TREA

Diuretic 2,6-diaryl-4-pyridine carboxylic acids

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Information

  • Patent Grant
  • 4474791
  • Patent Number
    4,474,791
  • Date Filed
    Monday, December 13, 1982
    42 years ago
  • Date Issued
    Tuesday, October 2, 1984
    40 years ago
Information
Abstract
The present invention provides novel methods of inducing diuresis and/or an antihypertensive effect employing certain 2,6-diaryl-4-pyridinecarboxylic acid derivatives. Also provided are novel compositions to be used in these methods.
Description

BACKGROUND OF THE INVENTION
The present invention relates to the use of certain 2,6-diaryl-4-pyridine carboxylic acids to induce diuresis and hypertension and provides certain novel compositions for this purpose. The preparation and use of these compounds and compositions is described in U.S. Pat. No. 4,377,586, which is expressly incorporated herein by reference.
PRIOR ART
Many classes of diuretics are known. See, e.g., Goth, Med. Pharma. 9th Ed. (1978); and Goodman and Gillman, The Pharmacological Basis of therapeutics, 5th ed. (1971). 2,6-Diaryl-4-pyridinecarboxylic acids are disclosed as intermediates for anti-malarial compounds in U.S. Pat. Nos. 3,753,997; 3,763,148; 3,764,604; and 3,600,396 and J. Med. Chem., 15:918-922 (1972); J. Med. Chem. 16:1040-1041 (1973); and J. Med. Chem., 15:808-812 (1972).
SUMMARY OF THE INVENTION
The present invention provides
(1) a method for inducing diuresis in a human which comprises administering to said human an amount effective to cause diuresis of a compound of the Formula IIA,
wherein
(1) R.sub.10 is hydrogen or methyl;
(2) R.sub.20 is hydrogen or a pharmacologically acceptable cation;
(3) X.sub.10 is hydrogen or trifluoromethyl;
(4) X.sub.20 is hydrogen, chloro, bromo, iodo, methyl, or trifluoromethyl;
(5) X.sub.30 is phenyl, p-fluorophenyl, phenoxy, p-fluorophenoxy, or thiophenoxy;
(6) X.sub.40 is hydrogen, chloro, fluoro, trifluoromethyl, or methyl; or
(7) X.sub.30 and X.sub.40 when taken together with the phenyl moiety to which they are attached form 2-naphthalenyl, 5,6,7,8-tetrahydro-2-napthalenyl, or 6-chloro-2-naphthalenyl; and
with the following provisos:
(a) at least one of X.sub.10 and X.sub.20 is other than hydrogen;
(b) X.sub.20 is methyl only when X.sub.30 and X.sub.40 form 2-naphthalenyl;
(c) X.sub.30 is thiophenoxy only when X.sub.10 and X.sub.40 are hydrogen; and
(d) X.sub.40 is fluoro only when X.sub.30 is phenyl;
(2) a compound of the Formula III,
wherein
(1) R.sub.10 is hydrogen or methyl;
(2) R.sub.20 is hydrogen or a pharmacologically acceptable cation;
(3) X.sub.21 is chloro, fluoro, bromo, iodo, methyl, or trifluoromethyl;
(4) X.sub.31 is hydrogen, methyl, chloro, bromo, iodo, trifluoromethyl, phenyl, p-fluorophenyl, phenoxy, p-fluorophenoxy, thiophenoxy, or --CH.sub.2 R.sub.50 wherein R.sub.50 is (C.sub.2 -C.sub.7) alkyl;
(5) X.sub.41 is hydrogen, chloro, fluoro, trifluoromethyl, or methyl; or
(6) X.sub.31 and X.sub.41 when taken together with the phenyl moiety to which they are attached form 2-naphthalenyl or 5,6,7,8-tetrahydro-2-naphthalenyl, or 6-chloro-2-naphthalenyl;
(7) X.sub.50 is hydrogen (C.sub.1 -C.sub.4) alkoxy or acetoxy;
with the following provisos:
(a) at least one of X.sub.31 and X.sub.41 is other than hydrogen;
(b) one of X.sub.31 and X.sub.41 is methyl only when the other is methyl;
(c) X.sub.21 and X.sub.31 are chloro, bromo, or trifluoromethyl (being the same or different) only when R.sub.10 or X.sub.50 is other than hydrogen;
(d) X.sub.21 is chloro only when X.sub.41 is not chloro;
(e) X.sub.21 is methyl only when X.sub.31 and X.sub.41 form 2-naphthalenyl;
(f) X.sub.50 is (C.sub.1 -C.sub.4) alkoxy or acetoxy only when X.sub.41 is hydrogen, X.sub.21 is chloro, bromo, iodo, or trifluoromethyl, and X.sub.31 is chloro, bromo, iodo, trifluoromethyl or CH.sub.2 R.sub.50 ;
(g) X.sub.21 is fluoro only when R.sub.10 is methyl and X.sub.31 is chloro;
(h) X.sub.31 is thiophenoxy only when X.sub.41 and X.sub.50 are hydrogen; and
(i) X.sub.41 is fluoro only when X.sub.31 is phenyl;
(3) a pharmaceutical composition comprising:
(a) a compound of the formula II,
wherein
(1) R.sub.10 is hydrogen or methyl;
(2) R.sub.20 is hydrogen or a pharmacologically acceptable cation;
(3) X.sub.10 is hydrogen or trifluoromethyl;
(4) X.sub.20 is hydrogen, chloro, fluoro, bromo, iodo, methyl, or trifluoromethyl;
(5) X.sub.30 is hydrogen, methyl, chloro, bromo, iodo, trifluoromethyl, phenyl, p-fluorophenyl, phenoxy, p-fluorophenoxy, thiophenoxy, or --CH.sub.2 --R.sub.50, wherein R.sub.50 is (C.sub.2 -C.sub.7) alkyl; or
(6) X.sub.40 is hydrogen, chloro, fluoro, trifluoromethyl, or methyl; or
(7) X.sub.30 and X.sub.40 when taken together with the phenyl moiety to which they are attached form 2-naphthalenyl 5,6,7,8-tetrahydro-2-napthalenyl, or 6-chloro-2-naphthalenyl; and
(8) X.sub.50 is hydrogen, (C.sub.1 -C.sub.4) alkoxy or acetoxy;
with the following provisos:
(a) at least one of X.sub.10 and X.sub.20 and at least one of X.sub.30 and X.sub.40 is other than hydrogen;
(b) X.sub.10 is trifluoromethyl only when X.sub.20 is hydrogen, X.sub.30 is hydrogen, and X.sub.40 is trifluoromethyl;
(c) X.sub.40 is chloro only when X.sub.30 is chloro;
(d) one of X.sub.30 and X.sub.40 is methyl only when the other is methyl;
(e) X.sub.20 is methyl only when X.sub.30 and X.sub.40 form 2-naphthalenyl;
(f) X.sub.50 is (C.sub.1 -C.sub.4) alkoxy or acetoxy only when X.sub.10 and X.sub.40 are hydrogen, X.sub.20 is chloro, bromo, iodo, or trifluoromethyl, and X.sub.30 is chloro, bromo, iodo, trifluoromethyl, or CH.sub.2 --R.sub.50 ;
(g) X.sub.20 is fluoro only when R.sub.10 is methyl and X.sub.30 is chloro;
(h) X.sub.30 is thiophenoxy only when X.sub.10, X.sub.40, and X.sub.50 are hydrogen; and
(i) X.sub.40 is fluoro only when X.sub.30 is phenyl; and
(b) a pharmaceutical excipient;
(4) a method for producing an antihypertensive effect in a human which comprises concomittantly administering to said human
(a) an amount effective to induce diuresis of a compound of the formula II
wherein
(1) R.sub.10 is hydrogen or methyl;
(2) R.sub.20 is hydrogen or a pharmacologically acceptable cation;
(3) X.sub.10 is hydrogen or trifluoromethyl;
(4) X.sub.20 is hydrogen, chloro, fluoro, bromo, iodo, methyl, or trifluoromethyl;
(5) X.sub.30 is hydrogen, methyl, chloro, bromo, iodo, trifluoromethyl, phenyl, p-fluorophenyl, phenoxy, p-fluorophenoxy, thiophenoxy, or --CH.sub.2 --R.sub.50, wherein R.sub.50 is (C.sub.2 -C.sub.7) alkyl; or
(6) X.sub.40 is hydrogen, chloro, fluoro, trifluoromethyl, or methyl; or
(7) X.sub.30 and X.sub.40 when taken together with the phenyl moiety to which they are attached form 2-naphthalenyl 5,6,7,8-tetrahydro-2-napthalenyl, or 6-chloro-2-naphthalenyl; and
(8) X.sub.50 is hydrogen, (C.sub.1 -C.sub.4) alkoxy or acetoxy;
with the following provisos:
(a) at least one of X.sub.10 and X.sub.20 and at least one of X.sub.30 and X.sub.40 is other than hydrogen;
(b) X.sub.10 is trifluoromethyl only when X.sub.20 is hydrogen, X.sub.30 is hydrogen, and X.sub.40 is trifluoromethyl;
(c) X.sub.40 is chloro only when X.sub.30 is chloro;
(d) one of X.sub.30 and X.sub.40 is methyl only when the other is methyl;
(e) X.sub.20 is methyl only when X.sub.30 and X.sub.40 form 2-naphthalenyl;
(f) X.sub.50 is (C.sub.1 -C.sub.4) alkoxy or acetoxy only when X.sub.10 and X.sub.40 are hydrogen, X.sub.20 is chloro, bromo, iodo, or trifluoromethyl, and X.sub.30 is chloro, bromo, iodo, trifluoromethyl, or CH.sub.2 --R.sub.50 ;
(g) X.sub.20 is fluoro only when R.sub.10 is methyl and X.sub.30 is chloro;
(h) X.sub.30 is thiophenoxy only when X.sub.10, X.sub.40, and X.sub.50 are hydrogen; and
(i) X.sub.40 is fluoro only when X.sub.30 is phenyl; and
(b) an antihypertensive agent; and
(5) a pharmaceutical composition comprising:
(a) a compound of the formula II;
wherein
(1) R.sub.10 is hydrogen or methyl;
(2) R.sub.20 is hydrogen or a pharmacologically acceptable cation;
(3) X.sub.10 is hydrogen or trifluoromethyl;
(4) X.sub.20 is hydrogen, chloro, fluoro, bromo, iodo, methyl, or trifluoromethyl;
(5) X.sub.30 is hydrogen, methyl, chloro, bromo, iodo, trifluoromethyl, phenyl, p-fluorophenyl, phenoxy, p-fluorophenoxy, thiophenoxy, or --CH.sub.2 --R.sub.50, wherein R.sub.50 is (C.sub.2 -C.sub.7) alkyl; or
(6) X.sub.40 is hydrogen, chloro, fluoro, trifluoromethyl, or methyl; or
(7) X.sub.30 and X.sub.40 when taken together with the phenyl moiety to which they are attached form 2-naphthalenyl 5,6,7,8-tetrahydro-2-napthalenyl, or 6-chloro-2-naphthalenyl; and
(8) X.sub.50 is hydrogen, (C.sub.1 -C.sub.4) alkoxy or acetoxy;
with the following provisos:
(a) at least one of X.sub.10 and X.sub.20 and at least one of X.sub.30 and X.sub.40 is other than hydrogen;
(b) X.sub.10 is trifluoromethyl only when X.sub.20 is hydrogen, X.sub.30 is hydrogen, and X.sub.40 is trifluoromethyl;
(c) X.sub.40 is chloro only when X.sub.30 is chloro;
(d) one of X.sub.30 and X.sub.40 is methyl only when the other is methyl;
(e) X.sub.20 is methyl only when X.sub.30 and X.sub.40 form 2-naphthalenyl;
(f) X.sub.50 is (C.sub.1 -C.sub.4) alkoxy or acetoxy only when X.sub.10 and X.sub.40 are hydrogen, X.sub.20 is chloro, bromo, iodo, or trifluoromethyl, and X.sub.30 is chloro, bromo, iodo, trifluoromethyl, or CH.sub.2 --R.sub.50 ;
(g) X.sub.20 is fluoro only when R.sub.10 is methyl and X.sub.30 is chloro;
(h) X.sub.30 is thiophenoxy only when X.sub.10, X.sub.40, and X.sub.50 are hydrogen; and
(i) X.sub.40 is fluoro only when X.sub.30 is phenyl; and
(b) an antihypertensive agent; and
(c) a pharmaceutical excipient.





DESCRIPTION OF THE PREFERRED EMBODIMENTS
Preferred embodiments of the present invention include:
(1) a method of inducing diuresis employing a compound selected from the group consisting of;
[2-[1,1'-biphenyl]-4-yl-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-methylphenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(5,6,7,8-tetrahydro-2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-chloro-2-methoxyphenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(2-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
2-(6-chloro-2-naphthalenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-[4-(phenylthio)phenyl]-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-[4-(4-fluorophenoxy)phenyl]-4-pyridinecarboxylic acid,
2-(1,1'-biphenyl)-4-yl-6-(4-bromophenyl)-4-pyridinecarboxylic acid, and
2-(4-bromophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid.
(2) novel compounds selected from the group consisting of;
2-(4-chlorophenyl)-6-[3-(trifluoromethyl)phenyl]-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-[3-(trifluoromethyl)phenyl]-4-pyridinecarboxylic acid,
2-[1,1'-biphenyl]-4-yl-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(3,4-dimethylphenyl)-4-pyridinecarboxylic acid,
2,6-bis(4-chlorophenyl)-3-methyl-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4-iodophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4-propylphenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4-phenoxyphenyl-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-[4-(2-phenylthio)phenyl]-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-[4-(2-methylpropyl)phenyl]-4-pyridinecarboxylic acid,
2-(4-methylphenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-butylphenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(5,6,7,8-tetrahydro-2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-[4-(3-methylbutyl)phenyl]-4-pyridinecarboxylic acid,
2-(4-chloro-2-methoxyphenyl)-6-(4-chlorophenyl)-4-pyridine carboxylic acid,
2-[2-(acetyloxy)-4-chlorophenyl]-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(2-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
2-(6-chloro-2-naphthalenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-[4-(phenylthio)phenyl]-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-[4-(4-fluorophenoxy)phenyl]-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4-fluorophenyl)-3-methyl-4-pyridinecarboxylic acid,
2-(1,1'-biphenyl)-4-yl-6-(4-bromophenyl)-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-(4-chlorophenyl)-5-methyl-4-pyridinecarboxylic acid,
2,6-bis[(3-trifluoromethyl)phenyl]-4-pyridinecarboxylic acid, and
2-(4-bromophenyl)-6-(4-chlorophenyl)-4-pyridine carboxylic acid;
(3) a method for inducing an antihypertensive effect employing a compound selected from the group consisting of:
2-(4-chlorophenyl)-6-[3-(trifluoromethyl)phenyl]-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-[3-(trifluoromethyl)phenyl]-4-pyridinecarboxylic acid,
2-[1,1'-biphenyl]-4-yl-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(3,4-dimethylphenyl)-4-pyridinecarboxylic acid,
2,6-bis(4-chlorophenyl)-3-methyl-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4-iodophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4-propylphenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4-phenoxyphenyl-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-[4-(phenylthio)phenyl]-4-pyridine-carboxylic acid,
2-(4-chlorophenyl)-6-[4-(2-methylpropyl)phenyl]-4-pyridinecarboxylic acid,
2-(4-methylphenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-butylphenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(5,6,7,8-tetrahydro-2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-[4-(3-methylbutyl)phenyl]-4-pyridinecarboxylic acid,
2-(4-chloro-2-methoxyphenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-[2-(acetyloxy)-4-chlorophenyl]-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(2-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
2-(6-chloro-2-naphthalenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-[4-(phenylthio)phenyl]-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-[4-(4-fluorophenoxy)phenyl]-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4-fluorophenyl)-3-methyl-4-pyridinecarboxylic acid,
2-(1,1'-biphenyl)-4-yl-6-(4-bromophenyl)-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-(4-chlorophenyl)-5-methyl-4-pyridinecarboxylic acid,
2,6-bis(4-chlorophenyl)-4-pyridinecarboxylic acid,
2,6-bis(4-chlorophenyl)-4-pyridine carboxylic acid, sodium salt hydrate,
2,6-bis[(3-trifluoromethyl)phenyl]-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-(4-chlorophenyl)-4-pyridine carboxylic acid,
1-(4-chlorophenyl)-6-[4-(trifluoromethyl)phenyl]-4-pyridinecarboxylic acid,
2,6-bis[4-(trifluoromethyl)-phenyl]-4-pyridine carboxylic acid,
2,6-bis(4-bromophenyl)-4-pyridine carboxylic acid,
2-(4-chlorophenyl)-6-(3,4-dichlorophenyl)-4-pyridinecarboxylic acid, and
2,6-Bis(4-chlorophenyl)-3-methyl-4-pyridinecarboxylic acid; and
(4) novel pharmaceutical compositions containing a compound selected from the group consisting of
2-(4-chlorophenyl)-6-[3-(trifluoromethyl)phenyl]-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-[3-(trifluoromethyl)phenyl]-4-pyridinecarboxylic acid,
2-[1,1'-biphenyl]-4-yl-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(3,4-dimethylphenyl)-4-pyridinecarboxylic acid,
2,6-bis(4-chlorophenyl)-3-methyl-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4-iodophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4-propylphenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4-phenoxyphenyl-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-[4-(2-phenylthio)phenyl]-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-[4-(2-methylpropyl)phenyl]-4-pyridinecarboxylic acid,
2-(4-methylphenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-butylphenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(5,6,7,8-tetrahydro-2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-[4-(3-methylbutyl)phenyl]-4-pyridinecarboxylic acid,
2-(4-chloro-2-methoxyphenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-[2-(acetyloxy)-4-chlorophenyl]-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(2-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
2-(6-chloro-2-naphthalenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-[4-(phenylthio)phenyl]-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-[4-(4-fluorophenoxy)phenyl]-4-pyridinecarboxylic acid,
2-(4-chlorophenyl)-6-(4-fluorophenyl)-3-methyl-4-pyridinecarboxylic acid,
2-(1,1'-biphenyl)-4-yl-6-(4-bromophenyl)-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-(4-chlorophenyl)-5-methyl-4-pyridinecarboxylic acid,
2,6-bis(4-chlorophenyl)-4-pyridinecarboxylic acid,
2,6-bis(4-chlorophenyl)-4-pyridine carboxylic acid, sodium salt hydrate,
2,6-bis([(3-trifluoromethyl)phenyl]-4-pyridinecarboxylic acid,
2-(4-bromophenyl)-6-(4-chlorophenyl)-4-pyridine carboxylic acid,
1-(4-chlorophenyl)-6-[4-(trifluoromethyl)phenyl]-4-pyridinecarboxylic acid,
2,6-bis[4-(trifluoromethyl)-phenyl]-4-pyridine carboxylic acid,
2,6-bis(4-bromophenyl)-4-pyridine carboxylic acid,
2-(4-chlorophenyl)-6-(3,4-dichlorophenyl)-4-pyridinecarboxylic acid, and
2,6-Bis(4-chlorophenyl)-3-methyl-4-pyridinecarboxylic acid.
Claims
  • 1. A method for inducing diuresis in a human which comprises administering to said human an amount effective to cause diuresis of a compound of the Formula IIA, ##STR1## wherein (1) R.sub.10 is hydrogen or methyl;
  • (2) R.sub.20 is hydrogen or a pharmacologically acceptable cation;
  • (3) X.sub.10 is hydrogen or trifluoromethyl;
  • (4) X.sub.20 is hydrogen, chloro, bromo, iodo, methyl, or trifluoromethyl;
  • (5) X.sub.30 is phenyl, p-fluorophenyl, phenoxy, p-fluorophenoxy, or thiophenoxy;
  • (6) X.sub.40 is hydrogen, chloro, fluoro, trifluoromethyl, or methyl; or
  • (7) X.sub.30 and X.sub.40 when taken together with the phenyl moiety to which they are attached form 2-naphthenyl, or 6-chloro-2-naphthalenyl;
  • with the following provisos:
  • (a) at least one of X.sub.10 and X.sub.20 is other than hydrogen;
  • (b) X.sub.20 is methyl only when X.sub.30 and X.sub.40 form 2-naphthalenyl;
  • (c) X.sub.30 is thiophenoxy only when X.sub.10 and X.sub.40 are hydrogen; and
  • (d) X.sub.40 is fluoro only when X.sub.30 is phenyl.
  • 2. A compound of the Formula III, ##STR2## wherein (1) R.sub.10 is hydrogen or methyl;
  • (2) R.sub.20 is hydrogen or a pharmacologically acceptable cation;
  • (3) X.sub.21 is chloro, fluoro, bromo, iodo, methyl, or trifluoromethyl;
  • (4) X.sub.31 is phenyl, p-fluorophenyl, phenoxy, p-fluorophenoxy, or thiophenoxy;
  • (5) X.sub.41 is hydrogen, chloro, fluoro, trifluoromethyl, or methyl; or
  • (6) X.sub.31 and X.sub.41 when taken together with the phenyl moiety to which they are attached form 2-naphthalenyl or 6-chloro-2-naphthalenyl;
  • (7) X.sub.50 is hydrogen (C.sub.1 -C.sub.4) alkoxy or acetoxy;
  • with the following provisos:
  • (a) X.sub.21 is chloro only when X.sub.41 is not chloro;
  • (b) X.sub.21 is methyl only when X.sub.31 and X.sub.41 form 2-naphthalenyl;
  • (c) X.sub.31 is thiophenoxy only when X.sub.41 and X.sub.50 are hydrogen; and
  • (d) X.sub.41 is fluoro only when X.sub.31 is phenyl.
  • 3. A diuretic composition consisting of:
  • (a) a diuretically effective amount of a compound of the formula II, ##STR3## wherein (1) R.sub.10 is hydrogen or methyl;
  • (2) R.sub.20 is hydrogen or a pharmacologically acceptable cation;
  • (3) X.sub.10 is hydrogen or trifluoromethyl;
  • (4) X.sub.20 is hydrogen, chloro, fluoro, bromo, iodo, methyl, or trifluoromethyl;
  • (5) X.sub.30 is phenyl, p-fluorophenyl, phenoxy, p-fluorophenoxy, or thiophenoxy;
  • (6) X.sub.40 is hydrogen, chloro, fluoro, trifluoromethyl, or methyl; or
  • (7) X.sub.30 and X.sub.40 when taken together with the phenyl moiety to which they are attached form 2-naphthalenyl or 6-chloro-2-naphthalenyl; and
  • (8) X.sub.50 is hydrogen, (C.sub.1 -C.sub.4) alkoxy or acetoxy;
  • with the following provisos:
  • (a) at least one of X.sub.10 and X.sub.20 and at least one of X.sub.30 and X.sub.40 is other than hydrogen;
  • (b) X.sub.20 is methyl only when X.sub.30 and X.sub.40 form 2-naphthalenyl;
  • (c) X.sub.30 is thiophenoxy only when X.sub.10, X.sub.40, X.sub.50 are hydrogen; and
  • (d) X.sub.40 is fluoro only when X.sub.30 is phenyl; and
  • (b) a pharmaceutical excipient.
  • 4. A method for producing an antihypertensive effect in a human which comprises concomittantly administering to said human
  • (a) an amount effective to induce diuresis of a compound of the formula II ##STR4## wherein (1) R.sub.10 is hydrogen or methyl;
  • (2) R.sub.20 is hydrogen or a pharmacologically acceptable cation;
  • (3) X.sub.10 is hydrogen or trifluoromethyl;
  • (4) X.sub.20 is hydrogen, chloro, fluoro, bromo, iodo, methyl, or trifluoromethyl;
  • (5) X.sub.30 is phenyl, p-fluorophenyl, phenoxy, p-fluorophenoxy, or thiophenoxy;
  • (6) X.sub.40 is hydrogen, chloro, fluoro, trifluoromethyl, or methyl; or
  • (7) X.sub.30 and X.sub.40 when taken together with the phenyl moiety to which they are attached form 2-naphthalenyl or 6-chloro-2-naphthalenyl; and
  • (8) X.sub.50 is hydrogen, (C.sub.1 -C.sub.4) alkoxy or acetoxy;
  • with the following provisos:
  • (a) at least one of X.sub.10 and X.sub.20 and at least one of X.sub.30 and X.sub.40 is other than hydrogen;
  • (b) X.sub.20 is methyl only when X.sub.30 and X.sub.40 form 2-nahthalenyl;
  • (c) X.sub.30 is thiophenoxy only when X.sub.10, X.sub.40, and X.sub.50 are hydrogen; and
  • (d) X.sub.40 is fluoro only when X.sub.30 is phenyl; and
  • (b) an antihypertensive agent.
  • 5. An antihypertensive composition consisting of:
  • (a) a diuretically effective amount of a compound of the formula II; ##STR5## wherein (1) R.sub.10 is hydrogen or methyl;
  • (2) R.sub.20 is hydrogen or a pharmacologically acceptable cation;
  • (3) X.sub.10 is hydrogen or trifluoromethyl;
  • (4) X.sub.20 is hydrogen, chloro, fluoro, bromo, iodo, methyl, or trifluoromethyl;
  • (5) X.sub.30 is phenyl, p-fluorophenyl, phenoxy, p-fluorophenoxy, or thiophenoxy;
  • (6) X.sub.40 is hydrogen, chloro, fluoro, trifluoromethyl, or methyl; or
  • (7) X.sub.30 and X.sub.40 when taken together with the phenyl moiety to which they are attached form 2-naphthalenyl or 6-chloro-2-naphthalenyl; and
  • (8) X.sub.50 is hydrogen, (C.sub.1 -C.sub.4) alkoxy or acetoxy;
  • with the following provisos:
  • (a) at least one of X.sub.10 and X.sub.20 and at least one of X.sub.30 and X.sub.40 is other than hydrogen;
  • (b) X.sub.20 is methyl only when X.sub.30 and X.sub.40 form 2-naphthalenyl;
  • (c) X.sub.30 is thiophenoxy only when X.sub.10, X.sub.40, and X.sub.50 are hydrogen; and
  • (d) X.sub.40 is fluoro only when X.sub.30 is phenyl;
  • (b) an antihypertensive agent; and
  • (c) a pharmaceutical excipient.
  • 6. A method of claim 1 wherein the compound of the Formula IIA is selected from the group consisting of
  • 2-[1,1'-biphenyl]-4-yl-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
  • 2-(4-methylphenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(2-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
  • 2-(6-chloro-2-naphthalenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
  • 2-(4-bromophenyl)-6-[4-(phenylthio)phenyl]-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-[4-(4-fluorophenyl)phenyl]-4-pyridinecarboxylic acid,
  • 2-(1,1'-biphenyl)-4-yl-6-(4-bromophenyl)-4-pyridinecarboxylic acid, and
  • 2-(4-bromophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid.
  • 7. A compound of claim 2 selected from the group consisting of
  • 2-[1,1'-biphenyl]-4-yl-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(4-phenoxyphenyl-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-[4-(2-phenylthio)phenyl]-4-pyridinecarboxylic acid,
  • 2-(4-methylphenyl)6-(2-naphthalenyl)4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(2-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
  • 2-(6-chloro-2-naphthalenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
  • 2-(4-bromophenyl)-6-[4-(phenylthio)phenyl]-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-[4-(4-fluorophenoxy)phenyl]-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(4-fluorophenyl)-3-methyl-4-pyridinecarboxylic acid,
  • 2-(1,1'-biphenyl)-4-yl-6-(4-bromophenyl)-4-pyridinecarboxylic acid and,
  • 2-(4-bromophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid.
  • 8. A pharmaceutical composition of claim 3, wherein the compound of the Formula II is selected from the group consisting of
  • 2-[1,1'-biphenyl]-4-yl-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(4-phenoxyphenyl-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-[4-(2-phenylthio)phenyl]-4-pyridinecarboxylic acid,
  • 2-(4-methylphenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(4'-fluoro-[1,1'-biphenyl]-4-yl)-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(2-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
  • 2-(6-chloro-2-naphthalenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
  • 2-(4-bromophenyl)-6-[4-(phenylthio)phenyl]-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-[4-(4-fluorophenoxy)phenyl]-4-pyridinecarboxylic acid,
  • 2-(1,1'-biphenyl)-4-yl-6-(4-bromophenyl)-4-pyridinecarboxylic acid and,
  • 2-(4-bromophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid.
  • 9. A method of claim 1 wherein the compound of the Formula II is selected from the group consisting of
  • 2-[1,1'-biphenyl]-4-yl-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(4-phenoxyphenyl-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-[4-(phenylthio)phenyl]-4-pyridine-carboxylic acid,
  • 2-(4-methylphenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(4'-fluoro-[1,1'-biphenyl]-4yl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(2-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
  • 2-(6-chloro-2-naphthalenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
  • 2-(4-bromophenyl)-6-[4-(phenylthio)phenyl]-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-[4-(4-fluorophenoxy)phenyl]-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(4-fluorophenyl)-3-methyl-4-pyridinecarboxylic acid,
  • 2-(1,1'-biphenyl)-4-yl-6-(4-bromophenyl)-4-pyridinecarboxylic acid, and
  • 2-(4-bromophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid.
  • 10. A pharmaceutical composition of claim 5, wherein the compound of the Formula II is selected from the group consisting of
  • 2-[1,1'-biphenyl]-4-yl-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(4-phenoxyphenyl-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-[4-(2-phenylthio)phenyl]-4-pyridinecarboxylic acid,
  • 2-(4-methylphenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(4'-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-(2-fluoro-[1,1'-biphenyl]-4-yl)-4-pyridinecarboxylic acid,
  • 2-(6-chloro-2-naphthalenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid,
  • 2-(4-bromophenyl)-6-[4-(phenylthio)phenyl]-4-pyridinecarboxylic acid,
  • 2-(4-chlorophenyl)-6-[4-(4-fluorophenoxy)phenyl]-4-pyridinecarboxylic acid,
  • 2-(1,1'-biphenyl)-4-yl-6-(4-bromophenyl)-4-pyridinecarboxylic acid and,
  • 2-(4-bromophenyl)-6-(2-naphthalenyl)-4-pyridinecarboxylic acid.
DESCRIPTION

This application is a division of copending application Ser. No. 259,135, filed Apr. 30, 1982, issued as U.S. Pat. No. 4,377,586.

US Referenced Citations (4)
Number Name Date Kind
3600396 Ash et al. Aug 1971
3753997 Ash et al. Aug 1973
3763148 Ash et al. Oct 1973
3764604 Ash et al. Oct 1973
Non-Patent Literature Citations (3)
Entry
Blumbergs, P. et al., Antimalarials, 2, 2,6--Bis(aryl)--4--pyridinemethanols, 1972, p. 808.
Markovac, A. et al., Antimalarials, 3, 2,6--Bis(aryl)--4--pyridinemethanols, 1972, p. 918.
La Montagne, M. P. et al., Antimalarials, 5, 2--aryl--6--trifluoromethyl--4--pyridine methanols, 1973, p. 1040.
Divisions (1)
Number Date Country
Parent 259135 Apr 1982