Claims
- 1. A compound of formula ##STR32## or a pharmaceutically acceptable salt thereof wherein R.sup.1 is one or more groups independently selected from the group consisting of
- (a) hydrogen,
- (b) halogen,
- (c) hydroxy,
- (d) cyano,
- (e) alkyl of one to six carbon atoms,
- (f) alkenyl of two to six carbon atoms,
- (g) alkynyl of two to six carbon atoms,
- (h) alkoxy of one to six carbon atoms,
- (i) alkanoyl of one to seven carbon atoms,
- (j) --COOR.sup.7, wherein R.sup.7 is
- hydrogen,
- alkyl of one to ten carbon atoms, or
- phenylalkyl wherein the alkyl portion is of one to four carbon atoms,
- (k) unsubstituted phenyl,
- (l) phenyl, substituted with
- alkyl of one to six carbon atoms,
- alkoxy of one to six carbon atoms,
- halogen,
- --NR.sup.8 R.sup.9, where R.sup.8 and R.sup.9 are independently selected from hydrogen and alkyl of one to six carbon atoms,
- or R.sup.8 and R.sup.9 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring,
- --COOR.sup.7,
- --C(O)NR.sup.8 R.sup.9, or
- --SO.sub.2 NR.sup.8 R.sup.9,
- (m) --C(O) NR.sup.8 R.sup.9,
- (n) --OC(O)NR.sup.8 R.sup.9,
- (o) --NHC(O)NR.sup.8 R.sup.9,
- (p) 2- or 3-furyl,
- (q) 2- or 3-thienyl,
- (r) 2-, 4-, or 5-thiazolyl,
- (s) 2-, 3-, or 4-pyridyl,
- (t) 2-, or 4-pyrimidyl,
- (u) phenylalkyl in which the alkyl portion is of one to six carbon atoms,
- (v) phenylalkyl, in which the alkyl portion is of one to six carbon atoms and the phenyl moiety is substituted with
- halogen,
- alkyl of from one to six carbon atoms, or
- alkoxy of from one to six carbon atoms,
- (w) unsubstituted benzoyl,
- (x) benzoyl substituted with
- halogen,
- alkyl of from one to six carbon atoms, or
- alkoxy of from one to six carbon atoms,
- (y) unsubstituted phenoxy,
- (z) phenoxy substituted with
- halogen,
- alkyl of from one to six carbon atoms, or
- alkoxy of from one to six carbon atoms,
- (aa) unsubstituted phenylalkyloxy, in which the alkyl portion is of one to six carbon atoms,
- (bb) phenylalkyloxy in which the alkyl portion is of one to six carbon atoms and the phenyl moiety is substituted with
- halogen,
- alkyl of from one to six carbon atoms, or
- alkoxy of from one to six carbon atoms,
- (cc) unsubstituted phenylalkanoyl, in which the alkanoyl portion is of one to seven carbon atoms, and
- (dd) phenylalkanoyl, in which the alkanoyl portion is of one to seven carbon atoms and the phenyl moiety is substituted with;
- halogen,
- alkyl of from one to six carbon atoms, or
- alkoxy of from one to six carbon atoms;
- R.sup.2 is selected from the group consisting of
- (a) hydrogen,
- (b) alkyl of one to six carbon atoms;
- (c) --(CH.sub.2).sub.p COOR.sup.7, where p is 0, 1, 2, 3, or 4,
- (d) --(CH.sub.2).sub.q NR.sup.8 R.sup.9, where q is 2, 3, or 4,
- (e) --(CH.sub.2).sub.p COR.sup.7
- (f) --(CH.sub.2).sub.q OR.sup.7,
- (g) --(CH.sub.2).sub.p SO.sub.2 R.sup.7,
- (h) --(CH.sub.2).sub.p SO.sub.2 NR.sup.8 R.sup.9,
- (i) --(CH.sub.2).sub.p CONR.sup.10 R.sup.11, where R.sup.10 and R.sup.11 are independently selected from the group consisting of
- hydrogen,
- alkyl of one to six carbon atoms,
- --(CH.sub.2).sub.r COOR.sup.7, where r is 1, 2, 3, or 4,
- --(CH.sub.2).sub.r NR.sup.8 R.sup.9,
- --(CH.sub.2).sub.r OR.sup.7,
- --(CH.sub.2).sub.r SO.sub.2 R.sup.7, and
- --(CH.sub.2).sub.r SO.sub.2 NR.sup.8 R.sup.9,
- or R.sup.10 and R.sup.11 taken together define a pyrrolidine, morpholine, or thiomorpholine ring,
- (j) --(CH.sub.2).sub.p CN,
- (k) --(CH.sub.2).sub.p -1H-tetrazol-5-yl,
- (l) --CONHNH.sub.2,
- (m) unsubstituted phenylalkyl wherein the alkyl portion is of one to four carbon atoms, and
- (n) phenylakyl wherein the alkyl portion is of one to four carbon atoms and the phenyl moiety is substituted with
- halogen,
- alkyl of from one to six carbon atoms, or
- alkoxy of from one to six carbon atoms;
- R.sup.3 is selected from the group consisting of hydrogen and alkyl of one to six carbon atoms;
- Y is selected from the group consisting of
- >C.dbd.O, and
- >S(O).sub.t, wherein t is 1 or 2;
- R.sup.4 is selected from the group consisting of
- (a) alkyl of one to six carbon atoms,
- (b) alkenyl of two to six carbon atoms,
- (c) alkynyl of two to six carbon atoms,
- (d) alkoxy of one to six carbon atoms,
- (e) alkylthio of one to six carbon atoms,
- (f) alkoxyalkyl in which the alkoxy and alkyl portions are independently of one to six carbon atoms,
- (g) alkylthioallcyl in which the alkyl portions each independently of one to six carbon atoms,
- (h) haloalkyl of one to six carbon atoms,
- (i) unsubstituted phenylalkyl wherein the alkyl portion is of one to six carbon atoms,
- (j) phenylalkyl wherein the alkyl portion io of one to six carbon atoms and the phenyl is substituted with
- alkyl of one to six carbon atoms,
- haloalkyl of one to six carbon atoms,
- alkoxy of one to six carbon atoms,
- hydroxy, or
- halogen,
- (k) cycloalkyl of three to eight carbon atoms,
- (l) unsubstituted thiophenyl, and
- (m) thiophenyl substituted with
- alkyl of one to six carbon atoms,
- haloalkyl of one to six carbon atoms,
- alkoxy of one to six carbon atoms,
- hydroxy, or
- halogen; and
- R.sup.5 and R.sup.6 are independently selected from the group consisting of
- hydrogen,
- alkyl of one to six carbon atoms,
- halogen,
- haloalkyl, and
- alkoxy of one to six carbon atoms.
- 2. A compound or pharmaceutically acceptable salt thereof as defined by claim 1 wherein Y is >C.dbd.O or >SO.sub.2.
- 3. A compound or pharmaceutically acceptable salt thereof as defined by claim 2 wherein
- R.sup.1 is one or more groups independently selected from the group consisting of
- hydrogen,
- halogen,
- alkyl of one to six carbon atoms,
- alkynyl of two to four carbon atoms,
- alkoxy of one to six carbon atoms,
- unsubstituted phenyl,
- phenyl, substituted with
- alkyl of one to six carbon atoms,
- alkoxy of one to six carbon atoms,
- halogen,
- --COOR.sup.7, wherein R.sup.7 is hydrogen, alkyl of one to ten carbon atoms, or phenylalkyl wherein the alkyl portion is of one to four carbon atoms,
- --C(O)NR.sup.8 R.sup.9,
- --OC(O)NR.sup.8 R.sup.9,
- 2- or 3-furyl, and
- 2- or 3-thienyl;
- R.sup.3, R.sup.5 and R.sup.6 are hydrogen; and
- R.sup.4 is alkyl of one to six carbon atoms.
- 4. A compound or pharmaceutically acceptable salt thereof as defined by claim 3 wherein
- R.sup.2 is selected from the group consisting of
- --CONR.sup.10 R.sup.11, where R.sup.10 and R.sup.11 are independently selected from
- hydrogen,
- alkyl of one to six carbon atoms, and
- --(CH.sub.2).sub.q OR.sup.7, wherein q is 2, 3, or 4, and R.sup.7 is alkyl of one to four carbon atoms.
- 5. A compound or pharmaceutically acceptable salt thereof as defined by claim 1 selected from the group consisting of
- 3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole-1,4-dicarboxylic acid 1-dimethyl amide 4-methyl ester hydrochloride,
- 6-(4-fluorophenyl)-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole-1-carboxylic acid dimethyl amide hydrochloride,
- 3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole hydrochloride,
- 4-chloro-3-[(4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole-1-carboxylic acid dimethyl amide hydrochloride,
- 1-(2-ethoxyethyl)-6-(4-fluorophenyl)-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole hydrochloride,
- 1-(2-ethoxyethyl)-4-chloro-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole hydrochloride.
- 6-(4-fluorophenyl)-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}sulfonyl]indole-1-carboxylic acid dimethyl amide,
- 4-(fur-2-yl)-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole-1-carboxylic acid dimethyl amide,
- 4-(thien-2-yl)-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole-1-carboxylic acid dimethyl amide,
- 4-ethynyl-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole-1-carboxylic acid dimethyl amide,
- 4-methoxy-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole-1-carboxylic acid dimethyl amide hydrochloride,
- 4-hydroxy-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole-1-carboxylic acid dimethyl amide hydrochloride,
- 4-(N,N-dimethylaminocarbonyloxy)-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole-1-carboxylic acid dimethyl amide hydrochloride,
- 4-(N,N-dimethylaminocarbonylamino)-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole-1-carboxylic acid dimethyl amide hydrochloride.
- 6. A compound or pharmaceutically acceptable salt thereof as defined by claim 1 selected from the group consisting of:
- 3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole-1,4-dicarboxylic acid 1-dimethyl amide 4-methyl ester hydrochloride,
- 6-(4-fluorophenyl)-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}carbonyl]indole-1-carboxylic acid dimethyl amide hydrochloride, and
- 6-(4-fluorophenyl)-3-[{4-[(2-(1H-2-methylimidazo[4.5-c]pyrid-1-yl)ethyl]piperazin-1-yl}sulfonyl]indole-1-carboxylic acid dimethyl amide.
- 7. A pharmaceutical composition useful for inhibiting PAF in a mammal in need of such treatment comprising a PAF-inhibitive effective amount of a compound as defined by claim 1 in combination with a pharmaceutically acceptable carrier.
- 8. A method of treating PAF mediated disorders comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound as defined by claim 1.
CROSS REFERENCE TO RELATED APPLICATIONS
This is a continuation in part of U.S. Ser. No. 08/424,911 filed Apr. 19, 1995, now issued U.S. Pat. No. 5,567,711.
US Referenced Citations (2)
| Number |
Name |
Date |
Kind |
|
5180723 |
Whittaker et al. |
Jan 1993 |
|
|
5180724 |
Bowles et al. |
Jan 1993 |
|
Foreign Referenced Citations (4)
| Number |
Date |
Country |
| 9214734 |
Jan 1992 |
WOX |
| 9301813 |
Feb 1993 |
WOX |
| 9314072 |
Jul 1993 |
WOX |
| 9516687 |
Jun 1995 |
WOX |
Continuation in Parts (1)
|
Number |
Date |
Country |
| Parent |
424911 |
Apr 1995 |
|
Patent Grant
5654305
