . A method for treating anxiety comprising administering the compound of claim 1
63 . A method for treating a sleep disorder comprising administering the compound of claim 1 .
64 . A method for treating a respiratory disorder comprising administering the compound of claim 1 .
65 . The method of claim 65 wherein the respiratory disorder is asthma.
66 . A method for inhibiting COX-2 activity in a patient, the method comprising administering the compound of claim 1 .
66 . A method for inhibiting FAAH activity in a patient, the method comprising administering the compound of claim 1 .
67 . The method of claim 65 wherein X 1 is O and R 4 is H.
68 . The method of claim 66 wherein X 1 is O and R 4 is other than H.
69 . A method for modulating CRTH2 activity on a patient, the method comprising administering the compound of claim 1 .
70 . The pharmaceutical composition of claim 60 further comprising an analgesic agent.
71 . The pharmaceutical composition of claim 60 further comprising an anti-inflammatory agent.
72 . The compound of claim 1 having Formula I.
73 . The compound of claim 1 having Formula II.
74 . The compound of claim 1 wherein R 8 is H.
75 . The compound of claim 1 having Formula I wherein R 8 is H.
76 . The compound of claim 1 having Formula I wherein Z is
77 . The compound of claim 1 having Formula II wherein Z is