TREA

Cyclohept[b]indolealkanoic acids, pharmaceutical compositions and use

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Information

  • Patent Grant
  • 5017593
  • Patent Number
    5,017,593
  • Date Filed
    Wednesday, October 4, 1989
    35 years ago
  • Date Issued
    Tuesday, May 21, 1991
    33 years ago
Information
Abstract
Cyclohept[b]indolealkanoic acids and acid derivatives are disclosed. The compounds act as prostaglandin and thromboxane antagonists and are useful in treating asthma, diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion, dysmenorrhea and nephrotoxicity caused by cyclosporin A and as cytoprotective agents.
Description

DESCRIPTION OF THE INVENTION
The present invention relates to novel compounds of Formula I: ##STR1## wherein:
A is --(CR.sup.9 R.sup.10).sub.r R.sup.11 ; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbon atoms;
(3) alkenyl having 2 to 6 carbon atoms;
(4) --(CH.sub.2).sub.n M
wherein n is 0 to 3 and M is
a) --C(O)R.sup.15 ;
b) --C(O)NR.sup.17 R.sup.17 ;
c) --CN;
d) --C(O)R.sup.16 ;
e) --C(O)CH.sub.2 OH (hydroxymethyl ketone);
f) --CF.sub.3 ;
g) --R.sup.14 ;
h) --tetrazole;
i) --OR.sup.12 ;
j) --OC(O)R.sup.16 ;
k) --OC(O)NR.sup.17 R.sup.17 ;
l) --OC(O)OR.sup.18 ;
m) --SR.sup.13 ;
n) --S(O)R.sup.13 ;
o) --S(O).sub.2 R.sup.13 ;
p) --S(O).sub.2 NR.sup.17 R.sup.17 ;
q) --NR.sup.17 R.sup.17 ;
r) --NHC(O)R.sup.16 ;
s) --NHS(O).sub.2 R.sup.13 ;
t) --N.sub.3 ;
u) --NO.sub.2 ;
v) --halogen.
each R.sup.7 is independently H or C.sub.1 to C.sub.6 alkyl;
each is independently H or C.sub.1 to C.sub.6 alkyl;
each R.sup.9 is independently H or Cl to C.sub.6 alkyl;
each R.sup.10 is independently H, OH, C.sub.1 to C.sub.4 alkoxy or C.sub.1 to C.sub.4 alkyl;
R.sub.11 is --C(O)--C(O)R.sup.20 ; CH.sub.2 OH; CHO; tetrazole; --C(O)NHS(O).sub.2 R.sup.13 ; NHS(O).sub.2 R.sup.13 ;--C(O)CH.sub.2 OH; --C(O)NR.sup.17 R.sup.17 or NHS(O).sub.2 OH;
each R.sup.12 is independently H; C.sub.1 to C.sub.6 alkyl; benzyl; or R.sup.14 ;
each R.sup.13 is independently C.sub.1 to C.sub.6 alkyl, CF.sub.3 or R.sup.14 ;
each R.sup.14 is independently phenyl, mono-substituted phenyl, or di substituted phenyl wherein the substituents are independently, C.sub.1 to C.sub.3 alkyl, C.sub.1 to C.sub.3 perfluoroalkyl, C.sub.1 to C.sub.3 alkoxy, halogen, CN, --C(O)OR.sup.15, or --CH.sub.2 --C(O)OR.sup.15 ;
each R.sup.15 is independently H, phenyl, benzyl or C.sub.1 to C.sub.6 alkyl;
each R.sup.16 independently is H, R.sup.13 or (CH.sub.2).sub.m C(O)OR.sup.15 ;
each R.sup.17 is independently R.sup.12, or two R.sup.17 groups may be joined to form a 5- or 6-membered saturated ring optionally containing an oxygen atom or a second nitrogen atom, the latter being substituted by H or C.sub.1 to C.sub.6 alkyl;
each R.sup.18 is independently C.sub.1 to C.sub.6 alkyl, benzyl or phenyl;
each R.sup.19 is H, C.sub.1 to C.sub.6 alkyl, R.sup.14, R.sup.21 or R.sup.22 ;
R.sup.20 is --(CH.sub.2).sub.t --C(R.sup.9).sub.2 --(CH.sub.2).sub.t --R.sup.23 ;
R.sup.21 is --CH.sub.2 --R.sup.14 ;
R.sup.22 is --CH.sub.2 --CH.sub.2 --R.sup.14
R.sup.23 is A) a monocyclic or bicyclic heterocyclic radical containing from 3 to 12 nuclear carbon atoms and 1 or 2 nuclear heteroatoms selected from N, S, or O and with each ring in the heterocyclic radical being formed of 5 to 6 atoms, or B) the radical W--R.sup.24 ;
R.sup.24 contains up to 21 carbon atoms and is (1) a hydrocarbon radical or (2) an acyl radical of an organic acyclic or monocyclic carboxylic acid containing not more than 1 heteroatom in the ring;
W is 0, S or NH;
m is 0 to 4
r is 0 to 6 and
t is 0 to 3.





The novel compounds in Table 1 are a further embodiment of the present invention.
TABLE 1__________________________________________________________________________Novel Cyclohept[6]indoleAlkanoic Acids ##STR2## ICompound R.sup.1 R.sup.2 R.sup.5 R.sup.6 R.sup.7 R.sup.8 (CR.sup.9 R.sup.10)r R.sup.11__________________________________________________________________________1 (Ex. 1) 2-F H 4'-Cl H H H 7-CH.sub.2 CO.sub.2 H2 (Ex. 1) 2-F H 4'-Cl H H H 10-CH.sub.2 CO.sub.2 H3 (Ex. 2) 2-F H 4'-Cl H H H r = 0 7-CO.sub.2 H4 (Ex. 3) 2-F H 4'-Cl H H H 6-CH.sub.2 CO.sub.2 H5 H H H H H H 7-CH.sub.2 CO.sub.2 H6 H H 4'-Cl H H H 6-CH.sub.2 CO.sub.2 H7 2-F 4-F 4'-Cl H H H 7-CH.sub.2 CO.sub.2 H8 2-F 4-F 4'-Cl H H H 6-CH.sub.2 CO.sub.2 H9 2-F 4-F 4'-Cl H H H r = 0 7-CO.sub.2 H10 2-OMe 4-F 4'-Cl H H H r = 0 6-CO.sub.2 H11 4-F H 4'-Cl H H H 7-CH.sub.2 CO.sub.2 H12 4-F H 4'-Cl H H H 6-CH.sub.2 CO.sub.2 H13 4-SMe H 4'-Cl H H H r = 0 7-CO.sub.2 H14 4-Ph H 4'-Cl H H H r = 0 6-CO.sub.2 H15 4-Me H 4'-Cl H H H 7-CH.sub.2 CO.sub.2 H16 4-Me H 4'-Cl H H H 6-CH.sub.2 CO.sub.2 H17 4-Me H 4'-Cl H H H r = 0 7-CO.sub.2 H18 4-Me H 4'-Cl H H H r = 0 6-CO.sub.2 H19 2-F 4-F 2'-Cl H H H 7-CH.sub.2 CO.sub.2 H20 2-F 4-F 2'-Cl H H H 6-CH.sub.2 CO.sub.2 H21 2-F 4-F 2'-Cl H H H r = 0 7-CO.sub.222 2-F 4-F 2'-Br H H H r = 0 6-CO.sub.2 H23 2-F 4-F 3'-CF.sub.3 H H H 7-CH.sub.2 CO.sub.2 H24 2-F 4-F 3'-Cl H H H 6-CH.sub.2 CO.sub.2 H25 2-F 4-F 3'-Cl H H H r = 0 7-CO.sub.2 H26 2-F 4-F 3'-Cl H H H r = 0 6-CO.sub.2 H27 2-F 4-F 2'-Cl 4'-Cl H H 7-CH.sub.2 CO.sub.2 H28 2-F 4-F 2'-Cl 4'-Cl H H 6-CH.sub.2 CO.sub.2 H29 (Ex. 7) 2-F H 4'-S(O).sub.2 Me H H H 6-CH.sub.2 CO.sub.2 H30 2-F 4-F 2'-Cl 4'-Cl H H r = 0 6-CO.sub.2 H31 2-F 4-F 3' -Cl 4'-Cl H H 7-CH.sub.2 CO.sub.2 H32 2-F 4-F 3'-Cl 4'-Cl H H 6-CH.sub.2 CO.sub.2 H33 2-F 4-F 3'-Cl 4'-Cl H H r = 0 7-CO.sub.2 H34 2-F 4-F 3'-Cl 4'-Cl H H r = 0 6-CO.sub.2 H35 2-F 4-F 4'-S(O).sub.2 Me H H H 6-CH.sub.2 CO.sub.2 H36 (Ex. 4) 2-F 4-F 4'-S(O).sub.2 Me H H H 7-CH.sub.2 CO.sub.2 H37 2-F 4-F 4'-S(O).sub.2 Me H H H r = 0 7-CO.sub.2 H38 2-F 4-F 4'-S(O).sub.2 Me H H H r = 0 6-CO.sub.2 H39 2-F 4-F 4'-SMe H H H 7-CH.sub.2 CO.sub.2 H40 2-F 4-F 4'-SMe H H H 6-CH.sub.2 CO.sub.2 H41 2-F 4-F 4'-SMe H H H r = 0 7-CO.sub.2 H42 2-F 4-F 4'-SMe H H H r = 0 6-CO.sub.2 H43 2-F 4-F 4'-S(O)Me H H H 7-CH.sub.2 CO.sub.2 H44 2-F 4-F 4'-S(O)Me H H H 6-CH.sub. 2 CO.sub.2 H45 2-F 4-F 4'-S(O)Me H H H r = 0 7-CO.sub.2 H46 2-F 4-F 4'-S(O)Me H H H r = 0 6-CO.sub.2 H47 2-F 4-F 4'CF.sub.3 H H H 7-CH.sub.2 CO.sub.2 H48 2-F 4-F 4'CF.sub.3 H H H 6-CH.sub.2 CO.sub.2 H49 2-F 4-F 4'-CF.sub.3 H H H r = 0 7-CO.sub.2 H50 2-F 4-F 4'-CF.sub.3 H H H r = 0 6-CO.sub.2 H51 2-F 4-F 4'-F H H H 7-CH.sub.2 CO.sub.2 H52 2-F 4-F 2'-F 4'F H H 7-CH.sub.2 CO.sub.2 H53 (Ex. 5) 2-F 4-F 4'-C(O)Me H H H 7-CH.sub.2 CO.sub.2 H54 2-F 4-F 4'-C(O)Me H H H 7-CH.sub.2 CO.sub.2 H55 (Ex. 6) 2-F 4-F 4'-S(O).sub.2 NMe.sub.2 H H H 7-CH.sub.2 CO.sub.2 H56 2-F 4-F 3'-S(O).sub.2 NMe.sub.2 H H H 6-CH.sub.2 CO.sub.2 H57 2-F 4-F 4'-C(O)NMe.sub.2 H H H 7-CH.sub.2 CO.sub.2 H58 2-F 4-F 4'-C(O)Me H H H 7-CH.sub.2 CO.sub.2 H59 2-F 4-F 4'-C(O)Me H H H 7-CH.sub.2 CO.sub.2 H60 2-F 4-F 4'NHC(O)Me H H H 7-CH.sub.2 CO.sub.2 H61 2-F 4-F 4'NHS(O).sub.2 Me H H H 7-CH.sub.2 CO.sub.2 H62 2-F 4-F 4'NHC(O)NHMe H H H 6-CH.sub.2 CO.sub.2 H63 2-F 4-F 4'OMe H H H 7-CH.sub.2 CO.sub.2 H64 2-F 4-F 4'OCH.sub.2 CO.sub.2 H H H H 7-CH.sub.2 CO.sub.2 H65 2-F 4-F 4'-H H H H 7-CH.sub.2 CO.sub.2 H66 2-F 4-F 4'-Br H H H 7-CH.sub.2 CO.sub.2 H67 2-F 4-F 4'-Cl H H H 7-CH.sub.2 CO.sub.2 H68 2-F 4-F 4'-S(O).sub.2 Me H H H 7-CH.sub.2 CH.sub.2 OH69 2-F 4-F 4'-Cl H H H 7-CH.sub.2 CHO70 2-F 4-F 4'-S(O).sub.2 Me H H H 7-CH.sub.2 CHO71 2-F 4-F 4'-Cl H H H 7-CH.sub.2 Tetrazol-5-yl)72 2-F 4-F 4'-S(O).sub.2 Me H H H 7-CH.sub.2 Tetrazol-5-yl)73 2-F 4-F 4' -Cl H H H 6-CH.sub.2 Tetrazol-5-yl)74 2-F 4-F 4'-S(O).sub.2 Me H H H 6-CH.sub.2 Tetrazol-5-yl)75 2-F 4-F 4'-S(O).sub.2 Me H H H r = 0 7-(Tetrazol-5-yl)76 2-F 4-F 4'-S(O).sub.2 Me H H H r = 0 7-(Tetrazol-5-yl)77 2-F 4-F 4'-Cl H H H 7-CH.sub.2 CONHS(O).sub.2 Ph78 2-F 4-F 4'-S(O).sub.2 Me H H H 7-CH.sub.2 CONH.sub.279 2-F 4-F 4'-Cl H H H 7-CH.sub.2 NHS(O).sub.2 OH80 2-F 4-F 4'-C(O)Me H H H 6-CHMe CO.sub.2 H81 2-F 4-F 4'-NO.sub.2 H H H 6-CMe.sub.2 CO.sub.2 H82 2-F 4-F 4'-S(O).sub.2 NMe.sub.2 H H H 6-(CH.sub.2).sub.2 CO.sub.2 H83 2-F 4-F 4'-Cl H H H 6-(CH.sub.2).sub.2 CO.sub.2 H84 2-F 4-F 4'-Cl H 7-Me H 7-CH.sub.2 CO.sub.2 H85 2-F 4-F 4'-Cl H 6-Me H 7-CH.sub.2 CO.sub.2 H86 2-F 4-F 4'-Cl H H Me 7-CH.sub.2 CO.sub.2 H87 2-F 4-F 4'-Cl H H H 8-CH.sub.2 CO.sub.2 H88 2-F 4-F 4'-Cl H H H 9-CH.sub.2 CO.sub.2 H89 2-F 4-F 4'-Cl H H H cycloprop-1-yl CO.sub.2 H90 2-F 4-F 4'-Cl H H H 7-CH-(c-C.sub.3 H.sub.5) CO.sub.2 H91 2-SMe H 4'-Cl H H H 7-CH.sub.2 CO.sub.2 H92 2-S(O)Me H 4'-Cl H H H 7-CH.sub.2 CO.sub.2 H93 S-2(O).sub.2 Me H 4'-Cl H H H 7-CH.sub.2 CO.sub.2 H (-)94 isomer 2-F 4-F 4'-S(O).sub.2 Me H H H 7-CH.sub.2 CO.sub.2 H (+)95 isomer 2-F 4-F 4'-S(O).sub.2 Me H H H 7-CH.sub.2 CO.sub.2 H (-)96 isomer 2-F 4-F 4'-S(O).sub.2 Me H H H 6-CH.sub.2 CO.sub.2 H (+)97 isomer 2-F 4-F 4'-S(O).sub.2 Me H H H 6-CH.sub.2 CO.sub.2 H__________________________________________________________________________
In Table I R.sup.3 .dbd.H and R.sup.4 .dbd.H.
Claims
  • 1. A compound of the formula: ##STR3## wherein: A is --(CR.sup.9 R.sup.10).sub.r R.sup.11 ;
  • R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently selected from:
  • (1) hydrogen;
  • (2) alkyl having 1 to 6 carbon atoms;
  • (3) alkenyl having 2 to 6 carbon atoms;
  • (4) --(CH.sub.2).sub.n M
  • wherein n is 0 to 3 and M is
  • a) --C(O)R.sup.15 ;
  • b) --C(O)NR.sup.12 R.sup.12 ;
  • c) --CN;
  • d) --C(O)R.sup.16 ;
  • e) --C(O)CH.sub.2 OH (hydroxymethyl ketone);
  • f) --CF.sub.3 ;
  • g) --R.sup.14 ;
  • h) --tetrazole;
  • i) --OR.sup.12 ;
  • j) --OC(O)R.sup.16 ;
  • k) --OC(O)NR.sup.12 R.sup.12 ;
  • l) --OC(O)OR.sup.18 ;
  • m) --SR.sup.13 ;
  • n) --S(O)R.sup.13 ;
  • o) --S(O).sub.2 R.sup.13 ;
  • p) --S(O).sub.2 NR.sup.12 R.sup.12 ;
  • q) --NR.sup.12 R.sup.12 ;
  • r) --NHC(O)R.sup.16 ;
  • s) --NHS(O).sub.2 R.sup.13 ;
  • t) --N.sub.3 ;
  • u) --NO.sub.2 ; or
  • v) --halogen;
  • each R.sup.7 is independently H or C.sub.1 or C.sub.6 alkyl;
  • each R.sup.8 is independently H or C.sub.1 or C.sub.6 alkyl;
  • each R.sup.9 is independently H or C.sub.1 or C.sub.6 alkyl;
  • each R.sup.10 is independently H, OH, C.sub.1 to C.sub.4 alkoxy or C.sub.1 to C.sub.4 alkyl;
  • R.sup.11 is tetrazole;
  • each R.sup.12 is independently H, C.sub.1 to C.sub.6 alkyl, benzyl, or R.sup.14 ;
  • each R.sup.13 is independently C.sub.1 to C.sub.6 alkyl, CF.sub.3, or R.sup.14 ;
  • each R.sup.14 is independently phenyl, mono-substituted phenyl, or di-substituted phenyl wherein the substituents are independently C.sub.1 to C.sub.3 alkyl, C.sub.1 to C.sub.3 perfluoroalkyl, C.sub.1 to C.sub.3 alkoxy, halogen, CN, --C(O)OR.sup.15, or --CH.sub.2 --C(O)OR.sup.15 ;
  • each R.sup.15 is independently H, phenyl, benzyl, or C.sub.1 to C.sub.6 alkyl;
  • each R.sup.16 independently is H, R.sup.13, or (CH.sub.2).sub.m C(O)OR.sup.15 ;
  • each R.sup.18 is independently C.sub.1 to C.sub.6 alkyl, benzyl, or phenyl;
  • m is 0 to 4;
  • r is 0 to 6; and
  • t is 0 to 3.
  • 2. A compound of claim 1, wherein:
  • R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5 and R.sup.6 are each independently selected from:
  • (1) hydrogen;
  • (2) alkyl having 1 to 6 carbon atoms;
  • (3) alkenyl having 2 to 6 carbon atoms;
  • (4) --(CH.sub.2).sub.n M, wherein n is 0 or 1; and r is 1 to 6.
  • 3. A compound of to claim 2, wherein:
  • A is attached to the 6- or 7-position;
  • n is 0; and
  • r is 1 or 2.
  • 4. A compound of claim 3, wherein:
  • A is attached to the 6- or 7-position;
  • R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each independently selected from:
  • (1) hydrogen;
  • (2) alkyl having 1 to 6 carbon atoms;
  • (3) M, wherein M is
  • a) --C(O)OR.sup.15 ;
  • b) --C(O)NR.sup.12 R.sup.12 ;
  • c) --CN;
  • d) --C(O)R.sup.16 ;
  • f) --CF.sub.3 ;
  • h) --tetrazole;
  • i) --OR.sup.12 ;
  • j) --OC(O)R.sup.16 ;
  • m) --SR.sup.13 ;
  • n) --S(O)R.sup.13 ;
  • o) --S(O).sub.2 R.sup.13 ;
  • p) --S(O).sub.2 NR.sup.12 R.sup.12 ;
  • t) --N.sub.3 ; or
  • v) --halogen;
  • R.sup.5 and R.sup.6 are independently selected from:
  • (1) hydrogen;
  • (2) alkyl having 1 to 6 carbon atoms;
  • (3) M, wherein M is
  • a) --C(O)OR.sup.15 ;
  • b) --C(O)NR.sup.12 R.sup.12 ;
  • c) --CN;
  • d) --C(O)R.sup.16 ;
  • f) --CF.sub.3 ;
  • h) --tetrazole;
  • n) --S(O)R.sup.13 ;
  • o) --S(O).sub.2 R.sup.13 ;
  • p) --S(O).sub.2 NR.sup.12 R.sup.12 ;
  • t) --N.sub.3 ;
  • u) --NO.sub.2 ; or
  • v) --halogen;
  • each R.sup.10 is independently H or C.sub.1 to C.sub.4 alkyl; and r is 1.
  • 5. A compound of claim 1 of the formula:
  • ______________________________________ ##STR4##Compound R.sup.5 (CR.sup.9 R.sup.10).sub.r R.sup.11______________________________________71 4'-Cl 7-CH.sub.2 Tetrazol-5-yl72 4'-S(O).sub.2 Me 7-CH.sub.2 Tetrazol-5-yl73 4'-Cl 6-CH.sub.2 Tetrazol-5-yl74 4'-S(O).sub.2 Me 6-CH.sub.2 Tetrazol-5-yl75 4'-S(O).sub.2 Me r = 0 7-(Tetrazol-5-yl)76 4'-S(O).sub.2 Me r = 0 7-(Tetrazol-5-yl)______________________________________
  • 6. A compound of claim 1, which is a pure optical isomer.
  • 7. A compound of claim 6, which is the (+)-isomer.
  • 8. A compound of claim 6, which is the (-)-isomer.
  • 9. A method of inhibiting leukotriene synthesis in a mammal, which comprises administering to a mammal an effective amount of a compound of claim 1.
  • 10. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.
CROSS-REFERENCE

This is a continuation-in-part of Ser. No. 211,800, June 27, 1988, now U.S. Pat. No. 4,906,654, which is a continuation of Ser. No. 76,096, July 21, 1987, now U.S. Pat. No. 4,775,680. U.S. Pat. No. 4,906,654 (Gillard et al.) is incorporated herein by reference in its entirety.

US Referenced Citations (1)
Number Name Date Kind
4316904 Brown et al. Feb 1982
Continuations (1)
Number Date Country
Parent 76096 Jul 1987
Continuation in Parts (1)
Number Date Country
Parent 211800 Jun 1988