Indole cyclohexyl platelet activating factor antagonists

• US 5,643,922 A
• Filed: 07/02/1996
• Issued: 07/01/1997
• Est. Priority Date: 04/19/1995
• Status: Expired due to Fees

• Current Assignee: Abbott Laboratories Incorporated
• Original Assignee: Abbott Laboratories Incorporated
• Inventors: Sheppard, George S., Davidsen, Steven K., Summers, James B.
• Primary Examiner(s): McKane, Joseph
• Assistant Examiner(s): Myers, Jr., Richard S.
• Application Number:
  US08/677,462
• Time in Patent Office: 364 Days
• Field of Search: 514/303, 514/228.5, 514/234.2, 514/256, 546/118, 544/62, 544/127, 544/333
• US Class Current: 514/303
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

The present invention provides compounds of formula ##STR1## and the pharmaceutically acceptable salts thereof which are potent antagonists of PAF and are useful in the treatment of PAF-related disorders including asthma, rhinitis, shock, respiratory distress syndrome, acute inflammation, transplanted organ rejection, gastrointestinal ulceration, allergic skin diseases, delayed cellular immunity, parturition, fetal lung maturation, and cellular differentiation.

Claims

1. A compound of formula ##STR30## or a pharmaceutically acceptable salt thereof wherein R¹ 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) --COOR⁷, wherein R⁷ 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,

--NR⁸ R⁹, where R⁸ and R⁹ are independently selected from hydrogen and

alkyl of one to six carbon atoms,

or R⁸ and R⁹ together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl ring,

--COOR⁷,

--C(O)NR⁸ R⁹, or

--SO₂ NR⁸ R⁹,

(m) --C(O)NR⁸ R⁹,

(n) --OC(O)NR⁸ R⁹,

(o) --NHC(O)NR⁸ R⁹,

(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;

R² is selected from the group consisting of

(a) hydrogen,

(b) alkyl of one to six carbon atoms;

(c) --(CH₂)_p COOR⁷, where p is 0, 1, 2, 3, or 4,

(d) --(CH₂)_q NR⁸ R⁹, where q is 2, 3, or 4,

(e) --(CH₂)_p COR⁷

(f) --(CH₂)_q OR⁷,

(g) --(CH₂)_p SO₂ R⁷,

(h) --(CH₂)_p SO₂ NR⁸ R⁹,

(i) --(CH₂)_p CONR¹⁰ R¹¹, where R¹⁰ and R¹¹ are independently selected from the group consisting of

hydrogen,

alkyl of one to six carbon atoms,

--(CH₂)_r COOR⁷, where r is 1, 2, 3, or 4,

--(CH₂)_r NR⁸ R⁹,

(CH₂)_r OR⁷,

--(CH₂)_r SO₂ R⁷, and

--(CH₂)_r SO₂ NR⁸ R⁹,

or R¹⁰ and R¹¹ taken together define a pyrrolidine, morpholine, or thiomorpholine ring,

(j) --(CH₂)_p CN,

(k) --(CH₂)_p -1H-tetrazo1-5-yl,

(l) --CONHNH₂,

(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;

R³ is selected from the group consisting of hydrogen and alkyl of one to six carbon atoms;

R⁴ 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) alkylthioalkyl 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 is 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

R⁵ and R⁶ 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

R¹ 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,

--COOR⁷, wherein R⁷ is hydrogen, alkyl of one to ten carbon atoms, or phenylalkyl wherein the alkyl portion is of one to four carbon atoms,

--C(O)NR⁸ R⁹,

--OC(O)NR⁸ R⁹,

or 3-furyl, and

or 3-thienyl;

R³, R⁵ and R⁶ are hydrogen; and

R⁴ is alkyl of one to six carbon atoms.

3. A compound or pharmaceutically acceptable salt thereof as defined by claim 2 wherein

R² is selected from the group consisting of

--CONR¹⁰ R¹¹, where R¹⁰ and R¹¹ are independently selected from the group consisting of

hydrogen and

alkyl of one to six carbon atoms, and

--(CH₂)_q OR⁷, wherein q is 2, 3, or 4, and R⁷ is alkyl of one to four carbon atoms.

4. A compound or pharmaceutically acceptable salt thereof as defined by claim 1 selected from the group consisting of

3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1,4-dicarboxylic acid 1-dimethyl amide 4-methyl ester hydrochloride,

6-(4-fluorophenyl)-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride,

6-(4-fluorophenoxy)-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride,

6-phenylmethyl-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride,

6-(4-methoxyphenyl)-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride,

6-(pyrid-3-yl)-3-{[trans-4-[(1H-2-methylimidazo[4,5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride,

5-methoxy-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride,

4-methyl-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride,

4-ethynyl-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl) methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride,

4-(fur-2-yl)-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride,

4-(thien-2-yl)-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride,

4-hydroxy-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride,

4-(N,N-dimethylaminocarbonyloxy)-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride,

4-chloro-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole-1 carboxylic acid dimethyl amide hydrochloride, and

1-(2-ethoxyethyl)-6-(4-fluorophenyl)-3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1-yl]carbonyl}indole hydrochloride.

5. A compound or pharmaceutically acceptable salt thereof as defined by claim 1 selected from the group consisting of:

3-{[trans-4-[(1H-2-methylimidazo[4.5-c]pyrid-1-yl)methylcyclohex-1 -yl]carbonyl}indole-1,4-dicarboxylic acid 1-dimethyl amide 4-methyl ester hydrochloride.

6. 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.

7. 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.