CA1179676A - 2,6-diaryl-pyridinecarboxylic acids - Google Patents
2,6-diaryl-pyridinecarboxylic acidsInfo
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- CA1179676A CA1179676A CA000446371A CA446371A CA1179676A CA 1179676 A CA1179676 A CA 1179676A CA 000446371 A CA000446371 A CA 000446371A CA 446371 A CA446371 A CA 446371A CA 1179676 A CA1179676 A CA 1179676A
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Abstract
ABSTRACT
The present invention provides 2 novel method of inducing diuresis by administering certain 2,6-diaryl-4-pyridinecarboxylic acid dertvatives. Also provided are novel compounds and pharmaceutical compositions to be used in this method.
The present invention provides 2 novel method of inducing diuresis by administering certain 2,6-diaryl-4-pyridinecarboxylic acid dertvatives. Also provided are novel compounds and pharmaceutical compositions to be used in this method.
Description
~L'7967~i This is a division of copending Canadian patent application serial number 398,962, filed March 22, 1982.
Back~round of t e Invention .
The present invention relates to a novel method of inducing diuresis in mammals. This invention further provides novel compounds to be used in this method. In particular, the present invention re-lates to the use of certain 2~6-diaryl-4-pyridinecarboxylic acids as diuretics.
Diuretics are agents which incre~se the rate of urine formation, to In particular, they increase net renal excretion of solute ( e.g., electrolytes such as sodium, potassium, chloride, and bicarbonate ions~ and water. They are useful for a variety of pharmacological purposes. The most important such purpose is the treatment of edema, i.e,, the presence o~ excess fluid in the intercellular tissue spaces o~ the body~ Diuretics are also useful in the treatment of certain types of hypertension.
In a healthy individual, a relatiYely constan~ volume of extr~cellular fluid is maintained. Thus, sodium and water excretion by the kidney is adjusted according to the variations in salt and water intake. In certain disease states, however, the rate o~
excretion of sodium and water may be so reduced that even a small daily intake of sodium and water is retalned and this leads to d progressive expansion o~ the volume o~ extracellular ~luid. Disease states which cause the rate of excre~ion of so~lium and water to be 25 reduced include congestive heart ~ailure, cirrhosis of the liver9 and various renal diseases. As a rule, untreated edematous states are characterized by expansion of extracellular fluid volume without distortion of the composition o~ that fluid.
Thus, since the goal of diuretic therapy is the mobilization of edematous fluid in such a manner that the extracellular fluid is restored toward normal~ in terms of both volume and compositionj it would be advantageous to employ diureti~ agents which have little or no effect on electrolyte concentrations~
A number of diuretic agents are known. These include mercurial diuretics, thiazide diuretics, "loop" diuretics, osmotic diuretics, and carbonic anhydrase inhibitors. Other diuretics include furosemide, ethacrynic acid, spironolactone, and triamterene. See Goth Medical Pharmacology, 9th Edition (1978~, and Goodman an 1~7~676 Gillman~ The Pharmacological Basis of Therapeutics, 5th Edition ( l9il ) ~
One problem with the prior ar~ diuretic agents is that generally the more potent the diuretic, the more it tends to distort the e1ec-trolyte composition of the extracellular fluid. Spironolactone andtriamterene conserve potassium, buk they are not very potent when used alone. The mercurial diurétics also do not greatly effect the potassium balanee, but they mus~ be administered intramuscularly.
Mercurial dicuretics have many undesirable side effects. They can cause an accumulation of mercury, which is highly toxic.
The 2,~-diaryl-pyridinecarboxylic acids of the present invention are trivially named as bis-aryl-isonicotinic acids. Some of the isonicotinic acids of the present invention are known and have been disclosed as useful as intermediates in the production of anti-mal~rial compounds. See M.P. LaMontagne, et al., J. Med. Chem.16:1040-1041 (1973), P. Blumbergs et al., J. Med. Chem. 15:808-812 (1972); A. Markovac, J. Med. Chem. 15:918-922 (1972); and U,S. Patents 3,753,997; 3,763,148; and 3,600,396.
The compounds employed in the method of the present invention are derivatives of 2,6-diphenylisonicotinic acid, which has the chemical structure and numbering as shown in Formula I. This compound is named
Back~round of t e Invention .
The present invention relates to a novel method of inducing diuresis in mammals. This invention further provides novel compounds to be used in this method. In particular, the present invention re-lates to the use of certain 2~6-diaryl-4-pyridinecarboxylic acids as diuretics.
Diuretics are agents which incre~se the rate of urine formation, to In particular, they increase net renal excretion of solute ( e.g., electrolytes such as sodium, potassium, chloride, and bicarbonate ions~ and water. They are useful for a variety of pharmacological purposes. The most important such purpose is the treatment of edema, i.e,, the presence o~ excess fluid in the intercellular tissue spaces o~ the body~ Diuretics are also useful in the treatment of certain types of hypertension.
In a healthy individual, a relatiYely constan~ volume of extr~cellular fluid is maintained. Thus, sodium and water excretion by the kidney is adjusted according to the variations in salt and water intake. In certain disease states, however, the rate o~
excretion of sodium and water may be so reduced that even a small daily intake of sodium and water is retalned and this leads to d progressive expansion o~ the volume o~ extracellular ~luid. Disease states which cause the rate of excre~ion of so~lium and water to be 25 reduced include congestive heart ~ailure, cirrhosis of the liver9 and various renal diseases. As a rule, untreated edematous states are characterized by expansion of extracellular fluid volume without distortion of the composition o~ that fluid.
Thus, since the goal of diuretic therapy is the mobilization of edematous fluid in such a manner that the extracellular fluid is restored toward normal~ in terms of both volume and compositionj it would be advantageous to employ diureti~ agents which have little or no effect on electrolyte concentrations~
A number of diuretic agents are known. These include mercurial diuretics, thiazide diuretics, "loop" diuretics, osmotic diuretics, and carbonic anhydrase inhibitors. Other diuretics include furosemide, ethacrynic acid, spironolactone, and triamterene. See Goth Medical Pharmacology, 9th Edition (1978~, and Goodman an 1~7~676 Gillman~ The Pharmacological Basis of Therapeutics, 5th Edition ( l9il ) ~
One problem with the prior ar~ diuretic agents is that generally the more potent the diuretic, the more it tends to distort the e1ec-trolyte composition of the extracellular fluid. Spironolactone andtriamterene conserve potassium, buk they are not very potent when used alone. The mercurial diurétics also do not greatly effect the potassium balanee, but they mus~ be administered intramuscularly.
Mercurial dicuretics have many undesirable side effects. They can cause an accumulation of mercury, which is highly toxic.
The 2,~-diaryl-pyridinecarboxylic acids of the present invention are trivially named as bis-aryl-isonicotinic acids. Some of the isonicotinic acids of the present invention are known and have been disclosed as useful as intermediates in the production of anti-mal~rial compounds. See M.P. LaMontagne, et al., J. Med. Chem.16:1040-1041 (1973), P. Blumbergs et al., J. Med. Chem. 15:808-812 (1972); A. Markovac, J. Med. Chem. 15:918-922 (1972); and U,S. Patents 3,753,997; 3,763,148; and 3,600,396.
The compounds employed in the method of the present invention are derivatives of 2,6-diphenylisonicotinic acid, which has the chemical structure and numbering as shown in Formula I. This compound is named
2~6-diphenyl-4-pyridinecarboxylic acid using the Chemical Abstracts numbering system. (See Naming and Indexing of Chemical Substances ~or Chemical Abstracts Durlng the 9th Collective Period, a reprlnt of Section 4 from the Chemical Abstacts Vol. 76 Index Guide (1972-1976).) Prior Art Many ~lasses o~ diuretics are known. See, e.g. 9 Goth, Med.
Pharma. 9th Ed. (1978); and Goodman and Gillman, The Pharmacological Basis of Therapeutics, 5th ed~ (1971). 2~6-Diaryl-4-pyridinecar-boxylic acids are disclosed as intermediates for anti-malarial compounds in U.S. Patents 3,753-,997; 3,763,148; 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~.
Summa~y of the Invention 3S The present invention provides 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 II, wherein 13 Rlo is hydrogen or methyl;
:, ~1~7~36'76
Pharma. 9th Ed. (1978); and Goodman and Gillman, The Pharmacological Basis of Therapeutics, 5th ed~ (1971). 2~6-Diaryl-4-pyridinecar-boxylic acids are disclosed as intermediates for anti-malarial compounds in U.S. Patents 3,753-,997; 3,763,148; 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~.
Summa~y of the Invention 3S The present invention provides 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 II, wherein 13 Rlo is hydrogen or methyl;
:, ~1~7~36'76
-3--2) R20 is hydrogen or a pharmacological1y acceptable cation, 3) XlO is hydrogen or trifluoromethyl;
4) X20 is hydrogen, chloro, f1uoro, bromo, ;odo, methyl, or trifluoromethyl;
5~ X30 is hydrogen, methyl, chloro, bromo, iodo, trifluoro-me~hyl, phenyl, p-fluorophenyl, phenoxy, p-fluorophenoxy, thiophenoxy, or -CH2-Rso~ wherein Rso is (C2-C7) alkyl;
6) X40 is hydrogen, chloro, fluoro, trifluoromethyl, or methyl, or
7) X30 and X40 when taken together with the phenyl moiety to which they are attached ~orm 2-naph~halenyl, 5,6,7,8-tetrahydro-2-naphthalenyl, or 6-chloro-2-naphthalenyl;
83 Xso is hydrogen, (Cl-C4) alkoxy or acetoxy; and with the following provisos:
a) at least one of XlO and X20 and at least one of X30 and X40 is other than hydrogen;
b) Xl~ is trifluoromethyl only when X20 is hydrogen, X30 is hydrogen, and X40 is trifluoromethyl;
c) X40 is chloro only when X30 is chloro;
d~ one of X30 and X40 is methyl only when the other is methyl;
e) X20 is methyl only when X30 and X40 form 2-naphthalenyl;
f) XcO is (Cl-C4) alkoxy or acetoxy only when XlO and X~0 are hydrogen, X20 is chloro, bromo, iodo~ or trifluaromethyl, and X30 is chloro, bromo, iodo, trifluororrlethyl, or CH2-Rso~
y) X20 is fluoro only when Rlo is methyl and X30 is chloro;
h) X30 iS thiophenoxy only when XlO, X~0, and Xso are hydrogen; and i) X40 is fluoro only when X30 is phenyl.
This invention also provides a compound of the Formula III, wherei n 13 Rlo is hydrogen or methyl;
2) R20 is hydrogen or a pharmacologically acceptable cation;
3) X2l is chloro, fluoro, bromo~ iodo, methyl, or trifluoro~
methyl, 4) X3l is hydrogen, mekhyl, chloro, bromo, iodo, trifluoro-methyl, phenyl, p-fluorophenyl, phenoxy, p-~luorophenoxy, thiophenoxy, or -CH2Rso wherein R50 is (C2-C7) alkyl;
1~7~76 .
53 X4l is hydrogen, chloro, ~luoro, trifluoromethyl, or methyl;
or 6~ X3l and X~l when taken together with the phenyl moiety to which they are attached form 2-naphthalenyl or 5,6,7,8-tetrahydro-2-naphtha1enyl, or 6-chloro-2-naphthalenyl;
7) X50 is hydrogen, (Cl-C4~ alkoxy or acetoxy; and with the following provisos:
a) at least one of X3l and X4l is other than hydrogen;
b) one of X3l and X4l is methyl onl~ when the other is methylj c) X2l and X3l are chlorol bromol or trifluoromethyl (being the same or different) only when R1o or Xso is other than hydrogen;
d) X2l ~s chloro only when X4l is not chloro, e) X2I is methyl only when X3l and X4l farm 2-naphthalenyl, 1~f) Xso is (Cl-C4) alkoxy or acetoxy only when X4l is ; hydrogen, X21 is chloro, bromo, iodo, or trifluoromethyl, X3l is chloro, bromo, iodo, trifluoromethyl, or CH2R50;
g) X21 is fluoro only when Rlo is methyl and X3l is chloro;
h) X3l is thiophenoxy only when X4l and X50 are hydrogen;
and i) X41 is fluoro only when X3l is phenyl.
This invention also provides:
1) a pharmaceutical compos1tlon ComprisincJ
- a) a compound of the Formula II, wherein all variables are defined as given above; and b) a pharmaceutical exclpient;
2) A method for producing an antihypertensive ef~ect in a human which comprises concomittantly administering to said human a) an amount e~fective to induce diuresis of a compound of the formula il, wherein all variables are defined as given above; and b) an antihypertensive agent, and 3~ A pharmaceutical composition comprising:
a~ a compound of the formula II, wherein all variables are as defined above;
35b) an antihypertensive agent; and c~ a pharmaceutical excipient.
The compounds of the present invention are administered orally or parenterally, (e.g., intravenously~ intraperitoneally, or intramuscu-larly). The preferred route of administration is oral, An amount ef~ective to induce diuresis of the compounds of the present invention when administered orally is typically from OoOl to 30 mg per kg daily, administered in a single dose or from 2 to 4 times ~aily~ When other routes of administration are used, equivalent dosages are employed.
The dosage regimen for inducing diuresis using the method of the present invention is selected in accordance with a variety of factors, including the type, age, weight, sex, and medical condition of the mammal, the severity of the condition being treated, and the particular compound employed. An ordinarily skilled physician will readily determine and prescribe the correct amount of the compound to induce the desired level of diuretic response. In so proceeding, the physician could employ relatively low dosages at first, assessing the patient's response, subsequently increasing the dose until the maximum desired response is obtained. For example when diuresis is employed in treating moderate hypertension (diastolic pressure less than 100 mm of mercury3 relatively low doses may prove fully effective, while severely hypertensive patients will ordinarily require larger doses to achieve a correspondingly greater antihypertensive e~fect.
When the compounds of the present invention are administered srally, they are ~ormulated as tablets, capsules, or as liqu~d preparations, with the usual pharmaceutical carriers, binders, and the like. For parenteral administration, pharmaceutically acceptable sterile suspensions or solutions are preferred.
The compounds of the present invention may also be administered rectally or vaginally in forms such as suppositories or bougies.
The compounds of the present invention may be combined with other diuretics such as hydrochlorothiazideg trichloromethiazide, furose-mide, ethoxzolamide, chlorthalidone, triamterene, spironolactone, andthe like. They may also be combined with anti-hypertensive agents such as reserpine, deserpidine, hydralazine hydrochloride, mecamyla-mine hydrochloride, guanethidine sulfate, methyldopa, pentaerythritol tetranitrate, minoxidil, clonidine, prazosin, propranolol, angio-tensin I converting enzyme inhibitor, and the like. They may also be com-bined with sedatives and tranquilizers such as butobarbital, amobarbi-tal, phenobarbital, chlordiazepoxide hydrochloride, chlorpromazine, thioridazine, rneprobamate, haloperidol, triazolam, alprazolam, diaze-~'7~367 pam and the like.
An ordinarily skilled physician will readily determine the necessity of employing a diuretic agent such as the compounds dis-closed herein with the other diuretics, anti-hypertensive agents, sedatives and tranquilizers, based upon the patient's particular medical needs and the condition being treated.
It has been suprisingly and unexpectedly found that the compounds of the present invention represent potent oral diuretics which virtually do not distort the electrolyte balance of extracellular fluid.
The compounds of the present invention induce diuresis in rats by oral administration. By measuring the volume and electrolyte con-centration of the urine of rats dosed orally with the compounds of the present invention versus the volume and electrolyte concentration of the urine of untreated control rats, the compounds of the present invention exhibit a greatly increased excretion of: ~1) fluid volume, (~) sodium ions and (3) chloride ions, while the total amount of potassium excretion remains virtually unchangedO Thus the method and compounds of the present invention represent a surprisingly and unexpectedly potent and efficacious means of inducing diuresis and natriuresis (sodium lon excretion) without the kaliuretic ~potassium ion excreting) side effect of other ora~ diuretic methods. Because of the diuretic and natriure~ic activity in khe absence o~ kaliuretic - activity the compounds of this invention do not distort electrolyte concentration or composition of body ~luids.
The compounds oF the present invention are prepared by the pro-cess as depicted in Chart A- Xlo~ X20~ X30, X40, X503 and Rlo are defined as above. R60 is hydrogen or alkyl of one to four carbon atoms. This process is essentially the process disclosed in J. Med.
Chem. 15:~08 (1972) and J. Med. Chem. 15:918 (1972~. A pyridinium salt of the Formula X is reacted with an aroyl acrylic acid or ester of the Formula XI in the presence of ammonium acetate in a suitable solvent such as methanol to yield a compound of the Formula XIIq When an ester o~ the Formula XI is used as the starting material, the ester moiety is removed by well known means to yield the Formula XII acid.
The Formula XII acid may be purified by forming the corresponding ester, purifying the ester by conventional means (e.g., chromatography or crystallization), saponifying the ester, and recrystallizing the ~ 7~367~
-acid. Formula XII includes all of the Formula II acids within its scope, and as well as all of the Formula III acids. ~hen R1o is methyl, R60 is other than hydrogen. Pharmacologically acceptable salts are prepared by well known means~ The pyridinium salts and aroyl acrylic acids are prepared from readily available acetophenones by the methods disclosed in the references cited above.
The carbon atom content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in ~he moiety, i.e., the prefix (Cj Cj3 indicates a moiety of the integer "i" to the integer "j" carbon atoms9 inclusive. Thus ~Cl-C3)alkyl refers to alkyl of one to 3 carbon atoms, inclusive, or methyl, ethyl, propyl3 and isopropyl.
Examples of alkyl of from 2 to 7 carbon atoms includes ethyl, propyl, butyl, pentyl, hexyl, heptyl, and isomeric forms thereofO
Examples of alkoxy of from one to 4 carbon atoms include methoxy, ethoxy, propoxy, butoxy, and isomeric forms thereof, Pharmacologically acceptable cations of the present invention include the pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.
Especially preferred metal cations are those derived ~rom the alkali metals, e~g., lithium, sodium, and potassium; and ~rom the alkaline earth metals, e.g., magnesium and calcium~ although cationic forms of other metals, e.g., alum1num, zinc3 and iron are within the scope of this invention.
Pharmacologically acceptable amine cations are those derived from prirnary, secondary, or tertiary amines. Examples oF suitable amines are methylamine, dimethylamineg trimethylamine, ethylamine, dibutyl-~mine, triisopropylamine, N methylhexylamine, decylamine5 dodecyla-mine, allylamine, crotylarnine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, ~-phenylethylamine, ~-phenylethylamine, ethylenediamine, diethylenetriamine, and the like aliphatic, cycloali phatio, araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, mor-pholine, pyrrolidine, piperazine9 and lower-alkyl derivatives thereof~
e.g., 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like, as well as amines containing water-solubilizing or hydro-philic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanol-- ~7~ 76
83 Xso is hydrogen, (Cl-C4) alkoxy or acetoxy; and with the following provisos:
a) at least one of XlO and X20 and at least one of X30 and X40 is other than hydrogen;
b) Xl~ is trifluoromethyl only when X20 is hydrogen, X30 is hydrogen, and X40 is trifluoromethyl;
c) X40 is chloro only when X30 is chloro;
d~ one of X30 and X40 is methyl only when the other is methyl;
e) X20 is methyl only when X30 and X40 form 2-naphthalenyl;
f) XcO is (Cl-C4) alkoxy or acetoxy only when XlO and X~0 are hydrogen, X20 is chloro, bromo, iodo~ or trifluaromethyl, and X30 is chloro, bromo, iodo, trifluororrlethyl, or CH2-Rso~
y) X20 is fluoro only when Rlo is methyl and X30 is chloro;
h) X30 iS thiophenoxy only when XlO, X~0, and Xso are hydrogen; and i) X40 is fluoro only when X30 is phenyl.
This invention also provides a compound of the Formula III, wherei n 13 Rlo is hydrogen or methyl;
2) R20 is hydrogen or a pharmacologically acceptable cation;
3) X2l is chloro, fluoro, bromo~ iodo, methyl, or trifluoro~
methyl, 4) X3l is hydrogen, mekhyl, chloro, bromo, iodo, trifluoro-methyl, phenyl, p-fluorophenyl, phenoxy, p-~luorophenoxy, thiophenoxy, or -CH2Rso wherein R50 is (C2-C7) alkyl;
1~7~76 .
53 X4l is hydrogen, chloro, ~luoro, trifluoromethyl, or methyl;
or 6~ X3l and X~l when taken together with the phenyl moiety to which they are attached form 2-naphthalenyl or 5,6,7,8-tetrahydro-2-naphtha1enyl, or 6-chloro-2-naphthalenyl;
7) X50 is hydrogen, (Cl-C4~ alkoxy or acetoxy; and with the following provisos:
a) at least one of X3l and X4l is other than hydrogen;
b) one of X3l and X4l is methyl onl~ when the other is methylj c) X2l and X3l are chlorol bromol or trifluoromethyl (being the same or different) only when R1o or Xso is other than hydrogen;
d) X2l ~s chloro only when X4l is not chloro, e) X2I is methyl only when X3l and X4l farm 2-naphthalenyl, 1~f) Xso is (Cl-C4) alkoxy or acetoxy only when X4l is ; hydrogen, X21 is chloro, bromo, iodo, or trifluoromethyl, X3l is chloro, bromo, iodo, trifluoromethyl, or CH2R50;
g) X21 is fluoro only when Rlo is methyl and X3l is chloro;
h) X3l is thiophenoxy only when X4l and X50 are hydrogen;
and i) X41 is fluoro only when X3l is phenyl.
This invention also provides:
1) a pharmaceutical compos1tlon ComprisincJ
- a) a compound of the Formula II, wherein all variables are defined as given above; and b) a pharmaceutical exclpient;
2) A method for producing an antihypertensive ef~ect in a human which comprises concomittantly administering to said human a) an amount e~fective to induce diuresis of a compound of the formula il, wherein all variables are defined as given above; and b) an antihypertensive agent, and 3~ A pharmaceutical composition comprising:
a~ a compound of the formula II, wherein all variables are as defined above;
35b) an antihypertensive agent; and c~ a pharmaceutical excipient.
The compounds of the present invention are administered orally or parenterally, (e.g., intravenously~ intraperitoneally, or intramuscu-larly). The preferred route of administration is oral, An amount ef~ective to induce diuresis of the compounds of the present invention when administered orally is typically from OoOl to 30 mg per kg daily, administered in a single dose or from 2 to 4 times ~aily~ When other routes of administration are used, equivalent dosages are employed.
The dosage regimen for inducing diuresis using the method of the present invention is selected in accordance with a variety of factors, including the type, age, weight, sex, and medical condition of the mammal, the severity of the condition being treated, and the particular compound employed. An ordinarily skilled physician will readily determine and prescribe the correct amount of the compound to induce the desired level of diuretic response. In so proceeding, the physician could employ relatively low dosages at first, assessing the patient's response, subsequently increasing the dose until the maximum desired response is obtained. For example when diuresis is employed in treating moderate hypertension (diastolic pressure less than 100 mm of mercury3 relatively low doses may prove fully effective, while severely hypertensive patients will ordinarily require larger doses to achieve a correspondingly greater antihypertensive e~fect.
When the compounds of the present invention are administered srally, they are ~ormulated as tablets, capsules, or as liqu~d preparations, with the usual pharmaceutical carriers, binders, and the like. For parenteral administration, pharmaceutically acceptable sterile suspensions or solutions are preferred.
The compounds of the present invention may also be administered rectally or vaginally in forms such as suppositories or bougies.
The compounds of the present invention may be combined with other diuretics such as hydrochlorothiazideg trichloromethiazide, furose-mide, ethoxzolamide, chlorthalidone, triamterene, spironolactone, andthe like. They may also be combined with anti-hypertensive agents such as reserpine, deserpidine, hydralazine hydrochloride, mecamyla-mine hydrochloride, guanethidine sulfate, methyldopa, pentaerythritol tetranitrate, minoxidil, clonidine, prazosin, propranolol, angio-tensin I converting enzyme inhibitor, and the like. They may also be com-bined with sedatives and tranquilizers such as butobarbital, amobarbi-tal, phenobarbital, chlordiazepoxide hydrochloride, chlorpromazine, thioridazine, rneprobamate, haloperidol, triazolam, alprazolam, diaze-~'7~367 pam and the like.
An ordinarily skilled physician will readily determine the necessity of employing a diuretic agent such as the compounds dis-closed herein with the other diuretics, anti-hypertensive agents, sedatives and tranquilizers, based upon the patient's particular medical needs and the condition being treated.
It has been suprisingly and unexpectedly found that the compounds of the present invention represent potent oral diuretics which virtually do not distort the electrolyte balance of extracellular fluid.
The compounds of the present invention induce diuresis in rats by oral administration. By measuring the volume and electrolyte con-centration of the urine of rats dosed orally with the compounds of the present invention versus the volume and electrolyte concentration of the urine of untreated control rats, the compounds of the present invention exhibit a greatly increased excretion of: ~1) fluid volume, (~) sodium ions and (3) chloride ions, while the total amount of potassium excretion remains virtually unchangedO Thus the method and compounds of the present invention represent a surprisingly and unexpectedly potent and efficacious means of inducing diuresis and natriuresis (sodium lon excretion) without the kaliuretic ~potassium ion excreting) side effect of other ora~ diuretic methods. Because of the diuretic and natriure~ic activity in khe absence o~ kaliuretic - activity the compounds of this invention do not distort electrolyte concentration or composition of body ~luids.
The compounds oF the present invention are prepared by the pro-cess as depicted in Chart A- Xlo~ X20~ X30, X40, X503 and Rlo are defined as above. R60 is hydrogen or alkyl of one to four carbon atoms. This process is essentially the process disclosed in J. Med.
Chem. 15:~08 (1972) and J. Med. Chem. 15:918 (1972~. A pyridinium salt of the Formula X is reacted with an aroyl acrylic acid or ester of the Formula XI in the presence of ammonium acetate in a suitable solvent such as methanol to yield a compound of the Formula XIIq When an ester o~ the Formula XI is used as the starting material, the ester moiety is removed by well known means to yield the Formula XII acid.
The Formula XII acid may be purified by forming the corresponding ester, purifying the ester by conventional means (e.g., chromatography or crystallization), saponifying the ester, and recrystallizing the ~ 7~367~
-acid. Formula XII includes all of the Formula II acids within its scope, and as well as all of the Formula III acids. ~hen R1o is methyl, R60 is other than hydrogen. Pharmacologically acceptable salts are prepared by well known means~ The pyridinium salts and aroyl acrylic acids are prepared from readily available acetophenones by the methods disclosed in the references cited above.
The carbon atom content of various hydrocarbon containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in ~he moiety, i.e., the prefix (Cj Cj3 indicates a moiety of the integer "i" to the integer "j" carbon atoms9 inclusive. Thus ~Cl-C3)alkyl refers to alkyl of one to 3 carbon atoms, inclusive, or methyl, ethyl, propyl3 and isopropyl.
Examples of alkyl of from 2 to 7 carbon atoms includes ethyl, propyl, butyl, pentyl, hexyl, heptyl, and isomeric forms thereofO
Examples of alkoxy of from one to 4 carbon atoms include methoxy, ethoxy, propoxy, butoxy, and isomeric forms thereof, Pharmacologically acceptable cations of the present invention include the pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.
Especially preferred metal cations are those derived ~rom the alkali metals, e~g., lithium, sodium, and potassium; and ~rom the alkaline earth metals, e.g., magnesium and calcium~ although cationic forms of other metals, e.g., alum1num, zinc3 and iron are within the scope of this invention.
Pharmacologically acceptable amine cations are those derived from prirnary, secondary, or tertiary amines. Examples oF suitable amines are methylamine, dimethylamineg trimethylamine, ethylamine, dibutyl-~mine, triisopropylamine, N methylhexylamine, decylamine5 dodecyla-mine, allylamine, crotylarnine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, ~-phenylethylamine, ~-phenylethylamine, ethylenediamine, diethylenetriamine, and the like aliphatic, cycloali phatio, araliphatic amines containing up to and including about 18 carbon atoms, as well as heterocyclic amines, e.g., piperidine, mor-pholine, pyrrolidine, piperazine9 and lower-alkyl derivatives thereof~
e.g., 1-methylpiperidine, 4-ethylmorpholine, 1-isopropylpyrrolidine, 2-methylpyrrolidine, 1,4-dimethylpiperazine, 2-methylpiperidine, and the like, as well as amines containing water-solubilizing or hydro-philic groups, e.g., mono-, di-, and triethanolamine, ethyldiethanol-- ~7~ 76
-8-amine~ N-butylethano7amine, 2-amino-2-ethyl-1,3-butylethanolamine, 2-amino-1-butanol, 2-amino-2-ethyl-1,3-propanediol, 2-amino-2-methyl-1-propanol, tris(hydroxymethyl)aminomethane, N-phenylethanolamine, N-~p-tert-amylphenyl)-diethanolamine, glactamine, N-methylglycamine, N-methylglucosamine, ephedrine, phenylephrine, epinephrine, procaine, and the like.
Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, ben-zyltrimethylammonium, phenyltriethylammonium, and the like.
The diuretic compounds of the present invention may be formulated into pharmaceutical compositions, employing a pharmaceutically acceptable carrier.
The pharmaceutical forms contemplated by this invention include pharmaceutical compositions suitable for oral, parenteral, vaginal, and rectal use, e.g.~ tablets, powder packets, cachets, dragees, capsules, solutions, suspensions, sterile injectable forms, suppositories, bougies, and the like. Suitable diluents or carriers such as carbohydrates (lactose), proteins, lipids, calcium phosphate, cornstarch, stearic acid, methylcellulose and the like may be used as carriers or for coating purposes. Oil, e.g., coconut oil, sesame oil, safflower oil, cottonseed oil 7 peanut oil may be used for preparing solutions or suspensions of the active drug. Sweetening, coloring and flavoring agents may be added. By "pharmaceutical excipient" is meant any of these and similar well known forms of drug formulatlons.
When used in conjunction with antihypertenslve therapy, the compounds may be formulated with antihypertensive agents by means well known in the art, employing a pharmaceutical excipient as defined above.
2,6-bis(4-Chlorophenyl)-4-pyridinecarboxylic acid is the most pre~erred compound for use in the methods of this invention.
Description of the Preferred Embodiments The novel compounds of the present invention are all prepared by the procedures illustrated by the Examples given below.
xample 1 2-(4-chlorophenyl)-6-~3-(trifluoromethyl)phenyl]-4-pyridinecarboxylic acid (Formula III: X2l is chloro, X41 is trifluoromethyl, and X31, X50, Rlo and R20 are hydrogen) A mixture of 3.5 g (0.01 mole) of m-trifluoromethylphenacylpy-~L~t7~
g ridinium bromide, 2.1 9 (0.01 mole) of p-chlorobenzoylacrylic acid and 6 9 of ammonium acetate and 10 ml of glacial acetic acid and 1 ml of ace~ic anhydride is heated at 120-130 C for 4 hr. The reaction mixture is cooled and diluted with 35 ml of water. The solid is then collected and partitioned between 150 ml of 2% potassium carbonate and chloroform. The agueous layer is extracted with chloroform and then ether. This aqueous layer is concentrated and treated with acetic acid to yield a gummy solid which is triturated with ether. This solid is then collected and recrystallized from ethanol-water to yield 1.3 9 (34.4%) of the titled solid with a melting point of 222 C. The C:H:N:Cl ratio is 60.69:3.03:3.79:9.42.
Example 2 2-(4-bromophenyl)-6-[3-(trifluoromethyl)phenyl]-4-pyridinecarboxylic acid (Formula III: X2l is bromo, X4l is trifluoromethyl~ X3l, Xso~ Rlo and R20 are hydrogen) A mixture of 2.0 9 ~0.0079 mole) of p-bromobenzoylacrylic acid, 2.7~ 9 ~0.0079 mole) of m-trifluoromethylphenacylpyridinium bromide and S g of ammonium acetate and 25 ml of methanol and 2.5 ml of glacial acetic acid is stirred at reflux for 6 hr. The mixture is concentrated in vacuo and the residue is treated with 50% acetic acid-water to give a solid which is recrystallized from ethanol yield-ing 1.35 9 (40%) of the titled crystals having a melting point of 233 - 234 C., The C:H:N ratio is 54.40:2.57:3.21.
Example 3 2-[1,1'-biphenyl~-4-yl-6-(4-chlorophenyl)-4-pyridine-carboxylic acid (Form~la III: X2l is chloro, X3l is phenyl, X41, X5p, Rlol and R20 are hydrogen) A mixture of 3.54 9 (0.01 mole) of the pyridinium salt cor-responding to the titled product, 2.11 9 (0.01 mole) of p-chloro-ben~oylacrylic acid and 8.5 g of ammonium acetate in 20 ml of methanol is s~irred at reflux for 6 hr. The solid is collected and recrys~al-lized from acetic acid-~ater. The yield ;s 3.3 9 (85.5%) of the titled crystals with a melting point of 258-260 C. The C:H:N ratio is 73.45:4.10:3.~Q.
Example 4 2-(4-chlorophenyl)-6-(2-naphthalenyl)-4-pyridinecarbox ylic acid (Formula III: X2l is chloro~ X3l and X
form 2-naphthalenyl, X50, Rlo and R20 are hydrogen) A mixture of 3.3 9 (0~01 mole) of the pyridinium salt cor-responding to the titled product, 2.1 9 (OoOl mole) of p-chloro-7~t~
, benzoylacrylic acid, 5.8 g of ammonium acetate and 10 ml of methanol, 10 ml of glacial acetic acid, and 1.2 ml of acetic anhydride is stir~
red at reflux ~or 1. 5 hr. The reaction is cooled and the solid is collected. The solid is then washed with cold methanol and recrystal-lized from ethyl acetate to yield 1.4 9 (39 ~) of the titled crystalswith a me1ting point of 274-276 C. The C:H:N ratio is 73.23:3.73:4.10.
Example 5 2-(4-chlorophenyl)-6-(394-dimethylphenyl)-4-pyridine-carboxylic acid (Formula III: X2l is chloro, X3l and X41 are methyl, X50, R1o, and R20 are hydrogen) A mixture of 3.06 9 (0.01 mole) Qf the pyridinium salt cor-responding to the titled product, 2.11 9 (0.01 mole~ of p-chloro-benzoylacrylic acid and 8.5 g of ammonium acetate in 20 ml of methanol is stirred at reflux for 6 hr.- The mixture is partitioned between methylene chloride and water and the organic layer is evaporated and the residue is recrystallized from ethanol-water to yield 2.10 9 (62%) of crystals having a melting point of 256-259 C. The C:H:N ratio is 7~.53~4.~9:4.34.
Example 6 2,6-bis(4-chlorophenyl~-3-methyl-4-pyridinecarboxylic acid (Formula III: X2l and X31 are chloro, Rlo is methyl, X41, Xso, and R20 are hydrogen) A mixture of 17 g (0.10 mole~ of p-chloropropiophenone and 17 g of glyoxyllc acid in 2n ml of acetic anhydride containing a drop of N,N-diisopropylethylamine is heated to 135 C. An additional 2 ml of N,N-diisopropylethylamine is added and the reaction ls maintained at 135 C for three hours. The mixture Is concentrated and then diluted with aqueous sodium carbonate. The mixture is then extracted with ether and the aqueous layer is acidified with hydrochloric acid and extracted with methylene chloride. The organic layer is concentrated and the residue is chromatographed on silica gel using 5% CH30H-1%
acetic acid and 94% CH2Cl2. The crude ~-methyl-~-(p-chlorobenzo-yl~acrylic acid is dried in high vacuum yielding 11.2 g of solid. The ethyl ester is prepared by heating this crude solid and 100 ml of absolute alcohol in 3 ml of concentrated sulfuric acid for 1 hr at reflux. This mixture is concentra~ed, the residue is partitioned between sodium carbonate and methylene chloride. The organic layer is dried and concentrated to yield 11.9 g of oil.
A mixture of this oil, 14.7 g ~0.047 mole) of the pyridinium salt ~7~6~76 corresponding ~o the titled product, 40 g of ammonium acetate and 100 ml of methanol is heated at reflux for 6 hr. This mixturP is con-centrated, diluted with water, and the solid is collected. The solid is crystallized from alcohol and chromatographed on silica gel eluting with methylene chloride to yield 9.9 9 (54%) of crystals with a melting point of 87-90 C. The product was recrystallized from ethanol to yield the ethyl ester of the titled product having a melting point 94-95~ C.
The titled product is obtained by hydrolysis of one g of the ethyl ester in warm methanol and 5 ml of 2~% sodium hydroxide solu-tion. This mixture is left at room temperature for 1.5 hr and concentrated. The residue is partitioned between ether and water.
The aqueous layer is acidified and the solid is collected. The product is recrystallized from alcohol yielding 0.60 9 (65%) of the titled crystals with a melting point of 236 C. The C:H:N ratio is 63.78:3.57:4.01.
Example 7 2-(4-chlorophenyl)-6-~4-iodophenyl~-4-pyridinecar-boxylic acid (Formula III: X2l is chloro, X3l is iodo~ X4l, X50, Rlo3 and R20 are hydrogen~
A mixture o~ 1.7 g (0.0042 mole) of p-iodophenacylpyridinium bromide, 0.88 9 (0.0042 mole) of p-chlorobenzoylacrylic acid, 2.44 9 of ammonium acetate, 5 ml of methanol, 4 ml of acetic acid, and 0.4 ml of acetic anhydride is stirred at reflux ~or 1.25 hr. 10 m1 oF
methanol is added and the mixture is cooled and the solid is col-lected. The solid is recrystallized from methanol-acetic acid-water to yield 0.90 g (49%) of the titled crystals with a melting point of 286-287 C. The C:H:N ratio is 49.67:2.68:3.24.
Example 8 2-~4-chlorophenyl)-6-(4-propylphenyl)-4-pyridine-carboxylic acid ~Formula III: X2l is chloro, X3l is n-propyl~ X41~ X5Q3 R1o, and R20 are hydroyen) A mixture of 3~2 g l0.01 mole) of the pyridinium salt cor-responding to the titled product, 2.11 9 (0.01 mole~ of p-chloroben-zoylacrylic acid, and 8.5 g of ammonium acetate and 20 ml of methanol is heated at reflux for 6 hr. The mixture is diluted with water and the semi-solid is extracted into 2% potassium carbonate and ether.
The ether layer is extracted with water and the aqueous layer is acidified with hydrochloric acid to precipitate a solid which is recrystallized frum ethanol-water to yield 1.26 g (36%) of the titled j7 6 crystals with a melting point of 226-227 C. The C:H:N ratio is 72.07:5.40:4.06.
Example 9 2-(4-chlorophenyl)-6-(4-phenoxyphenyl) 4-pyridine-carboxylic acid (Formula III: X2l is chloro~ X3l ;s phenoxy, X41, X50, Rlo, and R20 are hydrogen)-A mixture of 1.85 9 (0.005 mole) of the pyridinium sa1t cor-responding to the titled product, 1.05 9 (0.005 mole) of p chloro-benzoylacrylic acid and 2.7 9 of ammonium acetate in 5 ml of methanol, 5 ml of glacial acetic acid, and 0.5 ml of acetic anhydride is heaked at reflux for 1.5 hr. The reaction is diluted with ice water and the - preci~itate is partitioned between ether and water. The ether ex-tracts are treated with activated carbon, concentrated, and the residue recrystallized from methanol-acetic acid-water to yield O.S g (27.5%~ of the titled crystals with the melting point of 214-215 C.
The C:H:N ratio is 71.86:4.06:3.42.
Example 10 2-(4-chlorophenyl)-6-[4-(phenylthio)phenyl]-4-pyridine-carboxylic acid (Formula III: X21 is chloro, X3l is thiophenoxy1 X41, X50, Rlo, and R20 are hydrogen) A mixture of 3.86 9 (0.01 mole) of the appropriate pyridinium salt, 2.11 9 ~0.01 mole~ of p-chlorobenzoylacrylic acid, 5.4 9 of ammonium acetate, 10 ml of methano1, 10 ml of glacial acetic acid, and 1 ml of acetic anhydride ls heated at reflux for 1.5 hr. The mixture is washed and recrystallized as 1n Example 9 ~o yield ~.0 9 (48%) of the titled crystals having a melting point of 213 216 C. The C:H:N
ratio is 69.01:3.95:3.37.
Example_11 2-(4-chlorophenyl)~6-C4~(2-methylpropyl3phenyl]-4-pyridinecarboxylic acld (Formula III: X 21 is chloro, X31 is 2-methylpropyl, X4l, X50, Rlo~ and Rzo are hydrogen)O
A mixture of 8.65 9 (0.026 mole) of the appropriate pyridinium salt9 5.2~ 9 (0.025 mole) of p-chlorobenzoylacrylic acid and 13.5 9 of ammonium acetate in 25 ml of methanol, 25 ml of glacial acetic acid, and 5 ml of acetic anhydride is heated at reflux for 1.5 hr. The mixture is cooled, diluted with water, and partitioned between aqueous hydrochloric acid and ether. The aqueous layer is extracted with ether and the combined ether layers are treated with activated carbon, filtered, and concentrated. The residue is triturated with acetoni-trile and the solid is collected and recrystallized from methanol-67~
acetic acid-water to yield 4.7 9 (5l%) of the titled crystals with melting point of 220-221 C. The C:H:N ratio is 72.56:5.43:3.80.
Example 12 2-(4-methylphenyl)-6-(2-naphthalenyl~-4-pyridinecarbox ylic acid (formula III: X21 ls methyl, X3l and X
form 2 naphthalenyl, X41, X50, R1o, and R20 are hydrogen) A mixture of 2.92 9 (0.01 mole~ of the appropriate pyridinium salt5 2.26 g (0.01 mole) of ~-(2-naphthoyl)acrylic acid and 8.5 9 of ammon;um acetate in 20 ml of methanol is heated at reflux for 6 hr.
10 The mixture is concentrated and the residue is diluted with water and extracted with methylene chloride. The organic layer is concentrated and the residue is chromatographed on silica gel using 5% methanol-1%
acetic acid - 94% methylene chloride. The product is recrystallized from ethanol yielding 1.14 g (33.6%) of the titled crystals with a melting point of 272-274 C. The C:H:N ratio is 81.32:5,01:4.16.
Example 13 2-(4-butylphenyl)-6-(4-chlorophenyl)-4-pyridinecarbox-ylic acid (Formula III: X21 is chloro, X3l is n-butyl, X41~ Xso~ R1o~ and R20 are hydrogen) A mixture of 8.65 g (0.026 mole) of the appropriate pyridinium salt, 5.Z5 9 (0.025 mole) of p-chlorobenzoylacrylic acid and 13.5 g o-f ammonium acetate in 25 ml of methanol, 25 ml of glacial acetic acid, and 5 ml o-f acetic anhydride ~s heated at reflux for 2.5 hr. The mixture is worked up as in the preceeding Examples ancl recrystallized from methallol:acetic acid:water to yield 2.4 g ~26%) ot the titled crystals with melting polnk o~ 2~9~210 C. The C:H:N ratio is 72~19;5.~4:3-95-Example 14 2-~4-chlorophenyl)-6-(5,6,7,8-tetrahydro-2~naphtha-lenyl)-4~pyridinecarboxylic acid (Formula III: X21 is chloro, X3l and X41 form 5,6,7,8-tetrahydro-2-naph thalenyl, Xso, R1o, and R20 are hydrogen~.
A mixture of 6.6 9 (0.02 mole) of the apprapriate pyridinium salt, 4.2 9 (0.02 mole) of p-chlorobenzoy1acrylic acid and 10.8 9 of ammonium acetate in 20 ml of methanol, 2C ml of glacial acetic acid, and 4 ml of acetic anhydride is heated at reflux for one hr. The mixture is cooled, the solid is collected and washed with cold methanol and recrystallized from methanol:water to yield 2.7 g 137h) of the titled crystals with a melting point of 243-246~ C. The C:H:~
ratio is 72.39:5.28:3.$5 "367 Example 1S 2-(4-ehlorophenyl~-6~C4~(3-methylbutyl)phenyl]-4-pyridinecarboxylic acid (Formula III: X21 is chloro, X31 is 3-me~hylbutYl, X4l, Xso~ R1o~ and R20 are hydrogen).
A mixture of 7.0 9 (0.02 mole) of the appropriate pyridinium salt, 4.3 9 (0.02 mole) of p-chlorobenzoylacry1ic acid and 10.8 9 of ammonium acetate and 20 ml of methanol, 20 ml of glacial acetic acid, and 2 ml of acetic anhydride is heated at reflux for one hr. The mixture is partitioned between ether and water. The ether layer is ; I0 treated with activated carbon, concentrated and the dark gum formed is -triturated with acetonitrile. The solid is collected and recrystal-lized from acetic acid to yield 2.85 9 (37.5 %) of the titled crystals with a melting point of 198-200 C. The C:H:N:Cl ratio is 72.79:5.83:3.37:9.42.
Example 16 2-(4-chloro-2-methoxyphenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid (Formula III: Xso is methoxy, X2l and X3l are chloro~ X41, Rlo, and R20 are hydrogen) The acrylic acid is prepared as described in Example 6. A
mixture of 1.15 g (0.0048 mole~ of khe 4-chloro-2-methoxy benzoyl-acrylic acid, 1.5 g (000048 mole) of the p-chlorophenacylpyridinium salt, and 4.5 g of ammonium acetate in 10 ml oF methyl alcohol is heated at reflux for 6 hr~ The crude product is partitioned between methylene hloride-water. The organic layer is concentrated; residue reacted with methanol-sulfuric acid to yield the methyl ester which is purified and hydrolyzed as ~n Example 6 to yield 0.75 9 (42%~ of the titled compound wlth a melting polnt of 248-250. The C:H:N ratio is 60.69:3~59:3.67.
r~ 2-~2-(acetyloxy)-4-chlorophenyl~-6-~4-chlorophenyl) 4-pyridinecarboxylic acid (Formula III: Xs~ is acetyloxy, X~l and X3l are chloro, X4l, Rlo, and R20 are hydrogen).
A m-ixture of 0.22 9 (0.0006 mole) of 2-(4-chloro-2-hydroxy-phenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid (prepared by reaction of the 2-methoxy compound of Example 16 with pyridine hydrochloride), 3 ml of acetic anhydride, and 0.~ 9 of anhydrous sodium acetate is heated at 140 for 2 hrO The mixture is cooled, diluted with water, and the solid is collected and recrystallized from chloroform-petroleum ether to yield 0.18 g (73%) of the titled , '79~;76 compound with a melting point of 230-231. The C:H:N ratio is 58.24:3.25:3.32.
Example 18 2-(4-Chlorophenyl)-6-(4'-fl uoro-[1,1 ' -biphenyl~-4-yl)-4-pyridinecarboxylic acid (Formula III, X2l is chloro~
X3l is p-fluorophenyl~ X41, Xso~ R1o, and R20 are hydrogen) Following the procedure of the proceeding example, the titled crystals are obtained having a melting point of 285-286 C and a C:H:N
ratio of 70.89:3.75:2.97.
Example 19 2-(4-Chlorophenyl)-6-(2-fluoro-~ -biphenyl]-4-yl)-4 pyridinecarboxylic acid (Formula III. X21 is chloro, 31 is phenyl, X4l is fluoro, Xso, Rlo, and R20 are hydrogen) Fol 1 owi ng the procedures of the preceeding examples, the titled crystals are obtained at a melting point of 271-272 C and a ~:H:N
ratio of 70.34:3.83:3.07.
Example 20 2-(6-Chloro-2-naphthalenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid (Formula III: X2l is chloro, X3l and X41 form 6-chloro-2-naphthalenyl, X50, R1o, and ~20 are hydrogen) Following the procedures of the preceeding examples, the titled crystals are obtained having a melting point o~ 273-274 C and a C:H:N:Cl ratio of 66.82:3.40:3.30:18.04.
Example 21 2-(4-Bromophenyl)-6-~4-(phenylthio)phenyl~-4-pyridine carboxylic acid (Formula III: X2l is bromo, X31 is thiophenoxy, X4l, Xso, R1o and R20 are hydrogen) Following the procedures of the preceeding examples, the titled crystals are obtained having a melting point of 219-222 C and C:H:N
ratio of 62.56:3.68:2.71.
30 ~ 2-(4-Chlorophenyl)-6-[4-(4-fluorophenoxy)phenyl]~4-pyridinecarboxylic acid (Formula III: X2l is chloro, X31 is p-fluorophenoxy~ X41, Xso~ R1o~ and R20 are hydrogen~
Following the procedures of the preceeding examples, the titled crystals are obtained from methylene chlor1de:petroleum ether, having a melting point of 201-202 C and a C:H:N ratio of 68.70:3.77:3.68 Example 23 2-(4-Chlorophenyl)-6-(4-fluorophenyl)-3-methyl-4-pyridinecarboxylic acid (Formula III: X2l is fluoro, l~t7g676 X31 is chloro, R1o is methyl, X41, X50, and ~20 are hydrogen) Following the procedures of the preceeding examples, the titled crystals are obtained from alcohol:water, having a melting point of 239-240 C and a C:H:N ratio o-F 66~87:3.95:3.72.
Example 24 2-[1,1'-biphenyl]-4-yl-6-(4-bromophenyl)-4-pyridine carboxylic acid (Formula III: X2l is bromo, X3l is phenyl~ X41, Xs~ R1o, and R20 are hydrogen) Follo~ing the procedures of the preceeding examples, the titled crystals are obtained from alcohol:water, having a melting point of 272-274 C and a C:H:N ratio of 66.28:4.06:2.580 Example 25 2-(4-Bromophenyl)-6-(2-naphthalenyl)-4-pyridinecar-boxylic acid (Formula III: X2l is bromo, X3l and X
form 2-naphthalenyl, X50, R1o and R20 are hydrogen) Following the procedures of the preceeding examples, the titled crystals are obtained from alcohol, having a melting point of 285-286 C and a C:H:N ratio of 65:49:3.52:3.21.
Example 26 2-(4-Bromophenyl)-6-(4-chlorophenyl)-5-methyl-4-pyridine carboxylic acid (Formula III: X21 is bromo, X31 is chloro, R1o is methyl, X41, X50, and R20 are hydrogen) Followina the procedures oF the preceeding exarnples, the titled crystals are obtained from alcohol:water, having a melting point of 228-230~ C and a C:H:N ratio of 56.42:3.29:3.30.
2,6-bis(4-Chlorophenyl)-4-pyridinecarboxylic acid (Formula II: X2~ and X3o are chloro, R1ol R20, X10, X40, and X50 are hydrogen3 The pyridinium salt is prepared from 14 9 (0.06 moles) of 2-bromo-p-chloroace-tophenone and 6 ml (0~074 moles) of dry pyridine in 50 ml of absolute ethanol at reflux for 15 min. The mixture is cooled, and the salt is collected and washed with ether. The mixture is dried in vacuo to yield 18 g of the pyridinium salt.
A mixture of 12.2 9 (0.039 moles) of the above solid and 8.22 9 (0.039 moles) of p-chlorobenzoylacrylic acid, 23.4 g of ammonium acetateg 3.9 ml of acetic anhydride and 39 ml oF acetic acid is heated at reflux (145 C) for 4 hr. The reaction mixture is diluted with 140 ml o~F water, cooled to room temperakure, and a brown solid is col-i76 .
lected. This solid is suspended in 600 ml of 2% potassium carbonate.
The solid is recovered and stirred with 600 ml of 2% potassium car-bonate and methylene chloride for 0.5 hr. The mixture is filtered, and the aqueous layer is extracted 5 times with methylene chloride and twice with ether. The mixture is filtered once again and acidifed to pH 2 with 12 molar hydrochloric acid. The mixture is cooled, the 501id is collected and washed with water, air dried, and recrystal-lized from alcohol, yielding 4.9 9 (36.5%) of the titled crystals having a melting point of 288-290 C. The C:H:N:Cl rakio is 62 77:3.10:4.42:20.74.
- Example 28 2,6-bis(4-Ch1Orophenyl)-4-pyridine carboxylic acidJ
sodium salt hydrate (Formula II: X20 and X30 are chloro, Rlo, X10, X~0, and X50 are hydrogen, and R20 is sodium) A mixture of 12 9 of the product of Example 28 and 1.0-1.1 equivalents of sodium hydroxide in 100 ml of water is heated and the resulting solution is filtered. The sodium salt hydrate is crystallized on cooling in an icebath to yield 11.44 g of the titled crystals, having a melting point greater than 300 C. This compound may then be lyophilized to yield solid crystals.
Example 29 2,6-bis[3-(trifluoromethyl)phenyl~-4-pyridinecarboxylic acid) (Formula II: X10 and X40 are tri~luoromethyl, X20s X30, X50, Rlo and R20 are hydrogen) A mixture of m-trifluoromethyl phenacylpyridinium bromide (5.5 ~l 0.016 moles). ~-~3-trifluoromethylbenzoyl)acrylic acid (4.Z5 9, 0.017 moles~, 10 9 of ammonium acetate, 5 ml o~ acetic acid, and 50 ml of methanol are heated at reflux for 5 hr, and allowed to stand at room temperature overnight. The mixture is then heated at reFlux for an additional 2 hr, cooled, and concentrated to dryness in vacuo. The residue is treated with 7 ml of 50X acetic acid. The precipitate is collected9 washed with cold 50% acetic acid, crystallized from benzene, and recrystallized from ethanol:water, to yield 2.3 9 (35%) of the titled crystals, haviny a melting point of 220-221 C. The C:H:N ratio is 58.45:2.59:3.52.
Example 30 2-(4-Bromophenyl)-6-(4-chlorophenyl)-4-pyridinecar-boxylic acid (Formula II: X20 is bromo, X30 is chloro, R1o, R20, X10, X,~0, and Xso are hydrogen) Following the procedure of the preceeding examples, the titled ~7~6 .
crystals are prepared and are recrystallized from acetic acid:water in a 45.9% yield, having a melting point of 290-292 C with a C:H:N ratio Of 55.32:2.79:3.57-Example 31 1-(4-Chlorophenyl)-6-~4-(trifluoromethyl3phenyl~-4-pyridinecarboxylic acid (Formula II: X20 is tri-fluoromethyl, X30 is chloro, XlO, X~tO, Xso, Rlo and R20 are hydrogen) Follo~ing the procedure of the preceeding examples~ the titled cry~tals are ob~ained in 79% yield from acetic acid:water. These crystals have a melting point of 268-270 C. The C:H:N ratio is 60.08:2.79:3.82.
Example 32 2,6-bis~4-(Trifluoromethyl)phenyl]-4-pyridinecar-boxylic acid (Formula II: X20 and X30 are trifluoro-methyl~ XlO, X40, Xso~ Rlo and R20 are hydrogen~
Following the procedures of the preceeding examples, the titled crystals are obtained from ethanol:water with a melting point of 289-290 C and the C:H:N ratio of 57.56:3.94:3.48.
Example 33 2,6-bis(4-Bromophenyl)-4-pyridinecarbaxylic acid (Formula II: X20 and X30 are bromo, Xl03 X40, Xso, Rlo, and R20 are hydrogen) Following the procedure of the preceeding examples~ the titled crystals are obtained in 57% yield from ethanol, havlng a melting poirt o~ 292-294 C in a C:H:N ratio of 49.10.2.79:4.35.
~ 2-(4-Chlorophenyl)-6-(3,4-dichlorophenyl)-4-pyrid~ne-carboxylic acid (Formula II: XlO, X20, and X30 are chloro~ X,~0, X50, Rlo, and R20 are hydrogen) Following the procedure of the preceeding examples, the tltled crystals are obtained from acetonitrile in Z8~o yield having a melting point of 303-304 C and a C:H:N ratio of 5Ç.20:2.64:3.86O
Example 35 Ten ~housand hard gelatin capsules for oral use, each containing 25 mg of 2,6-bis(4-Chlorophenyl)-4-pyridine carboxylic acid and 2.5 mg of minoxidil are prepared from the following ingredients:
Gm.
2,6-bis~4-Chlorophenyl)-4 pyridinecarboxyl ic acid 250 Minoxidil 25 1 ~ 7 ~36 7 6 Starch 350 Talc 250 Calcium stearate 150 Lactose. 1750 One capsule one to 4 times a day is useful in the treatment of hypertension.
Example 36 Ten thousand tablets for oral use, each containing 25 mg of 2,6-lb bis(4-chlorophenyl)-4-pyridine carboxylic acid are prepared from the following ingredients:
Gm.
2,6-bis(4-Chlorophenyl)-4-pyridinecarboxylic acid 250 Lactose 1200 Corn starch 500 Talc 500 Calcium stearate 25 The powdered ingredlents are thoroughly mixed and slugged. The slugs are broken into granules which are then compressed 1nto kahletsO
To induce diuresis in adult humans, 1 tablet Is adminlstered 1 to 4 times daily.
Example 37 Following the procedures of the preceeding Examples, and the procedures given in the Markovac, LaMontagne, and Blumbergs references and U.S. Patents 3,753,997, 3,763,148, and 3,600,396, all of the remaining compounds within the scope of this invention are prepared.
~17~76 FORMlJLAS
COOH
1~
x,~ r 11 X2,~X31 ~9~7~i - - CHART A
~ R ~ /=\
X2~ C-CH2--N~ X
Br :
+
X3~e-F-CHCOOH XI
\=/ R1 0 \X50 COOH
25 X~ ~ r ~
. X40
Examples of suitable pharmacologically acceptable quaternary ammonium cations are tetramethylammonium, tetraethylammonium, ben-zyltrimethylammonium, phenyltriethylammonium, and the like.
The diuretic compounds of the present invention may be formulated into pharmaceutical compositions, employing a pharmaceutically acceptable carrier.
The pharmaceutical forms contemplated by this invention include pharmaceutical compositions suitable for oral, parenteral, vaginal, and rectal use, e.g.~ tablets, powder packets, cachets, dragees, capsules, solutions, suspensions, sterile injectable forms, suppositories, bougies, and the like. Suitable diluents or carriers such as carbohydrates (lactose), proteins, lipids, calcium phosphate, cornstarch, stearic acid, methylcellulose and the like may be used as carriers or for coating purposes. Oil, e.g., coconut oil, sesame oil, safflower oil, cottonseed oil 7 peanut oil may be used for preparing solutions or suspensions of the active drug. Sweetening, coloring and flavoring agents may be added. By "pharmaceutical excipient" is meant any of these and similar well known forms of drug formulatlons.
When used in conjunction with antihypertenslve therapy, the compounds may be formulated with antihypertensive agents by means well known in the art, employing a pharmaceutical excipient as defined above.
2,6-bis(4-Chlorophenyl)-4-pyridinecarboxylic acid is the most pre~erred compound for use in the methods of this invention.
Description of the Preferred Embodiments The novel compounds of the present invention are all prepared by the procedures illustrated by the Examples given below.
xample 1 2-(4-chlorophenyl)-6-~3-(trifluoromethyl)phenyl]-4-pyridinecarboxylic acid (Formula III: X2l is chloro, X41 is trifluoromethyl, and X31, X50, Rlo and R20 are hydrogen) A mixture of 3.5 g (0.01 mole) of m-trifluoromethylphenacylpy-~L~t7~
g ridinium bromide, 2.1 9 (0.01 mole) of p-chlorobenzoylacrylic acid and 6 9 of ammonium acetate and 10 ml of glacial acetic acid and 1 ml of ace~ic anhydride is heated at 120-130 C for 4 hr. The reaction mixture is cooled and diluted with 35 ml of water. The solid is then collected and partitioned between 150 ml of 2% potassium carbonate and chloroform. The agueous layer is extracted with chloroform and then ether. This aqueous layer is concentrated and treated with acetic acid to yield a gummy solid which is triturated with ether. This solid is then collected and recrystallized from ethanol-water to yield 1.3 9 (34.4%) of the titled solid with a melting point of 222 C. The C:H:N:Cl ratio is 60.69:3.03:3.79:9.42.
Example 2 2-(4-bromophenyl)-6-[3-(trifluoromethyl)phenyl]-4-pyridinecarboxylic acid (Formula III: X2l is bromo, X4l is trifluoromethyl~ X3l, Xso~ Rlo and R20 are hydrogen) A mixture of 2.0 9 ~0.0079 mole) of p-bromobenzoylacrylic acid, 2.7~ 9 ~0.0079 mole) of m-trifluoromethylphenacylpyridinium bromide and S g of ammonium acetate and 25 ml of methanol and 2.5 ml of glacial acetic acid is stirred at reflux for 6 hr. The mixture is concentrated in vacuo and the residue is treated with 50% acetic acid-water to give a solid which is recrystallized from ethanol yield-ing 1.35 9 (40%) of the titled crystals having a melting point of 233 - 234 C., The C:H:N ratio is 54.40:2.57:3.21.
Example 3 2-[1,1'-biphenyl~-4-yl-6-(4-chlorophenyl)-4-pyridine-carboxylic acid (Form~la III: X2l is chloro, X3l is phenyl, X41, X5p, Rlol and R20 are hydrogen) A mixture of 3.54 9 (0.01 mole) of the pyridinium salt cor-responding to the titled product, 2.11 9 (0.01 mole) of p-chloro-ben~oylacrylic acid and 8.5 g of ammonium acetate in 20 ml of methanol is s~irred at reflux for 6 hr. The solid is collected and recrys~al-lized from acetic acid-~ater. The yield ;s 3.3 9 (85.5%) of the titled crystals with a melting point of 258-260 C. The C:H:N ratio is 73.45:4.10:3.~Q.
Example 4 2-(4-chlorophenyl)-6-(2-naphthalenyl)-4-pyridinecarbox ylic acid (Formula III: X2l is chloro~ X3l and X
form 2-naphthalenyl, X50, Rlo and R20 are hydrogen) A mixture of 3.3 9 (0~01 mole) of the pyridinium salt cor-responding to the titled product, 2.1 9 (OoOl mole) of p-chloro-7~t~
, benzoylacrylic acid, 5.8 g of ammonium acetate and 10 ml of methanol, 10 ml of glacial acetic acid, and 1.2 ml of acetic anhydride is stir~
red at reflux ~or 1. 5 hr. The reaction is cooled and the solid is collected. The solid is then washed with cold methanol and recrystal-lized from ethyl acetate to yield 1.4 9 (39 ~) of the titled crystalswith a me1ting point of 274-276 C. The C:H:N ratio is 73.23:3.73:4.10.
Example 5 2-(4-chlorophenyl)-6-(394-dimethylphenyl)-4-pyridine-carboxylic acid (Formula III: X2l is chloro, X3l and X41 are methyl, X50, R1o, and R20 are hydrogen) A mixture of 3.06 9 (0.01 mole) Qf the pyridinium salt cor-responding to the titled product, 2.11 9 (0.01 mole~ of p-chloro-benzoylacrylic acid and 8.5 g of ammonium acetate in 20 ml of methanol is stirred at reflux for 6 hr.- The mixture is partitioned between methylene chloride and water and the organic layer is evaporated and the residue is recrystallized from ethanol-water to yield 2.10 9 (62%) of crystals having a melting point of 256-259 C. The C:H:N ratio is 7~.53~4.~9:4.34.
Example 6 2,6-bis(4-chlorophenyl~-3-methyl-4-pyridinecarboxylic acid (Formula III: X2l and X31 are chloro, Rlo is methyl, X41, Xso, and R20 are hydrogen) A mixture of 17 g (0.10 mole~ of p-chloropropiophenone and 17 g of glyoxyllc acid in 2n ml of acetic anhydride containing a drop of N,N-diisopropylethylamine is heated to 135 C. An additional 2 ml of N,N-diisopropylethylamine is added and the reaction ls maintained at 135 C for three hours. The mixture Is concentrated and then diluted with aqueous sodium carbonate. The mixture is then extracted with ether and the aqueous layer is acidified with hydrochloric acid and extracted with methylene chloride. The organic layer is concentrated and the residue is chromatographed on silica gel using 5% CH30H-1%
acetic acid and 94% CH2Cl2. The crude ~-methyl-~-(p-chlorobenzo-yl~acrylic acid is dried in high vacuum yielding 11.2 g of solid. The ethyl ester is prepared by heating this crude solid and 100 ml of absolute alcohol in 3 ml of concentrated sulfuric acid for 1 hr at reflux. This mixture is concentra~ed, the residue is partitioned between sodium carbonate and methylene chloride. The organic layer is dried and concentrated to yield 11.9 g of oil.
A mixture of this oil, 14.7 g ~0.047 mole) of the pyridinium salt ~7~6~76 corresponding ~o the titled product, 40 g of ammonium acetate and 100 ml of methanol is heated at reflux for 6 hr. This mixturP is con-centrated, diluted with water, and the solid is collected. The solid is crystallized from alcohol and chromatographed on silica gel eluting with methylene chloride to yield 9.9 9 (54%) of crystals with a melting point of 87-90 C. The product was recrystallized from ethanol to yield the ethyl ester of the titled product having a melting point 94-95~ C.
The titled product is obtained by hydrolysis of one g of the ethyl ester in warm methanol and 5 ml of 2~% sodium hydroxide solu-tion. This mixture is left at room temperature for 1.5 hr and concentrated. The residue is partitioned between ether and water.
The aqueous layer is acidified and the solid is collected. The product is recrystallized from alcohol yielding 0.60 9 (65%) of the titled crystals with a melting point of 236 C. The C:H:N ratio is 63.78:3.57:4.01.
Example 7 2-(4-chlorophenyl)-6-~4-iodophenyl~-4-pyridinecar-boxylic acid (Formula III: X2l is chloro, X3l is iodo~ X4l, X50, Rlo3 and R20 are hydrogen~
A mixture o~ 1.7 g (0.0042 mole) of p-iodophenacylpyridinium bromide, 0.88 9 (0.0042 mole) of p-chlorobenzoylacrylic acid, 2.44 9 of ammonium acetate, 5 ml of methanol, 4 ml of acetic acid, and 0.4 ml of acetic anhydride is stirred at reflux ~or 1.25 hr. 10 m1 oF
methanol is added and the mixture is cooled and the solid is col-lected. The solid is recrystallized from methanol-acetic acid-water to yield 0.90 g (49%) of the titled crystals with a melting point of 286-287 C. The C:H:N ratio is 49.67:2.68:3.24.
Example 8 2-~4-chlorophenyl)-6-(4-propylphenyl)-4-pyridine-carboxylic acid ~Formula III: X2l is chloro, X3l is n-propyl~ X41~ X5Q3 R1o, and R20 are hydroyen) A mixture of 3~2 g l0.01 mole) of the pyridinium salt cor-responding to the titled product, 2.11 9 (0.01 mole~ of p-chloroben-zoylacrylic acid, and 8.5 g of ammonium acetate and 20 ml of methanol is heated at reflux for 6 hr. The mixture is diluted with water and the semi-solid is extracted into 2% potassium carbonate and ether.
The ether layer is extracted with water and the aqueous layer is acidified with hydrochloric acid to precipitate a solid which is recrystallized frum ethanol-water to yield 1.26 g (36%) of the titled j7 6 crystals with a melting point of 226-227 C. The C:H:N ratio is 72.07:5.40:4.06.
Example 9 2-(4-chlorophenyl)-6-(4-phenoxyphenyl) 4-pyridine-carboxylic acid (Formula III: X2l is chloro~ X3l ;s phenoxy, X41, X50, Rlo, and R20 are hydrogen)-A mixture of 1.85 9 (0.005 mole) of the pyridinium sa1t cor-responding to the titled product, 1.05 9 (0.005 mole) of p chloro-benzoylacrylic acid and 2.7 9 of ammonium acetate in 5 ml of methanol, 5 ml of glacial acetic acid, and 0.5 ml of acetic anhydride is heaked at reflux for 1.5 hr. The reaction is diluted with ice water and the - preci~itate is partitioned between ether and water. The ether ex-tracts are treated with activated carbon, concentrated, and the residue recrystallized from methanol-acetic acid-water to yield O.S g (27.5%~ of the titled crystals with the melting point of 214-215 C.
The C:H:N ratio is 71.86:4.06:3.42.
Example 10 2-(4-chlorophenyl)-6-[4-(phenylthio)phenyl]-4-pyridine-carboxylic acid (Formula III: X21 is chloro, X3l is thiophenoxy1 X41, X50, Rlo, and R20 are hydrogen) A mixture of 3.86 9 (0.01 mole) of the appropriate pyridinium salt, 2.11 9 ~0.01 mole~ of p-chlorobenzoylacrylic acid, 5.4 9 of ammonium acetate, 10 ml of methano1, 10 ml of glacial acetic acid, and 1 ml of acetic anhydride ls heated at reflux for 1.5 hr. The mixture is washed and recrystallized as 1n Example 9 ~o yield ~.0 9 (48%) of the titled crystals having a melting point of 213 216 C. The C:H:N
ratio is 69.01:3.95:3.37.
Example_11 2-(4-chlorophenyl)~6-C4~(2-methylpropyl3phenyl]-4-pyridinecarboxylic acld (Formula III: X 21 is chloro, X31 is 2-methylpropyl, X4l, X50, Rlo~ and Rzo are hydrogen)O
A mixture of 8.65 9 (0.026 mole) of the appropriate pyridinium salt9 5.2~ 9 (0.025 mole) of p-chlorobenzoylacrylic acid and 13.5 9 of ammonium acetate in 25 ml of methanol, 25 ml of glacial acetic acid, and 5 ml of acetic anhydride is heated at reflux for 1.5 hr. The mixture is cooled, diluted with water, and partitioned between aqueous hydrochloric acid and ether. The aqueous layer is extracted with ether and the combined ether layers are treated with activated carbon, filtered, and concentrated. The residue is triturated with acetoni-trile and the solid is collected and recrystallized from methanol-67~
acetic acid-water to yield 4.7 9 (5l%) of the titled crystals with melting point of 220-221 C. The C:H:N ratio is 72.56:5.43:3.80.
Example 12 2-(4-methylphenyl)-6-(2-naphthalenyl~-4-pyridinecarbox ylic acid (formula III: X21 ls methyl, X3l and X
form 2 naphthalenyl, X41, X50, R1o, and R20 are hydrogen) A mixture of 2.92 9 (0.01 mole~ of the appropriate pyridinium salt5 2.26 g (0.01 mole) of ~-(2-naphthoyl)acrylic acid and 8.5 9 of ammon;um acetate in 20 ml of methanol is heated at reflux for 6 hr.
10 The mixture is concentrated and the residue is diluted with water and extracted with methylene chloride. The organic layer is concentrated and the residue is chromatographed on silica gel using 5% methanol-1%
acetic acid - 94% methylene chloride. The product is recrystallized from ethanol yielding 1.14 g (33.6%) of the titled crystals with a melting point of 272-274 C. The C:H:N ratio is 81.32:5,01:4.16.
Example 13 2-(4-butylphenyl)-6-(4-chlorophenyl)-4-pyridinecarbox-ylic acid (Formula III: X21 is chloro, X3l is n-butyl, X41~ Xso~ R1o~ and R20 are hydrogen) A mixture of 8.65 g (0.026 mole) of the appropriate pyridinium salt, 5.Z5 9 (0.025 mole) of p-chlorobenzoylacrylic acid and 13.5 g o-f ammonium acetate in 25 ml of methanol, 25 ml of glacial acetic acid, and 5 ml o-f acetic anhydride ~s heated at reflux for 2.5 hr. The mixture is worked up as in the preceeding Examples ancl recrystallized from methallol:acetic acid:water to yield 2.4 g ~26%) ot the titled crystals with melting polnk o~ 2~9~210 C. The C:H:N ratio is 72~19;5.~4:3-95-Example 14 2-~4-chlorophenyl)-6-(5,6,7,8-tetrahydro-2~naphtha-lenyl)-4~pyridinecarboxylic acid (Formula III: X21 is chloro, X3l and X41 form 5,6,7,8-tetrahydro-2-naph thalenyl, Xso, R1o, and R20 are hydrogen~.
A mixture of 6.6 9 (0.02 mole) of the apprapriate pyridinium salt, 4.2 9 (0.02 mole) of p-chlorobenzoy1acrylic acid and 10.8 9 of ammonium acetate in 20 ml of methanol, 2C ml of glacial acetic acid, and 4 ml of acetic anhydride is heated at reflux for one hr. The mixture is cooled, the solid is collected and washed with cold methanol and recrystallized from methanol:water to yield 2.7 g 137h) of the titled crystals with a melting point of 243-246~ C. The C:H:~
ratio is 72.39:5.28:3.$5 "367 Example 1S 2-(4-ehlorophenyl~-6~C4~(3-methylbutyl)phenyl]-4-pyridinecarboxylic acid (Formula III: X21 is chloro, X31 is 3-me~hylbutYl, X4l, Xso~ R1o~ and R20 are hydrogen).
A mixture of 7.0 9 (0.02 mole) of the appropriate pyridinium salt, 4.3 9 (0.02 mole) of p-chlorobenzoylacry1ic acid and 10.8 9 of ammonium acetate and 20 ml of methanol, 20 ml of glacial acetic acid, and 2 ml of acetic anhydride is heated at reflux for one hr. The mixture is partitioned between ether and water. The ether layer is ; I0 treated with activated carbon, concentrated and the dark gum formed is -triturated with acetonitrile. The solid is collected and recrystal-lized from acetic acid to yield 2.85 9 (37.5 %) of the titled crystals with a melting point of 198-200 C. The C:H:N:Cl ratio is 72.79:5.83:3.37:9.42.
Example 16 2-(4-chloro-2-methoxyphenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid (Formula III: Xso is methoxy, X2l and X3l are chloro~ X41, Rlo, and R20 are hydrogen) The acrylic acid is prepared as described in Example 6. A
mixture of 1.15 g (0.0048 mole~ of khe 4-chloro-2-methoxy benzoyl-acrylic acid, 1.5 g (000048 mole) of the p-chlorophenacylpyridinium salt, and 4.5 g of ammonium acetate in 10 ml oF methyl alcohol is heated at reflux for 6 hr~ The crude product is partitioned between methylene hloride-water. The organic layer is concentrated; residue reacted with methanol-sulfuric acid to yield the methyl ester which is purified and hydrolyzed as ~n Example 6 to yield 0.75 9 (42%~ of the titled compound wlth a melting polnt of 248-250. The C:H:N ratio is 60.69:3~59:3.67.
r~ 2-~2-(acetyloxy)-4-chlorophenyl~-6-~4-chlorophenyl) 4-pyridinecarboxylic acid (Formula III: Xs~ is acetyloxy, X~l and X3l are chloro, X4l, Rlo, and R20 are hydrogen).
A m-ixture of 0.22 9 (0.0006 mole) of 2-(4-chloro-2-hydroxy-phenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid (prepared by reaction of the 2-methoxy compound of Example 16 with pyridine hydrochloride), 3 ml of acetic anhydride, and 0.~ 9 of anhydrous sodium acetate is heated at 140 for 2 hrO The mixture is cooled, diluted with water, and the solid is collected and recrystallized from chloroform-petroleum ether to yield 0.18 g (73%) of the titled , '79~;76 compound with a melting point of 230-231. The C:H:N ratio is 58.24:3.25:3.32.
Example 18 2-(4-Chlorophenyl)-6-(4'-fl uoro-[1,1 ' -biphenyl~-4-yl)-4-pyridinecarboxylic acid (Formula III, X2l is chloro~
X3l is p-fluorophenyl~ X41, Xso~ R1o, and R20 are hydrogen) Following the procedure of the proceeding example, the titled crystals are obtained having a melting point of 285-286 C and a C:H:N
ratio of 70.89:3.75:2.97.
Example 19 2-(4-Chlorophenyl)-6-(2-fluoro-~ -biphenyl]-4-yl)-4 pyridinecarboxylic acid (Formula III. X21 is chloro, 31 is phenyl, X4l is fluoro, Xso, Rlo, and R20 are hydrogen) Fol 1 owi ng the procedures of the preceeding examples, the titled crystals are obtained at a melting point of 271-272 C and a ~:H:N
ratio of 70.34:3.83:3.07.
Example 20 2-(6-Chloro-2-naphthalenyl)-6-(4-chlorophenyl)-4-pyridinecarboxylic acid (Formula III: X2l is chloro, X3l and X41 form 6-chloro-2-naphthalenyl, X50, R1o, and ~20 are hydrogen) Following the procedures of the preceeding examples, the titled crystals are obtained having a melting point o~ 273-274 C and a C:H:N:Cl ratio of 66.82:3.40:3.30:18.04.
Example 21 2-(4-Bromophenyl)-6-~4-(phenylthio)phenyl~-4-pyridine carboxylic acid (Formula III: X2l is bromo, X31 is thiophenoxy, X4l, Xso, R1o and R20 are hydrogen) Following the procedures of the preceeding examples, the titled crystals are obtained having a melting point of 219-222 C and C:H:N
ratio of 62.56:3.68:2.71.
30 ~ 2-(4-Chlorophenyl)-6-[4-(4-fluorophenoxy)phenyl]~4-pyridinecarboxylic acid (Formula III: X2l is chloro, X31 is p-fluorophenoxy~ X41, Xso~ R1o~ and R20 are hydrogen~
Following the procedures of the preceeding examples, the titled crystals are obtained from methylene chlor1de:petroleum ether, having a melting point of 201-202 C and a C:H:N ratio of 68.70:3.77:3.68 Example 23 2-(4-Chlorophenyl)-6-(4-fluorophenyl)-3-methyl-4-pyridinecarboxylic acid (Formula III: X2l is fluoro, l~t7g676 X31 is chloro, R1o is methyl, X41, X50, and ~20 are hydrogen) Following the procedures of the preceeding examples, the titled crystals are obtained from alcohol:water, having a melting point of 239-240 C and a C:H:N ratio o-F 66~87:3.95:3.72.
Example 24 2-[1,1'-biphenyl]-4-yl-6-(4-bromophenyl)-4-pyridine carboxylic acid (Formula III: X2l is bromo, X3l is phenyl~ X41, Xs~ R1o, and R20 are hydrogen) Follo~ing the procedures of the preceeding examples, the titled crystals are obtained from alcohol:water, having a melting point of 272-274 C and a C:H:N ratio of 66.28:4.06:2.580 Example 25 2-(4-Bromophenyl)-6-(2-naphthalenyl)-4-pyridinecar-boxylic acid (Formula III: X2l is bromo, X3l and X
form 2-naphthalenyl, X50, R1o and R20 are hydrogen) Following the procedures of the preceeding examples, the titled crystals are obtained from alcohol, having a melting point of 285-286 C and a C:H:N ratio of 65:49:3.52:3.21.
Example 26 2-(4-Bromophenyl)-6-(4-chlorophenyl)-5-methyl-4-pyridine carboxylic acid (Formula III: X21 is bromo, X31 is chloro, R1o is methyl, X41, X50, and R20 are hydrogen) Followina the procedures oF the preceeding exarnples, the titled crystals are obtained from alcohol:water, having a melting point of 228-230~ C and a C:H:N ratio of 56.42:3.29:3.30.
2,6-bis(4-Chlorophenyl)-4-pyridinecarboxylic acid (Formula II: X2~ and X3o are chloro, R1ol R20, X10, X40, and X50 are hydrogen3 The pyridinium salt is prepared from 14 9 (0.06 moles) of 2-bromo-p-chloroace-tophenone and 6 ml (0~074 moles) of dry pyridine in 50 ml of absolute ethanol at reflux for 15 min. The mixture is cooled, and the salt is collected and washed with ether. The mixture is dried in vacuo to yield 18 g of the pyridinium salt.
A mixture of 12.2 9 (0.039 moles) of the above solid and 8.22 9 (0.039 moles) of p-chlorobenzoylacrylic acid, 23.4 g of ammonium acetateg 3.9 ml of acetic anhydride and 39 ml oF acetic acid is heated at reflux (145 C) for 4 hr. The reaction mixture is diluted with 140 ml o~F water, cooled to room temperakure, and a brown solid is col-i76 .
lected. This solid is suspended in 600 ml of 2% potassium carbonate.
The solid is recovered and stirred with 600 ml of 2% potassium car-bonate and methylene chloride for 0.5 hr. The mixture is filtered, and the aqueous layer is extracted 5 times with methylene chloride and twice with ether. The mixture is filtered once again and acidifed to pH 2 with 12 molar hydrochloric acid. The mixture is cooled, the 501id is collected and washed with water, air dried, and recrystal-lized from alcohol, yielding 4.9 9 (36.5%) of the titled crystals having a melting point of 288-290 C. The C:H:N:Cl rakio is 62 77:3.10:4.42:20.74.
- Example 28 2,6-bis(4-Ch1Orophenyl)-4-pyridine carboxylic acidJ
sodium salt hydrate (Formula II: X20 and X30 are chloro, Rlo, X10, X~0, and X50 are hydrogen, and R20 is sodium) A mixture of 12 9 of the product of Example 28 and 1.0-1.1 equivalents of sodium hydroxide in 100 ml of water is heated and the resulting solution is filtered. The sodium salt hydrate is crystallized on cooling in an icebath to yield 11.44 g of the titled crystals, having a melting point greater than 300 C. This compound may then be lyophilized to yield solid crystals.
Example 29 2,6-bis[3-(trifluoromethyl)phenyl~-4-pyridinecarboxylic acid) (Formula II: X10 and X40 are tri~luoromethyl, X20s X30, X50, Rlo and R20 are hydrogen) A mixture of m-trifluoromethyl phenacylpyridinium bromide (5.5 ~l 0.016 moles). ~-~3-trifluoromethylbenzoyl)acrylic acid (4.Z5 9, 0.017 moles~, 10 9 of ammonium acetate, 5 ml o~ acetic acid, and 50 ml of methanol are heated at reflux for 5 hr, and allowed to stand at room temperature overnight. The mixture is then heated at reFlux for an additional 2 hr, cooled, and concentrated to dryness in vacuo. The residue is treated with 7 ml of 50X acetic acid. The precipitate is collected9 washed with cold 50% acetic acid, crystallized from benzene, and recrystallized from ethanol:water, to yield 2.3 9 (35%) of the titled crystals, haviny a melting point of 220-221 C. The C:H:N ratio is 58.45:2.59:3.52.
Example 30 2-(4-Bromophenyl)-6-(4-chlorophenyl)-4-pyridinecar-boxylic acid (Formula II: X20 is bromo, X30 is chloro, R1o, R20, X10, X,~0, and Xso are hydrogen) Following the procedure of the preceeding examples, the titled ~7~6 .
crystals are prepared and are recrystallized from acetic acid:water in a 45.9% yield, having a melting point of 290-292 C with a C:H:N ratio Of 55.32:2.79:3.57-Example 31 1-(4-Chlorophenyl)-6-~4-(trifluoromethyl3phenyl~-4-pyridinecarboxylic acid (Formula II: X20 is tri-fluoromethyl, X30 is chloro, XlO, X~tO, Xso, Rlo and R20 are hydrogen) Follo~ing the procedure of the preceeding examples~ the titled cry~tals are ob~ained in 79% yield from acetic acid:water. These crystals have a melting point of 268-270 C. The C:H:N ratio is 60.08:2.79:3.82.
Example 32 2,6-bis~4-(Trifluoromethyl)phenyl]-4-pyridinecar-boxylic acid (Formula II: X20 and X30 are trifluoro-methyl~ XlO, X40, Xso~ Rlo and R20 are hydrogen~
Following the procedures of the preceeding examples, the titled crystals are obtained from ethanol:water with a melting point of 289-290 C and the C:H:N ratio of 57.56:3.94:3.48.
Example 33 2,6-bis(4-Bromophenyl)-4-pyridinecarbaxylic acid (Formula II: X20 and X30 are bromo, Xl03 X40, Xso, Rlo, and R20 are hydrogen) Following the procedure of the preceeding examples~ the titled crystals are obtained in 57% yield from ethanol, havlng a melting poirt o~ 292-294 C in a C:H:N ratio of 49.10.2.79:4.35.
~ 2-(4-Chlorophenyl)-6-(3,4-dichlorophenyl)-4-pyrid~ne-carboxylic acid (Formula II: XlO, X20, and X30 are chloro~ X,~0, X50, Rlo, and R20 are hydrogen) Following the procedure of the preceeding examples, the tltled crystals are obtained from acetonitrile in Z8~o yield having a melting point of 303-304 C and a C:H:N ratio of 5Ç.20:2.64:3.86O
Example 35 Ten ~housand hard gelatin capsules for oral use, each containing 25 mg of 2,6-bis(4-Chlorophenyl)-4-pyridine carboxylic acid and 2.5 mg of minoxidil are prepared from the following ingredients:
Gm.
2,6-bis~4-Chlorophenyl)-4 pyridinecarboxyl ic acid 250 Minoxidil 25 1 ~ 7 ~36 7 6 Starch 350 Talc 250 Calcium stearate 150 Lactose. 1750 One capsule one to 4 times a day is useful in the treatment of hypertension.
Example 36 Ten thousand tablets for oral use, each containing 25 mg of 2,6-lb bis(4-chlorophenyl)-4-pyridine carboxylic acid are prepared from the following ingredients:
Gm.
2,6-bis(4-Chlorophenyl)-4-pyridinecarboxylic acid 250 Lactose 1200 Corn starch 500 Talc 500 Calcium stearate 25 The powdered ingredlents are thoroughly mixed and slugged. The slugs are broken into granules which are then compressed 1nto kahletsO
To induce diuresis in adult humans, 1 tablet Is adminlstered 1 to 4 times daily.
Example 37 Following the procedures of the preceeding Examples, and the procedures given in the Markovac, LaMontagne, and Blumbergs references and U.S. Patents 3,753,997, 3,763,148, and 3,600,396, all of the remaining compounds within the scope of this invention are prepared.
~17~76 FORMlJLAS
COOH
1~
x,~ r 11 X2,~X31 ~9~7~i - - CHART A
~ R ~ /=\
X2~ C-CH2--N~ X
Br :
+
X3~e-F-CHCOOH XI
\=/ R1 0 \X50 COOH
25 X~ ~ r ~
. X40
Claims (2)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of general formula:
III
wherein:
R10 represents a group selected from H and -CH3;
R20 represents a group selected from H and a pharmacologically acceptable cation;
X21 represents a group selected from F, Cl, Br, I, -CH3 and -CF3;
X31 represents a group selected from H, C1, Br, I, -CH3, CF3, phenyl, p-flurophenyl, phenoxy, p-flurophenoxy, thio-phenoxy and -CH2R50, wherein R50 represents (C2-C7)alkyl;
X41 represents a group selected from H, F, Cl, -CH3 and -CF3; or X31 and X41, when taken together, with the phenyl moiety to which they are attached form a group selected from 2-naphthalenyl, 5,6,7,8-tetrahydro-2-naphthalenyl and 6-chloro-2-naphthalenyl; and X50 represents a group selected from H, (C1-C4)alkoxy and (C1-C4) acetoxy;
with the following provisos:
(a) at least one of X31 and X41 represents other than H;
(b) one of X31 and X41 represents -CH3 only when the other also represents -CH3;
(c) X21 and X31, independently, represent a group selected from Cl, Br and -CF3 only when R10 or X50 represents other than H;
(d) X21 represents Cl only when X41 does not represent Cl;
(e) X21 represents -CH3 only when X31 and X41, when taken together, with the phenyl moiety to which they are attached form 2-naphthalenyl;
(f) X50 represents a group selected from (C1-C4)alkoxy and (C1-C4)acetoxy only when X41 represents H, X21 represents a group selected from Cl, Br, I and -CF3, and X31 represents a group selected from Cl, Br, I, -CF3 and -CH2R50, wherein R50 is as defined above;
(g) X21 represents F only when R10 represents -CH3 and represents Cl;
(h) X31 represents thiophenoxy only when X41 and X50 represent H; and (i) X41 represents F only when X31 represents phenyl;
said process comprising:
(A) reacting a pyridinium salt of general formula:
X
wherein X21 is as defined above, with an aroyl acrylic acid or ester of general formula:
XI
R10, X31, X41 and X50 are as defined above and R60 represents a group selected from H and (C1-C4)alkyl, in the presence of ammonium acetate in an inert solvent;
(B) when R60 represents H, recovering the desired compound of general formula III, wherein R20 represents H, from step (A); or (C) when R60 represents (C1-C4)alkyl, hydrolyzing the ester group of the product of step IA) and recovering the desired compound of general formula III, wherein R20 represents H; or (D) reacting the products of steps (B) or (C) with a suitable reagent to introduce a pharmacologically acceptable cation, as R20, in the desired compound of general formula III.
III
wherein:
R10 represents a group selected from H and -CH3;
R20 represents a group selected from H and a pharmacologically acceptable cation;
X21 represents a group selected from F, Cl, Br, I, -CH3 and -CF3;
X31 represents a group selected from H, C1, Br, I, -CH3, CF3, phenyl, p-flurophenyl, phenoxy, p-flurophenoxy, thio-phenoxy and -CH2R50, wherein R50 represents (C2-C7)alkyl;
X41 represents a group selected from H, F, Cl, -CH3 and -CF3; or X31 and X41, when taken together, with the phenyl moiety to which they are attached form a group selected from 2-naphthalenyl, 5,6,7,8-tetrahydro-2-naphthalenyl and 6-chloro-2-naphthalenyl; and X50 represents a group selected from H, (C1-C4)alkoxy and (C1-C4) acetoxy;
with the following provisos:
(a) at least one of X31 and X41 represents other than H;
(b) one of X31 and X41 represents -CH3 only when the other also represents -CH3;
(c) X21 and X31, independently, represent a group selected from Cl, Br and -CF3 only when R10 or X50 represents other than H;
(d) X21 represents Cl only when X41 does not represent Cl;
(e) X21 represents -CH3 only when X31 and X41, when taken together, with the phenyl moiety to which they are attached form 2-naphthalenyl;
(f) X50 represents a group selected from (C1-C4)alkoxy and (C1-C4)acetoxy only when X41 represents H, X21 represents a group selected from Cl, Br, I and -CF3, and X31 represents a group selected from Cl, Br, I, -CF3 and -CH2R50, wherein R50 is as defined above;
(g) X21 represents F only when R10 represents -CH3 and represents Cl;
(h) X31 represents thiophenoxy only when X41 and X50 represent H; and (i) X41 represents F only when X31 represents phenyl;
said process comprising:
(A) reacting a pyridinium salt of general formula:
X
wherein X21 is as defined above, with an aroyl acrylic acid or ester of general formula:
XI
R10, X31, X41 and X50 are as defined above and R60 represents a group selected from H and (C1-C4)alkyl, in the presence of ammonium acetate in an inert solvent;
(B) when R60 represents H, recovering the desired compound of general formula III, wherein R20 represents H, from step (A); or (C) when R60 represents (C1-C4)alkyl, hydrolyzing the ester group of the product of step IA) and recovering the desired compound of general formula III, wherein R20 represents H; or (D) reacting the products of steps (B) or (C) with a suitable reagent to introduce a pharmacologically acceptable cation, as R20, in the desired compound of general formula III.
2. A compound of general formula III, as defined in claim 1, when prepared by the process defined in claim 1 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA000446371A CA1179676A (en) | 1981-04-30 | 1984-01-30 | 2,6-diaryl-pyridinecarboxylic acids |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/259,135 US4377586A (en) | 1981-04-30 | 1981-04-30 | Diuretic 2,6-diaryl-4-pyridine carboxylic acids |
| US259,135 | 1981-04-30 | ||
| CA000398962A CA1182397A (en) | 1981-04-30 | 1982-03-22 | 2,6-diaryl-pyridinecarboxylic acids |
| CA000446371A CA1179676A (en) | 1981-04-30 | 1984-01-30 | 2,6-diaryl-pyridinecarboxylic acids |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000398962A Division CA1182397A (en) | 1981-04-30 | 1982-03-22 | 2,6-diaryl-pyridinecarboxylic acids |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1179676A true CA1179676A (en) | 1984-12-18 |
Family
ID=27167224
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000446371A Expired CA1179676A (en) | 1981-04-30 | 1984-01-30 | 2,6-diaryl-pyridinecarboxylic acids |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1179676A (en) |
-
1984
- 1984-01-30 CA CA000446371A patent/CA1179676A/en not_active Expired
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