US3454587A - Novel substituted 4-aminonicotinoyl compounds and salts thereof - Google Patents

Novel substituted 4-aminonicotinoyl compounds and salts thereof Download PDF

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US3454587A
US3454587A US593638A US3454587DA US3454587A US 3454587 A US3454587 A US 3454587A US 593638 A US593638 A US 593638A US 3454587D A US3454587D A US 3454587DA US 3454587 A US3454587 A US 3454587A
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toluidino
nicotinic acid
acid
trifluoro
nicotinate
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Ruddy Littell
James Miller Smith Jr
Duff Shederic Allen Jr
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Wyeth Holdings LLC
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American Cyanamid Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3

Definitions

  • This invention relates to new organic compounds. More particularly, it relates to derivatives of nicotinic acid, compositions containing said derivatives and methods of administering said compositions.
  • novel compounds of the present invention can be represented as compounds of the formula:
  • R is selected from the group consisting of (lower alkyl)-phenyl, xylyl, nitrophenyl, halophenyl, hydroxyphenyl, carboxyphenyl, aminophenyl, a,a,a-trifluorotolyl, halo-u,a,a-trifluorotolyl and dihalotolyl; R is selected from the group consisting of hydroxy, lower alkoxy, dilower alkylamino lower alkoxy, amino, lower alkylamino and di-lower alkylamino and pharmaceutically acceptable salts thereof.
  • the compounds of this invention form water-soluble acid addition salts. Since these compounds are valuable therapeutic agents, medicinally acceptable acid addition salts formed from pharmaceutically acceptable acids are preferred. These addition salts may be formed with both organic and inorganic acids such as hydrochloric acid, nitric acid, citric acid, maleic acid, fumaric acid, cussinic acid, sulfuric acid, phosphoric acid, tartaric acid and the like.
  • the nicotinic acid derivatives of this invention form alkaline metal salts such as the sodium and potassium the aluminum or magnesium salts or salts of alkaline earth metals, examples of which are barium and calcium.
  • nicotinic acid esters of this invention react with unsymmetrically disubstituted hydrazines to furnish nicotinic acid salts of the formula:
  • R is as defined hereinbefore, and R R and R are selected from the group consisting of lower alkyl and aryl and R and R taken together with nitrogen are selected from the group consisting of pyrrolidino, piperidino, morpholino, 4-lower alkyl piperazino, 4-(B- hydroxyloweralkyl)piperazino, and hydroxypiperidino.
  • R R and R are selected from the group consisting of lower alkyl and aryl and R and R taken together with nitrogen are selected from the group consisting of pyrrolidino, piperidino, morpholino, 4-lower alkyl piperazino, 4-(B- hydroxyloweralkyl)piperazino, and hydroxypiperidino.
  • the free bases of compounds of this invention are, in general, crystalline solids, at least somewhat soluble in the usual organic solvents and water.
  • the compounds of this invention are physiologically active and therefore useful in the pharmaceutical field. We have found that they are particularly advantageous as anti-inflammatory agents and diuretics in Warm-blooded animals.
  • Diuretic property in mature rats was determined by the following procedure: Four cages (2 rats per cage) of mature male rats weighing between and 300 grams were allowed a normal fluid intake prior to testing. The single oral administration of 400 micrograms of the test compound was given in 0.5 milliliter of 2 percent aqueous starch suspension. Four cages (2 rats per cage) served as controls. Control animals received only the starch suspension. After administration, the test animals were placed in metabolism cages. Observations of the amount of urine excreted were made after 5 hours. These urine measurements were then adjusted to compensate for differing weights of individual animals. The 5 hour urine samples of both control and treated rats were assayed for sodium and chloride content.
  • An illustrative group of compounds within the scope of the present invention include for example, 4-(oz,ct,utrifluoro-m-toluidino)nicotinic acid; 4-(2,3-Xylidino)nicotinic acid; 4-(2,6-dichloro-m-toluidino)nicotinic acid; 4- (2,6-dichloroanilino)nicotinic acid; 4-(o-toluidino)nicotinic acid; 4-(m-toluidino)nicotinic acid; 4-(p-toluidino) nicotinic acid; 4-(m-chloroanilino)nicotinic acid; 4-(mbromoanilino)nicotinic acid; 4-(m-fluoroanilino)nicotinic acid; methyl 4-(oz,oc,ct trifluoro-m toluidino)nicotinate; dimethylaminoethyl 4-
  • Flowsheet A shows a specific illustrae tion of the preparation of a specific final product of this invention.
  • OOH nicotinate (IX) is prepared by treatment of 4-(u,ot,oc-Irifluoro-m-toluidino)nicotinic acid (IV) with methanol and sulfuric acid. Treatment of (IX) with ammonia affords 4-(a,a,u-trifiuoro-m-tolnidino)nicotinamide (XI).
  • N,N- dimethyl 4-(a,a,a-trifiuoro rn toluidino)nicotinarnide (XII).
  • N-methyl-4-(a,a,a-trifluro m toluidino nicotinamide is prepared by treatment of (IX) with sodium methoxide in methylforrnamide.
  • suitable oral unit dosage forms in accord with this invention are tablets, capsules, pills, powder, packets,
  • a B O Methyl4(a,a,a-trifluoro-m-toluidino)- unsym-Diphenylhydrazine l-methyl-1,1-diphenylhydrazinium 4(zz,a,0z-lZIlfl11OT0-mnicotinate. toluidino)nicotinate.
  • Methyl 4-(ne,a,a-trifiuoro-m-toluidin0)- l-amino-ermethylpiperazine 1amino-1,4-dimethylpiperazinium 4-(a,a,a-tirfluoro-mnicotinate. toluidino)nicotinate.
  • the compounds of the present invention may be ad+ ministered as active components of compositions for administration in unit dosage form as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions and the like.
  • the dosage found effective may vary from 1 mg. to 200 mg. per kilogram depending upon the warm-blooded animal.
  • the principal active ingredient is mixed with conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium siearate, dicalcium phosphate, gums, and functionally similar materials as pharmaceutical diluents or carriers.
  • the tablets or pills of the novel compositions can be laminated or otherwise compounded to provide a dosage form affording the advantage of prolonged or delayed action or predetermined successive action of the enclosed medication.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate, and the like.
  • a particularly advantageous enteric coating comprises a styrene maleic acid copolymer together with known materials contributing to the enteric properties of the coating.
  • liquid forms in which the novel composition of the present invention may be incorporated for administration include aqueous solutions, suitable flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil, and the like, as well as elixirs and similar pharmaceutical vehicles.
  • suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, gelatin and the like.
  • Sterile suspensions or solutions are required for parenteral use. Isotonic preparations containing suitable preservatives are also highly desirable for injection use.
  • unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle.
  • the specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristic of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for therapeutic use in warm-blooded animals, as disclosed in detail in this specification, these being features of the present invention. Examples of granules, Wafers, cachets, teaspoonfuls, dropperfuls, ampules; vials, segregated multiples of any of the foregoing and other forms as herein described.
  • Example 2 Preparation of 4-(a,a,u-trifiuoro-m toluidino -nicotinic acid (A) A suspension of 4.0 g. of 4-(u,a,a-trifiuoro-mtoluidino)-nicotinic acid l-oxide and 800 mg. of 10% palladium-on-carbon catalyst is hydrogenated at 60 and 45 lb. pressure for 2.5 hours. The catalyst is filtered and Washed with ethanol. The combined filtrates are evaporated to a pink crystalline mass, melting point 258- 260 C. dec. which is crystallized from ethanol to give 2.0 g.
  • the above oxide is suspended in 150 ml. of acetic acid containing 800 mg. of 10% palladium-on-carbon catalyst and is hydrogenated at 60 and 45 lb. pressure for 8 hours.
  • the catalyst is filtered and the filtrate is concentrated to give, upon addition of ethanol, 1.3 g. of 4-(2,3-xylidino)-nicotinic acid, melting point 295- 300 C. dec.
  • a sample for analysis is prepared by sublimation at 200 C. and 0.01 mm. Hg to give colorless crystals, melting point 296300 C. dec. This compound is particularly useful as an anti-inflammatory agent.
  • Example 4 Preparation of 4-(m-chloroanilino)- nicotinic acid A mixture of 4.0 g. of 4-nitronicotinic acid l-oxide and ml. of m-chloroaniline is heated at 160 C. for 2 hours. Upon cooling, a 10% potassium hydroxide solution is added and the resulting solution is washed several times with ether. The ether extracts are discarded and the aqueous layer is neutralized with 6 .N hydrochloric acid to give 4.4 g. of 4-(m-chloroanilino)nicotinic acid 1- oxide, melting point 288-290 C.
  • a 750 mg. portion of 4-(m-chloroanilino)-nicotinic acid l-oxide in 150 ml. of acetic acid containing 500 mg. of 10% palladium-on-carbon is hydrogenated at 60 C. and 35 lb. pressure for 24 hours. Filtration of the catalyst and evaporation of the filtrate gives 700 mg. of tan solid which upon suspension in acetone and filtration gives 450 mg. of 4-(m-chloroanilino) -nicotinic acid, melting point 250 C. dec. Crystallization from water gives colorless needles, melting point 285 28 9 C. dec.
  • Example 5 Preparation of 4-(m-toluidino)- nicotinic acid
  • a mixture of 3 g. of 4-nitronicotinic acid l-oxide and 10 ml. of m-toluidine is heated at 100 C. from 1 hour and at 140 C. for 4 hours.
  • a 10% aqueous potassium hydroxide solution is aded and the resulting solution is washed several times with ether.
  • the ether extracts are discarded and the aqueous layer is filtered and neutralized with 6 N hydrochloric acid to give 3.1 g. of 4-(m-toluidino)-nicotinic acid l-oxide, melting point 270272 C.
  • a suspension of 2.5 g. of the above 4-(m-toluidino)- nicotinic acid l-oxide in 200 ml. of acetic acid containing 800 mg. of 10% palladium-on-carbon is hydrogenated at 60 C. and 45 lb. pressure for 24 hours. It incomplete reduction is observed, the reaction may be repeated using methanol as solvent. Filtration of the catalyst and concentration of the methanol gives 4-(m-toluidino)-nicotinic acid, melting point 276-278 C.
  • Example 19 Preparation of sodium 4-'(a,oc,oz-tlifi1lOIO- m-toluidino) -nicotinate
  • a solution of 1.41 g. of '4-(OL,OL,OL-tI'lfiUOI'O-II1-t0ll.1idlll0)- nicotinic acid in 50 ml. of 0.10 N sodium hydroxide is evaporated to a creamy white paste which is dissolved in ethanol, filtered and concentrated until crystallization occurs. Filtration gives 400 mg. of sodium 4-(a,ot,a-[I'ifluoro-m-toluidino)-nicotinate as a white, water soluble powder which has high diuretic activty.
  • Example 20 --Preparation of .N-(Z-dimethylaminoethyl)- 4(o e,a-trifiuoro-m-toluidino)-nicotinate
  • Example 21 -Preparation of methyl-4-(u,a,a-trifluoro-m-toluidino)-nicotinate
  • a mixture of 3.25 g. of sodium 4-(u,a,ot-trifluoro-mtoluidino)-nicotiuate and 10 ml. of methyl iodide in 100 ml. of ethanol is stirred at room temperature for 16 hours.
  • the mixture is filtered and the filtrate is concentrated under reduced pressure to give methyl 4(a,a,u-tl'ifluoro-m-toluidino)-nicotinate, melting point 118-12'l C. after purification by sublimation.
  • Example 22 'Preparation of 4(a,a,u-trifluorom-toluidino) -nicotin amide
  • Example 23 -Preparation of N,N-dimethyl-4-(a,a,atrifluoro-m-toluidino)-nicotinamide
  • a solution of 1.33 g. of methyl 4-(a,a,m-trifiuoro-mtoluidino)-nicotinate and 14 ml. of dimethylamine in ml. of ethanol is heated in a steel autoclave at 50 C. for 8 hours.
  • the residue obtained on concentration of the mixture to dryness is crystallized from methanol and water to give N,N-dimethyl-4-(u,a,a-trifluoro-m-toluidino)-nicotinamide.
  • Example 24 Preparation of n-n1ethyl-4-(a,a,a-trifluorom-toluidino)-nicotinamide
  • a solution of 300 g. of methyl 4-(ot,ot,oc-tl'ifil10lO-mtoluidino)-nicotinate and 300 mg. of sodium methoxide and 1 ml. of methylformamide is heated at 95 C. for 18 hours. After cooling and diluting with Water, the reaction mixture is extracted with ether, and the ether solution washed With water dried and evaporated to give 300 mg. of oil-white crystals, melting point 140144 C. The product is crystallized from acetone-hexane to give N-methyl- 4-(ix,a,a-trifluoro-m-toluidino) nicotinamide as white crystals, melting point 144-146" C.
  • Example 25 Preparation of butyl 4-(a,u,a-trifiuoro-mtoluidino -nicotinate
  • a solution of 3.0 g. of 4-(a,a,u-trifluoro-m-toluidino)- nicotinic acid in 20 ml. of n-butyl alcohol and 4 ml. of H 80 is heated at reflux for 16 hours, cooled and neutralized with NH OH.
  • the product is extracted into chloroform, and the extract is Washed with NaOH and with water. After evaporation, the resulting oil is chromatographed on 150 g. of silica gel. Ether-dichloromethane (3:7) gives, upon evaporation, 1.5 g.
  • Example 26.4-(m-fiuoroanilino) -nicotinic acid A mixture of 4.0 g. of 4-nitronicotinic acid l-oxide and 12 ml. of m-fluoroaniline is heated at 200 for 4 hours, cooled and dissolved in 10% aqueous sodium hydroxide. After extraction with ether, the aqueous layer is filtered and acidified. The resulting product 3.0 g. of 4- (m-fluoroanilino)-nicotinic acid l-oxide is hydrogenated at 60 and 35 lb. pressure for 18 hours in 200 ml. of acetic acid containing 1.0 g. of 10% palladium-on-carbon. The catalyst is filtered and the filtrate is evaporated. Addition of methanol gives 4-(m-fluoroanilino)-nicotinic acid as white needles, melting point 292294 C. A sample for analysis may be prepared by sublimation.
  • Example 27 Preparation of 4-(m-aminoanilino)- nicotinic acid
  • Example 28 -Preparation of 4-(oc,0t,oc-tlifll10r0-m-IOlllidino)-nicotinic acid hydrochloride
  • a solution of 1.0 g. of 4-(a,oz,u-trifluoro-m-toluidino)- nicotinic acid in 100 ml. of methanol is saturated with a rated and the residue is filtered from dichloromethane to give 1.1 g. of 4-(0t,06,1X-t1'lfil1OI'O-lI1-t0ll1idll'l0)-IliCOliIliC acid hydrochloride as a white powder, melting point 278- 282 C.
  • Example 29 Preparation of 1,1,1-trimethylhydrazinium 4-(a,a,a-trifluoro-m-toluidino)-nicotinate
  • a solution of 2.2 g. of methyl 4-(a,ot,a-trifluoro-m-toluidino)-nicotinate in 15 ml. of unsymmetrical dimethylhydrazine is heated at reflux overnight. After evaporation of the solvent, the residue is crystallized from dichloromethane-ether to give 2.3 g.
  • a 4-amino-nicotinoyl compound selected from the group consisting of a compound of the formula:
  • R is selected from the group consisting of (lower alkyl)phenyl, halophenyl, 0t,0L,0t-trlfl11OI'0tOlyl, and halooc,oc,oz-lI'ifll10r0t0lyl; R is selected from the group consisting of hydroxy, lower alkoxy and amino, and pharmaceutically acceptable salts.
  • the 4-amino-nicotinoyl compound according to claim 1 4-(u,a,a-trifluoro-p-toluidino)-nicotinic acid.
  • the 4-amino-nicotinoyl compound according to claim 1 methyl 4-(a,a,a-trifluoro-m-toluidino)-nicotinate.
  • the 4-aminonicotinoyl compound according to claim 1 4-(m-chloroanilino)-nicotinic acid.
  • the 4-amino-nicotinoyl compound according to claim 1 sodium 4-(a,a,a-trifluoro-m-toluidino)-nicotinate.
  • the 4-amino-nicotinoyl compound according to claim 1 4-(u,a,u-trifluoro-m-toluidino)-nicotinic acid.
  • the 4-amino-nicotinoyl compound according to claim 1 4-(o-toluidino)-nicotinic acid.

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Description

United States Patent 3,454,587 NOVEL SUBSTITUTED 4-AMINONICOTINOYL COMPOUNDS AND SALTS THEREOF Ruddy Littell, River Vale, James Miller Smith, Jr., Ridgewood, and Dulf Shederic Allen, Jr., Dobbs Ferry, N.J., assignors to American Cyanamid Company, Stamford, Conn., a corporation of Maine No Drawing. Continuation-impart of application Ser. No. 459,893, May 28, 1965. This application Nov. 14, 1966, Ser. No. 593,638
Int. Cl. C07d 31/34,- A61k 27/00 US. Cl. 260295.5 9 Claims ABSTRACT OF THE DISCLOSURE Compounds of the type substituted 4-amino-nicotinic acids, nicotinates, nicotinamides and salts are described. The compounds are useful for their diuretic and antiinfiammatory activity.
This invention is a continuation-in-part of our application Ser. No. 459,893, filed May 28, 1965, and now abandoned.
This invention relates to new organic compounds. More particularly, it relates to derivatives of nicotinic acid, compositions containing said derivatives and methods of administering said compositions.
The novel compounds of the present invention can be represented as compounds of the formula:
wherein R is selected from the group consisting of (lower alkyl)-phenyl, xylyl, nitrophenyl, halophenyl, hydroxyphenyl, carboxyphenyl, aminophenyl, a,a,a-trifluorotolyl, halo-u,a,a-trifluorotolyl and dihalotolyl; R is selected from the group consisting of hydroxy, lower alkoxy, dilower alkylamino lower alkoxy, amino, lower alkylamino and di-lower alkylamino and pharmaceutically acceptable salts thereof.
The compounds of this invention form water-soluble acid addition salts. Since these compounds are valuable therapeutic agents, medicinally acceptable acid addition salts formed from pharmaceutically acceptable acids are preferred. These addition salts may be formed with both organic and inorganic acids such as hydrochloric acid, nitric acid, citric acid, maleic acid, fumaric acid, cussinic acid, sulfuric acid, phosphoric acid, tartaric acid and the like.
The nicotinic acid derivatives of this invention form alkaline metal salts such as the sodium and potassium the aluminum or magnesium salts or salts of alkaline earth metals, examples of which are barium and calcium.
The nicotinic acid esters of this invention react with unsymmetrically disubstituted hydrazines to furnish nicotinic acid salts of the formula:
wherein R is as defined hereinbefore, and R R and R are selected from the group consisting of lower alkyl and aryl and R and R taken together with nitrogen are selected from the group consisting of pyrrolidino, piperidino, morpholino, 4-lower alkyl piperazino, 4-(B- hydroxyloweralkyl)piperazino, and hydroxypiperidino. These salts are also to be considered within the scope of the present invention.
The free bases of compounds of this invention are, in general, crystalline solids, at least somewhat soluble in the usual organic solvents and water.
The compounds of this invention are physiologically active and therefore useful in the pharmaceutical field. We have found that they are particularly advantageous as anti-inflammatory agents and diuretics in Warm-blooded animals.
These compounds were shown to possess anti-inflammatory activity by a test that involves reduction of the edema caused by the injection of a 1% carageenin solution into the paws of rats.
These compounds were also shown to produce diuresis in both rats and dogs. Diuretic property in mature rats, for example, was determined by the following procedure: Four cages (2 rats per cage) of mature male rats weighing between and 300 grams were allowed a normal fluid intake prior to testing. The single oral administration of 400 micrograms of the test compound was given in 0.5 milliliter of 2 percent aqueous starch suspension. Four cages (2 rats per cage) served as controls. Control animals received only the starch suspension. After administration, the test animals were placed in metabolism cages. Observations of the amount of urine excreted were made after 5 hours. These urine measurements were then adjusted to compensate for differing weights of individual animals. The 5 hour urine samples of both control and treated rats were assayed for sodium and chloride content.
An illustrative group of compounds within the scope of the present invention include for example, 4-(oz,ct,utrifluoro-m-toluidino)nicotinic acid; 4-(2,3-Xylidino)nicotinic acid; 4-(2,6-dichloro-m-toluidino)nicotinic acid; 4- (2,6-dichloroanilino)nicotinic acid; 4-(o-toluidino)nicotinic acid; 4-(m-toluidino)nicotinic acid; 4-(p-toluidino) nicotinic acid; 4-(m-chloroanilino)nicotinic acid; 4-(mbromoanilino)nicotinic acid; 4-(m-fluoroanilino)nicotinic acid; methyl 4-(oz,oc,ct trifluoro-m toluidino)nicotinate; dimethylaminoethyl 4-(u,oc,a-triflu01'0-m toluidino)nicotinate; 4-(a,a,a-trifluoro-m-toluidino)nicotinamide, and the like. i
The following Flowsheet A shows a specific illustrae tion of the preparation of a specific final product of this invention.
3 FLOWSHEET I III LNH,
COOH V l VI IV CF; (FF! o OOH 0 0 on I HQ N02 c 0011 NH: o OOH nicotinate (IX) is prepared by treatment of 4-(u,ot,oc-Irifluoro-m-toluidino)nicotinic acid (IV) with methanol and sulfuric acid. Treatment of (IX) with ammonia affords 4-(a,a,u-trifiuoro-m-tolnidino)nicotinamide (XI). Treatment of (IX) with dimethylamine in a suitable solvent or sodium methoxide in dimethylformamide gives N,N- dimethyl 4-(a,a,a-trifiuoro rn toluidino)nicotinarnide (XII). N-methyl-4-(a,a,a-trifluro m toluidino nicotinamide is prepared by treatment of (IX) with sodium methoxide in methylforrnamide. Treatment of sodium 4-(a,a,a-triflu0ro m toluidino)nicotinate (XIII) with fi-dimethylaminoethylchloride affords dimethylaminoethyl 4-(a,a,a-trifluoro-m-toluidino)nicotinate (XIV).
COOCH: CONE:
IX XI CF; CF;
Q (EEG XIII oxide and potassium carbonate to give 4-(a,oz,oc-t1iflu0r0- m-toluidino)nicotinic acid (IV):
C F Br NH: NH- 0003 N 00011 VII VIII 1v OOCHzCH:N(OHa): CO Hs):
XIV XII Treatment of methyl 4(a,ot,a-t1ifill01'0 m toluidino) nicotinate (IX) with unsym-dimethylhydrazine using an 60 excess of the hydrazine as solvent, or in the presence of an inert solvent, produces the hydrazinium salt (X).
CF; 3 (CH3):NNHI N 000011: N
IX X
The above described 4-aryl nicotinic acid may be trans- Similarly, by the above described procedure, the reacformed to related derivatives (Flowsheet B). For examtion of the various 4-substituted mcotlmc esters m 11st A ple, the ester, methyl 4-(a,a,m-tl'iflu01'0 m toluidino) 75 with the unsymmetrically substituted hydrazmes in list B produces the desired hydrazinium derivatives indicated in list C as follows:
suitable oral unit dosage forms in accord with this invention are tablets, capsules, pills, powder, packets,
A B O Methyl4(a,a,a-trifluoro-m-toluidino)- unsym-Diphenylhydrazine l-methyl-1,1-diphenylhydrazinium 4(zz,a,0z-lZIlfl11OT0-mnicotinate. toluidino)nicotinate.
Do l-methyl-l-phenylhydrazine 1,1-dimethyl-l-phenylhydrazinium 4-(a,zx,a-trlfil10rO-II1- toluidino)nicotinate. Butyl 4-(a,a,a-trifluoro-m-toluidino)- l-aminopyrrolidine l-amino l-butylpyrrolidinium 4-(a,a,a-trifluoro-m-toluidino)- nicotinate. nicotinate. Methyl 4-(a,a,a-trifiuorom-toluidino)- l-aminopiperidine l-amino-l-methylpiperidinium 4-(a,a,a-trifluoro-m-toluidino)- nicotinate. nicotinate. Methyl 4(p chloro-a,a,a-trifluoro-ml-aminomorpholine l-amino-l-methylmorpholinium 4-(p-chloro a,a,a-triflu0r0-mtoluidino)nicotinatc. toluidino)nicotinate. Methyl 4-(ne,a,a-trifiuoro-m-toluidin0)- l-amino-ermethylpiperazine 1amino-1,4-dimethylpiperazinium 4-(a,a,a-tirfluoro-mnicotinate. toluidino)nicotinate.
Do l-amino-3-hydroxypiperidine l-amino-B-hydroxy-l-methylpipcridinium 4(a,a,a-trifluoro-mtoluidino)nicotinate. Do l-aminol-(13-hydroxyethyD-piperazine 1-arnino-4-(fl-hydroxyethyl)-1-methylpiperizinium 4 (cr,a,a-
trifluoiom-toluidino)-nicotinate.
The compounds of the present invention may be ad+ ministered as active components of compositions for administration in unit dosage form as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, oral solutions or suspensions and the like. The dosage found effective may vary from 1 mg. to 200 mg. per kilogram depending upon the warm-blooded animal. For preparing solid compositions such as tablets, the principal active ingredient is mixed with conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium siearate, dicalcium phosphate, gums, and functionally similar materials as pharmaceutical diluents or carriers. The tablets or pills of the novel compositions can be laminated or otherwise compounded to provide a dosage form affording the advantage of prolonged or delayed action or predetermined successive action of the enclosed medication. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids or mixtures of polymeric acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate, and the like. A particularly advantageous enteric coating comprises a styrene maleic acid copolymer together with known materials contributing to the enteric properties of the coating.
The liquid forms in which the novel composition of the present invention may be incorporated for administration include aqueous solutions, suitable flavored syrups, aqueous or oil suspensions, flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil, and the like, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, gelatin and the like. Sterile suspensions or solutions are required for parenteral use. Isotonic preparations containing suitable preservatives are also highly desirable for injection use.
The term unit dosage form as used in the specification and claims, refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical diluent, carrier or vehicle. The specifications for the novel unit dosage forms of this invention are dictated by and are directly dependent on (a) the unique characteristic of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for therapeutic use in warm-blooded animals, as disclosed in detail in this specification, these being features of the present invention. Examples of granules, Wafers, cachets, teaspoonfuls, dropperfuls, ampules; vials, segregated multiples of any of the foregoing and other forms as herein described.
The following examples describe in detail the preparation of intermediates and nicotinic acid derivatives final products of the present invention.
Example 1.Preparation of 4-(a,a,u-trifluoro-mtoluidino)-nicotinic acid l-oxide (A) A mixture of 3.0 g. of 3-nitronicotinic acid 1- oxide and 12 ml. of a,a,a-trifluoro-m-toluidine is heated at l40-150 C. for 3 hours. Upon cooling, the mixture is dissolved in 10% aqueous potassium hydroxide and washed with ether. The aqueous layer is acidified to give 4.1 g. of 4-(a,a,u-trifluoro-m-toluidino)-nicotinic acid 1- oxide as a tan powder, melting point 277280= C. dec.
(B) A mixture of 1.0 g. of 4-chloronicotinic acid 1- oxide and 3 ml. of a,a,a-trifluoro-m-toluidine is heated at C. for 1.5 hours, cooled and filtered, to give 2.0 g. of white crystals. The solid is stirred into 70 ml. of warm water, cooled and filtered to give 1.2 g. of 4-(oz,ot,atrifluoro-m-toluidino)nicotinic acid l-oxide as a tan powder, melting point 282 C. dec.
Example 2.Preparation of 4-(a,a,u-trifiuoro-m toluidino -nicotinic acid (A) A suspension of 4.0 g. of 4-(u,a,a-trifiuoro-mtoluidino)-nicotinic acid l-oxide and 800 mg. of 10% palladium-on-carbon catalyst is hydrogenated at 60 and 45 lb. pressure for 2.5 hours. The catalyst is filtered and Washed with ethanol. The combined filtrates are evaporated to a pink crystalline mass, melting point 258- 260 C. dec. which is crystallized from ethanol to give 2.0 g. of 4-(04,11,a-trifiuoro-m-toluidino)nicotinic acid as colorless crystals, melting point 260-262 C., dec. A sample is prepared for analysis by sublimation at 180 C. and 0.01 mm. Hg to give melting point 265 267 C.
(B) A mixture of 1.0 g. of 4-aminonicotinic acid, 1.0 g. of potassium carbonate, 5 mg. of cupric oxide, 5 mg. of copper powder, 18 g. of 3-bromo-a,a,a-trifluorotoluene and 5 ml. of n-hexanol is heated at reflux in an inert atmosphere for 70 hours, cooled, diluted with ether and filtered. The resulting brown paste is dissolved in 10% potassium hydroxide solution, filtered, is neutralized with 6 N hydrochloric acid. Filtration gives 160 mg. of brown powder which, after crystallization from methanol, gives 70 mg. of 4-(a,u,a-trifluoro-m-toluidino)-nicotinic acid, melting point 264-266 C. Infrared spectral analysis shows this product to be identical with the authentic sample described in paragraph A above.
(C) A mixture of 200 mg. of 4-chloronicotinic acid and 1.4 ml. of a,a,a-trifluoro-m-toluidine is heated at C. for 1 hour and at 200 C. for 1 hour. Upon cooling, 40 ml. of Water is added and the mixture is dis tilled until all a,a,a-trifluoro-m-toluidine is removed. Crystallization occurs in the still during distillation. Filtration gives 265 mg. of 4-(a,a,a-trifluoro-m-toluidino) nicotinic acid, melting point 262 C. dec. The compound of this example is particularly useful as a diuretic.
7 Example 3.Preparation of 4-(2,3-xylidino)- nicotinic acid A mixture of 3.0 g. of 4-nitronicotinic acid 1-oxide and 12 ml. of 2,3-dimethylaniline is heated at 150 C.
8 Examples 6-18 I In the manner described in Example 2, part C, treatment of 4-chloronicotinic acid with the appropriate amine gives the products of Table 'I.
TABLE I Example No. Starting Amine Product Melting point, (3.
ti a,a-Trilluoro-p-toluidino 4-(zz,a,a-trifiuoro-p-toluidino)nicotinic acid 269-271 7 o-Ghloroanilino. 4-(2-ehloroaniliuo)nicotinic acid 286-288 8 p-Chloroaniline- 4-(4-chlor0anilino)nicotinic acid. 277-270 3,4 xylidine 4-(3,4-xylidino)nicotinie acid. 260271 10 3,5xylidine 4-(3,5xy1idino)nicotinic acid 294-290 11 m-Ethylaniline 4(3-ethylanilino)nieotinic acid 248-250 12 o-Aminobenzoie acid- 4-(o-carboxyani1ino)nicotinic acid. 3244126 13 m-Aminobenzoic acid 4-(m-carboxyanilino) nicotinic acid 302-304 14.- m-Fluoroaniline 4-(m-fluoroanilino)nicotinic acid" 205-297 15 m-Aminophenol- 4-(m-hydroxyani1ino)nicotinic acid 318-320 16 -amiuo-2-chlorobsnzotrifiuoride 4-(p-chloro-zx,m,a-trifluoro-m-toluidino) nicotinic acid- 266-269 17 m-Nitroaniline 4-(m-nitroanilino)nicotinic acid 288-290 18 2,6-dichlcro-m-toluidine 4-(2,6-diehlordm-toluidino)nicotinic acid 310-312 for 4 hours, cooled and poured into aqueous potassium hydroxide. After extraction with ether, the aqueous layer is filtered and neutralized to give 2.5 g. of 4-(2,3-xylidino)-nicotinic acid l-oxide as a tan powder, melting point 262265 C. dec.
The above oxide is suspended in 150 ml. of acetic acid containing 800 mg. of 10% palladium-on-carbon catalyst and is hydrogenated at 60 and 45 lb. pressure for 8 hours. The catalyst is filtered and the filtrate is concentrated to give, upon addition of ethanol, 1.3 g. of 4-(2,3-xylidino)-nicotinic acid, melting point 295- 300 C. dec. A sample for analysis is prepared by sublimation at 200 C. and 0.01 mm. Hg to give colorless crystals, melting point 296300 C. dec. This compound is particularly useful as an anti-inflammatory agent.
Example 4.Preparation of 4-(m-chloroanilino)- nicotinic acid A mixture of 4.0 g. of 4-nitronicotinic acid l-oxide and ml. of m-chloroaniline is heated at 160 C. for 2 hours. Upon cooling, a 10% potassium hydroxide solution is added and the resulting solution is washed several times with ether. The ether extracts are discarded and the aqueous layer is neutralized with 6 .N hydrochloric acid to give 4.4 g. of 4-(m-chloroanilino)nicotinic acid 1- oxide, melting point 288-290 C.
A 750 mg. portion of 4-(m-chloroanilino)-nicotinic acid l-oxide in 150 ml. of acetic acid containing 500 mg. of 10% palladium-on-carbon is hydrogenated at 60 C. and 35 lb. pressure for 24 hours. Filtration of the catalyst and evaporation of the filtrate gives 700 mg. of tan solid which upon suspension in acetone and filtration gives 450 mg. of 4-(m-chloroanilino) -nicotinic acid, melting point 250 C. dec. Crystallization from water gives colorless needles, melting point 285 28 9 C. dec.
Example 5.-Preparation of 4-(m-toluidino)- nicotinic acid A mixture of 3 g. of 4-nitronicotinic acid l-oxide and 10 ml. of m-toluidine is heated at 100 C. from 1 hour and at 140 C. for 4 hours. Upon cooling, a 10% aqueous potassium hydroxide solution is aded and the resulting solution is washed several times with ether. The ether extracts are discarded and the aqueous layer is filtered and neutralized with 6 N hydrochloric acid to give 3.1 g. of 4-(m-toluidino)-nicotinic acid l-oxide, melting point 270272 C.
A suspension of 2.5 g. of the above 4-(m-toluidino)- nicotinic acid l-oxide in 200 ml. of acetic acid containing 800 mg. of 10% palladium-on-carbon is hydrogenated at 60 C. and 45 lb. pressure for 24 hours. It incomplete reduction is observed, the reaction may be repeated using methanol as solvent. Filtration of the catalyst and concentration of the methanol gives 4-(m-toluidino)-nicotinic acid, melting point 276-278 C.
Example 19.-Preparation of sodium 4-'(a,oc,oz-tlifi1lOIO- m-toluidino) -nicotinate A solution of 1.41 g. of '4-(OL,OL,OL-tI'lfiUOI'O-II1-t0ll.1idlll0)- nicotinic acid in 50 ml. of 0.10 N sodium hydroxide is evaporated to a creamy white paste which is dissolved in ethanol, filtered and concentrated until crystallization occurs. Filtration gives 400 mg. of sodium 4-(a,ot,a-[I'ifluoro-m-toluidino)-nicotinate as a white, water soluble powder which has high diuretic activty.
Example 20.--Preparation of .N-(Z-dimethylaminoethyl)- 4(o e,a-trifiuoro-m-toluidino)-nicotinate A mixture of 2.74 g. of sodium 4-(a,oz,cz-triflUO1'O-mtoluidino)-nicotinate and 1.05 g. of 2chloro-'N,N-dimethylethylamine in 30 ml. of ethanol is stirred for 24 hours at room temperature. The mixture is filtered and the filtrate is concentrated under reduced pressure. Crystallization from methanol-petroleum ether gives N (2-dimethylaminoethyl)-4-(a,u,a-trifluoro-m toluidino)-nicotinate.
Example 21.-Preparation of methyl-4-(u,a,a-trifluoro-m-toluidino)-nicotinate A mixture of 3.25 g. of sodium 4-(u,a,ot-trifluoro-mtoluidino)-nicotiuate and 10 ml. of methyl iodide in 100 ml. of ethanol is stirred at room temperature for 16 hours. The mixture is filtered and the filtrate is concentrated under reduced pressure to give methyl 4(a,a,u-tl'ifluoro-m-toluidino)-nicotinate, melting point 118-12'l C. after purification by sublimation.
Example 22.'Preparation of 4(a,a,u-trifluorom-toluidino) -nicotin amide Example 23.-Preparation of N,N-dimethyl-4-(a,a,atrifluoro-m-toluidino)-nicotinamide A solution of 1.33 g. of methyl 4-(a,a,m-trifiuoro-mtoluidino)-nicotinate and 14 ml. of dimethylamine in ml. of ethanol is heated in a steel autoclave at 50 C. for 8 hours. The residue obtained on concentration of the mixture to dryness is crystallized from methanol and water to give N,N-dimethyl-4-(u,a,a-trifluoro-m-toluidino)-nicotinamide.
Example 24.Preparation of n-n1ethyl-4-(a,a,a-trifluorom-toluidino)-nicotinamide A solution of 300 g. of methyl 4-(ot,ot,oc-tl'ifil10lO-mtoluidino)-nicotinate and 300 mg. of sodium methoxide and 1 ml. of methylformamide is heated at 95 C. for 18 hours. After cooling and diluting with Water, the reaction mixture is extracted with ether, and the ether solution washed With water dried and evaporated to give 300 mg. of oil-white crystals, melting point 140144 C. The product is crystallized from acetone-hexane to give N-methyl- 4-(ix,a,a-trifluoro-m-toluidino) nicotinamide as white crystals, melting point 144-146" C.
Example 25.Preparation of butyl 4-(a,u,a-trifiuoro-mtoluidino -nicotinate A solution of 3.0 g. of 4-(a,a,u-trifluoro-m-toluidino)- nicotinic acid in 20 ml. of n-butyl alcohol and 4 ml. of H 80 is heated at reflux for 16 hours, cooled and neutralized with NH OH. The product is extracted into chloroform, and the extract is Washed with NaOH and with water. After evaporation, the resulting oil is chromatographed on 150 g. of silica gel. Ether-dichloromethane (3:7) gives, upon evaporation, 1.5 g. of colorless crystals (7), melting point 48-52. The ether is recrystallized from etherhexane, cooled to 60 to give butyl 4-(a,a,u-trifluoro-m-toluidino)-nicotinate as crystals, melting point 44-46" C.
Example 26.4-(m-fiuoroanilino) -nicotinic acid A mixture of 4.0 g. of 4-nitronicotinic acid l-oxide and 12 ml. of m-fluoroaniline is heated at 200 for 4 hours, cooled and dissolved in 10% aqueous sodium hydroxide. After extraction with ether, the aqueous layer is filtered and acidified. The resulting product 3.0 g. of 4- (m-fluoroanilino)-nicotinic acid l-oxide is hydrogenated at 60 and 35 lb. pressure for 18 hours in 200 ml. of acetic acid containing 1.0 g. of 10% palladium-on-carbon. The catalyst is filtered and the filtrate is evaporated. Addition of methanol gives 4-(m-fluoroanilino)-nicotinic acid as white needles, melting point 292294 C. A sample for analysis may be prepared by sublimation.
Example 27.Preparation of 4-(m-aminoanilino)- nicotinic acid A mixture of 1.0 g. of 4-(m-nitroanilino)-nicotinic acid in 60 ml. of acetic acid containing 250 mg. of 10% palladium-on-carbon catalyst is hydrogenated at 60 and 25 lb. pressure for 1 hour. After cooling and filtering, the solvent is evaporated. The addition of methanol gives, after filtration, 570 mg. of white plates, melting point 291292 C. Several crystallizations from methanol gives 4-(m-aminoanilino)-nicotinic acid as crystals, melting point 298-299 C.
Example 28.-Preparation of 4-(oc,0t,oc-tlifll10r0-m-IOlllidino)-nicotinic acid hydrochloride A solution of 1.0 g. of 4-(a,oz,u-trifluoro-m-toluidino)- nicotinic acid in 100 ml. of methanol is saturated with a rated and the residue is filtered from dichloromethane to give 1.1 g. of 4-(0t,06,1X-t1'lfil1OI'O-lI1-t0ll1idll'l0)-IliCOliIliC acid hydrochloride as a white powder, melting point 278- 282 C.
Example 29.Preparation of 1,1,1-trimethylhydrazinium 4-(a,a,a-trifluoro-m-toluidino)-nicotinate A solution of 2.2 g. of methyl 4-(a,ot,a-trifluoro-m-toluidino)-nicotinate in 15 ml. of unsymmetrical dimethylhydrazine is heated at reflux overnight. After evaporation of the solvent, the residue is crystallized from dichloromethane-ether to give 2.3 g. of 1,1,1-trimethylhydrazinium 4-(a,ot,ot-tl'lflllOIO-IIl-tOlllidlIlO)-11iC0fiI1at6 as white needles, melting point 118121 C.
We claim:
1. A 4-amino-nicotinoyl compound selected from the group consisting of a compound of the formula:
wherein R is selected from the group consisting of (lower alkyl)phenyl, halophenyl, 0t,0L,0t-trlfl11OI'0tOlyl, and halooc,oc,oz-lI'ifll10r0t0lyl; R is selected from the group consisting of hydroxy, lower alkoxy and amino, and pharmaceutically acceptable salts.
2. The 4-amino-nicotinoyl compound according to claim 1: 4-(u,a,a-trifluoro-p-toluidino)-nicotinic acid.
3. The 4-amino-nicotinoyl compound according to claim 1: methyl 4-(a,a,a-trifluoro-m-toluidino)-nicotinate.
4. The 4-aminonicotinoyl compound according to claim 1: 4-(m-chloroanilino)-nicotinic acid.
5. The 4-amino-nic0tinoyl compound according to claim 1: 4-(o-chloroanilino)-nicotinic acid.
6. The 4-amino-nicotinoyl compound according to claim 1: sodium 4-(a,a,a-trifluoro-m-toluidino)-nicotinate.
7. The 4-amino-nicotinoyl compound according to claim 1: 4-(u,a,u-trifluoro-m-toluidino)-nicotinic acid.
8. The 4-amino-nicotinoyl compound according to claim 1: 4 (a,a,a-trifiuoro-p-chloro-m-toluidino)nicotim'c acid.
9. The 4-amino-nicotinoyl compound according to claim 1: 4-(o-toluidino)-nicotinic acid.
HENRY R. JILES, Primary Examiner.
A. L. ROTMAN, Assistant Examiner.
U.'S. Cl. X.R.
stream of hydrogen chloride gas. The solution is evapo- 260-2472, 268, 270, 294, 568; 424-266
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3538106A (en) * 1968-01-22 1970-11-03 Lab U P S A Sa 2-(trihalogenoanilino)-nicotinuric acid,the corresponding glycinates and derivatives thereof
US4179509A (en) * 1978-09-18 1979-12-18 Warner-Lambert Company (Substituted 2-carboxyanilino)nicotinic acids as inhibitors of allergic reactions
US4273779A (en) * 1976-12-23 1981-06-16 Ciba-Geigy Corporation Treating hypertension with substituted-5-amino-2-pyridinecarboxylic acids
US4859663A (en) * 1985-04-18 1989-08-22 Hoechst Aktiengesellschaft Multiply substituted pyridine 1-oxide compounds which are useful in treating brain disorders
EP0435222A2 (en) * 1989-12-27 1991-07-03 Hoechst-Roussel Pharmaceuticals Incorporated Aminopyridinylmethanols and aminomethylpyridinamines and related compounds, a process for their preparation and their use as medicaments

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4205073A (en) * 1975-04-30 1980-05-27 Schering Corporation Anti-diarrheal anilino nicotinic acids and method of using same

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3337570A (en) * 1965-10-23 1967-08-22 Schering Corp Substituted nicotinic acids and method for the manufacture thereof

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3337570A (en) * 1965-10-23 1967-08-22 Schering Corp Substituted nicotinic acids and method for the manufacture thereof

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3538106A (en) * 1968-01-22 1970-11-03 Lab U P S A Sa 2-(trihalogenoanilino)-nicotinuric acid,the corresponding glycinates and derivatives thereof
US4273779A (en) * 1976-12-23 1981-06-16 Ciba-Geigy Corporation Treating hypertension with substituted-5-amino-2-pyridinecarboxylic acids
US4179509A (en) * 1978-09-18 1979-12-18 Warner-Lambert Company (Substituted 2-carboxyanilino)nicotinic acids as inhibitors of allergic reactions
US4859663A (en) * 1985-04-18 1989-08-22 Hoechst Aktiengesellschaft Multiply substituted pyridine 1-oxide compounds which are useful in treating brain disorders
EP0435222A2 (en) * 1989-12-27 1991-07-03 Hoechst-Roussel Pharmaceuticals Incorporated Aminopyridinylmethanols and aminomethylpyridinamines and related compounds, a process for their preparation and their use as medicaments
EP0435222A3 (en) * 1989-12-27 1991-12-11 Hoechst-Roussel Pharmaceuticals Incorporated Aminopyridinylmethanols and aminomethylpyridinamines and related compounds, a process for their preparation and their use as medicaments

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