US3725417A - Carboxamidobenzoic acids as hypolipemic agents - Google Patents

Carboxamidobenzoic acids as hypolipemic agents Download PDF

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Publication number
US3725417A
US3725417A US00194922A US3725417DA US3725417A US 3725417 A US3725417 A US 3725417A US 00194922 A US00194922 A US 00194922A US 3725417D A US3725417D A US 3725417DA US 3725417 A US3725417 A US 3725417A
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United States
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acid
carbomethoxy
chloro
benzoic acid
compound
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US00194922A
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G Holland
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Pfizer Corp Belgium
Pfizer Inc
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Pfizer Corp Belgium
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom

Definitions

  • Z is selected from the group comprising 0, S, NH and (CH wherein said m is an integer from 0 to 3, and methyl, benzyl and dimethyl substituted derivatives of said heterocyclic rings; and X is selected from the group comprising fluorine, chlorine, bromine, methoxy, methylthio and benzylthio and substituted benzylthio wherein said substituent is selected from the group comprising fluorine, chlorine, bromine, trifluoromethyl, methyl and methoxy, are hypolipemic agents in mammals.
  • the preferred compounds of the instant invention are those congeners wherein X is chlorine and R is alkyl containing from 1 to 4 carbon atoms and R is alkyl containing from 1 'to 4 carbon atoms or substituted phenylalkyl where said alkyl contains from 1 to 2 carbon atoms and said substituent is fluorine, chlorine, bromine, methyl or methoxy. Also of interest are those compounds where-X is chlorine and R, and R taken together with the nitrogen to which they are attached form a piperidine ring which is substituted by dimethyl or benzyl.
  • the starting acid halide preferably the chloride
  • a reaction-inert solvent such as benzene, methylene chloride, ether or dim'ethylforma mide
  • the solvent is removed and the resulting crude product, I, is subsequently dissolved in ethanol and hydrolyzed with 1N aqueous sodium hydroxide.
  • the desired product, II is isolated by removal of the ethanol and acidification of the residual aqueous solution.
  • the hydrolysis of I is effected at room temperature and requires approximately 1-3 hours for completion.
  • the newly formed product can be filtered from the acidified solution or extracted with a water immiscible solvent such as ethyl acetate.
  • the starting reagent leading to the synthesis of the above-mentioned acid halides is methyl 2-amino-5-carboxybenzoate, synthesized according to the procedure of Wegscheider, Monatsh. Chem., 37, 219 (1916); C.A., 10, 3009 (1916).
  • R R Nl-l employed as starting reagents are either commercially available or can be synthesized according to one of the procedures reported by Wagner and Zook, Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York, 1956, page 653.
  • Acid congeners of the present invention are converted to basic salts by the interaction of said acid with an appropriate base in an aqueous or non-aqueous medium.
  • Said basic reagents suitably employed in the preparation of said salts can vary in nature, and are meant to contemplate such bases as organic amines, ammonia, alkali metal hydroxides, carbonates, bicarbonates, hydrides and alkoxides, as well as alkali earth metal hydroxides, hydrides, alkoxides and carbonates.
  • bases are ammonia, primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethylamine, octylamine, tertiary amines such as diethylaniline, N-methylpyrrolidine, N-methylmorpholine and 1,5-diazabicyclo-[4,3,0]-nonene; sodium hydroxide, potassium hydroxide, ammonium hydroxide, sodium ethoxide, potassium methoxide, magnesium "hydroxide, calcium hydride and barium hydroxide.
  • primary amines such as n-propylamine, n-butylamine, aniline, cyclohexylamine, benzylamine, p-toluidine, ethylamine, octylamine, tertiary amines such as diethylaniline, N-methylpyrrol
  • the chemotherapeutic activity of those compounds of the present invention which form basic salts it is preferred, of course, to use pharmaceutically acceptable salts.
  • pharmaceutically acceptable salts water-insolubility, high toxicity, or lack of crystalline nature may make some salt species unsuitable or less desirable for use as such in a given pharmaceutical.application, the water insoluble or toxic salts can be converted to the corresponding acids by decomposition of the salts as described above, or alternately they can be converted to any desired pharmaceutically acceptable basic salt.
  • the said pharmaceutically acceptable salts preferred are those wherein the cation is ammonium, sodium or potassium.
  • benzoic acids of the present invention are all readily adapted to therapeutic use as hypolipemic agents in mammals.
  • Outstanding for their effectiveness in this regard include the following agents:
  • the products of the invention are tested in vivo for hypolipemic activity in rats.
  • Groups, each comprising 4 animals, of normal Sprague-Dawley (Charles River) male rats weighing from to 220 grams are fed rat chow containing the compound under test for two overnight feeding periods.
  • the animals On the morning of the third day the animals are anesthetized and bled from the ab dominal aorta.
  • the total plasma cholesterol is then determined by the method of J. J. Carr and I. J. Drekter, reported in Clin. Chem., 2, 353 (1956).
  • the use of the present invention is directed toward the treatment of mammals in general, the preferred subject is humans.
  • results of animal testing are frequently extrapolated and a correlation is assumed between animal test behavior and proposed human dosage.
  • the dose level of the clinical candidate in humans is frequently determined by comparison of its performance with the'standard in an animal test.
  • Atromid-S is employed as a standard hypolipemic agent and is administered to humans at the rate of 2.0 g. daily in individual doses. It is assumed, then, that if compounds of the present invention have activity comparable to Atromid-S in the test assay, that similar doses will provide comparable responses in humans.
  • an effective daily dosage of the compounds of the present invention in humans will generally range from 0.3 to 5 g. per day in single or divided doses. These values are illustrative, and there may, of course, be individual cases where higher or lower dose ranges are merited.
  • the benzoic acids of this invention can be administered either alone, or, preferably, in combination with a pharmaceutically acceptable carrier. They may be combined with various pharmaceutically acceptable, inert carriers in the form of tablets, capsules, lozenges, troches, powders, aqueous suspensions or solutions, elixirs, syrups and the like. Suitable carriers include solid diluents or aqueous media and non-toxic organic .solvents.
  • the oral pharmaceutical compositions of this invention may be suitable sweetened and flavored by means of various agents commonly em ployed for such'a purpose.
  • solutions or suspensions of the herein described benzoic acids in sesame or peanut oil or in aqueous propylene glycol solutions can be employed, as well as sterile aqueous solutions of the corresponding water-soluble salts.
  • Such solutions are suitable for intramuscular and subcutaneous administration.
  • Sterile aqueous solutions are additionally useful for intravenous injection, provided that their pH is suitably adjusted and buffered, if necessary, and the limitations of this invention, many variations of which 7 are possible without departing from the spirit or scope thereof.
  • the residual solid is dissolved in 25 ml. of ethanol, treated with 20 ml. of an aqueous 1N sodium hydroxide solution and allowed'to stand at room temperature for 1 hour.
  • the ethanol is removed from the reaction mixture under reduced pressure and the residual aqueous solution acidified with 12N hydrochloric acid.
  • the product is extracted with ethyl acetate, and the organic phase separated, dried over sodium sulfate and concentrated to dryness in vacuo, 1.1 g., m.p. l20-l22 C. Recrystallization from acetone-hexane provides the pure product, m.p. l2l-l23 C.
  • the solvent is removed in vacuo and the residue is treated with 30 ml. of ethanol and 18 ml. ofa 1N aqueous sodium hydroxide solution. After one hour at room temperature the ethanol is removed under reduced pressure, and the remaining aqueous solution is acidified with 6N hydrochloric acid. The precipitated product is extracted into chloroform, and the organic layer separated, dried over sodium sulfate and concentrated to dryness to provide the desired product.
  • EXAMPLE 8 The procedure of Example 7 is repeated, using the requisite heterocyclic amine and the appropriately substituted benzoyl chloride, to provide the following 2-Chloro-5-(4-Morpholinocarbonyl)benzoic acid
  • 1.75 g. (20 m moles) of morpholine and 1.5 g. (7m mols) of 3-carbomethoxy-4-chlorobenzoyl chloride gives, after recrystallization from acetone, 700 mg. of the desired product, m.p. l73l75 C.
  • EXAMPLE 1 1 2-Chloro-5-(4-benzylpiperidinocarbonyl)benzoic Acid Starting with 3.5 g. (20 m moles) of 4-benzylpiperidine and 1.5 g. (7 m moles) of 3-carbomethoxy- 4-chlor0benzoyl chloride in 25 ml. of methylene chloride, and following the general procedure of Example 1, there is obtained 1.5 g. of an amorphous product, m.p. 80-85 C.
  • test compound consumed is computed from feed consumption over the 2-day period and is tabulated, in milligrams per kilogram body weight per day, along with the associated percent cholesterol fall measured:
  • the dry mixture is thoroughly agitated to obtain a completely uniform blend.
  • Soft elastic and hard gelatin capsules containing this composition are then prepared, employing sufficient material to provide each capsule with 190 mg. of active ingredient.
  • EXAMPLE 16 A dry solid pharmaceutical composition is prepared by blending the following materials together in the specified weight proportions:
  • tablets are punched from the mixture, each tablet being of. such size as to contain mg. of the active ingredient. Tablets are also prepared containing, respectively, 5, 10, 25 and 50 mg. of the active ingredient, by
  • EXAMPLE 17 2-Chloro-5-(3 ,5-dimethylpiperidinocarbonyl)benzoic acid Sodium Salt To a solution of 400 mg. (0.01 mole) of sodium hydroxide in 30 ml. of water is added, in portions and with stirring, 2.95 g. (0.01 mole) of 2-chloro-5-(3,5- dimethylpiperidinocarbonyl)benzoic acid. The slightly hazy solution is filtered and the filtrate concentrated at room temperature and under reduced pressure to dryness. The residual sodium salt is triturated with acetone and filtered.
  • 3-carbomethoxy-4-methoxybenzoic acid 1 In a manner similar to that employed in Preparation A-a, 2.9 g. (15 m moles) of 3-carbomethoxy-4- aminobenzoie acid is diazotized with 4.5 ml. of water containing 8 g. of ice, 3.3 ml. of concentrated sulfuric acid and 1.05 g. (15.2 m moles) of sodium nitrile. The precipitated solid diazonium salt is separated from the supernatant by decantation and added in small portions to a hot solution of 10 ml. of water and 10 ml. of concentrated sulfuric acid. When nitrogen evolution ceases, the solution is cooled and the product, 3 carbomethoxy-4-hydroxybenzoic acid, is filtered and dried.
  • 3-carbomethoxy-4-benzylthiobenzoic acid 3-carbomethoxy-4-benzylthiobenzoic acid; 3-carbomethoxy-4-p-chlorobenzylthiobenzoic acid; 3-carbornethoxy-4-m-trifluoromethylbenzylthiobenzoic acid; 3-carbomethoxy-4-m-methoxybenzylthiobenzoic acid; 3-carbomethoxy-4o-methylbenzylthiobenzoic acid; 3-carbomethoxy-4-p-bromobenzylthiobenzoic acid; 3-carbomethoxy-4-m-methylbenzylthiobenzoic acid, 3 -carbomethoxy-4-o-.methoxybenzylthiobenzoic acid and 3-carbomethoxy-4-p-fiuorobenzylthiobenzoic acid.
  • R, and R when considered separately are each selected from the group consisting of hydrogen, alkyl containing from 1 to 4 carbon atoms, phenylalkyl and substituted phenylalkyl wherein said alkyl contains from I to 2 carbon atoms and said substituent is selected from the group consisting of fluorine, chlorine, bromine, methyl and methoxy; R, and R, when taken together with the nitrogen to which they are attached form a heterocyclic ring of the formula:
  • Z is selected from the group consisting of O, S,
  • X is selected from the group consisting of fluorine
  • R is alkyl containing from 1 to 4 carbon atoms and X is chlorine.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Obesity (AREA)
  • Diabetes (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
US00194922A 1971-11-02 1971-11-02 Carboxamidobenzoic acids as hypolipemic agents Expired - Lifetime US3725417A (en)

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JP (1) JPS5653536B2 (enExample)
BE (1) BE790859A (enExample)
DE (1) DE2253748A1 (enExample)
FR (1) FR2158444B1 (enExample)
GB (1) GB1380095A (enExample)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4182775A (en) * 1976-09-04 1980-01-08 Hoechst Aktiengesellschaft Benzoic acids and process for their preparation
US4297503A (en) * 1978-07-31 1981-10-27 Asahi Kasei Kogyo Kabushiki Kaisha Novel benzamide derivative and method of preparing metoclopramide using same
US6525078B1 (en) 2002-06-25 2003-02-25 Cesare Casagrande Compound for the treatment of atherosclerotic-thrombotic pathological conditions
US20070105859A1 (en) * 2003-09-19 2007-05-10 Yoshiaki Isshiki 4-Phenylamino-benzaldoxime derivatives and uses thereof as mitogen-activated protein kinase kinase (mek) inhibitors
US20090233915A1 (en) * 2004-07-26 2009-09-17 Yoshiaki Isshiki 5-Substituted-2-Phenylamino Benzamides as MEK Inhibitors

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1476633A (en) * 1973-10-03 1977-06-16 Unilever Ltd Dentifrice composition

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3268526A (en) * 1962-09-12 1966-08-23 Monsanto Co Heterocyclic polyhalobenzamide derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3268526A (en) * 1962-09-12 1966-08-23 Monsanto Co Heterocyclic polyhalobenzamide derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. Indian Chem. Soc. 34 : 371 374 (1957) Patel et al. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4182775A (en) * 1976-09-04 1980-01-08 Hoechst Aktiengesellschaft Benzoic acids and process for their preparation
US4297503A (en) * 1978-07-31 1981-10-27 Asahi Kasei Kogyo Kabushiki Kaisha Novel benzamide derivative and method of preparing metoclopramide using same
US6525078B1 (en) 2002-06-25 2003-02-25 Cesare Casagrande Compound for the treatment of atherosclerotic-thrombotic pathological conditions
US20070105859A1 (en) * 2003-09-19 2007-05-10 Yoshiaki Isshiki 4-Phenylamino-benzaldoxime derivatives and uses thereof as mitogen-activated protein kinase kinase (mek) inhibitors
US8084645B2 (en) 2003-09-19 2011-12-27 Chugai Seiyaku Kabushiki Kaisha 4-phenylamino-benzaldoxime derivatives and uses thereof as mitogen-activated protein kinase kinase (MEK) inhibitors
US20090233915A1 (en) * 2004-07-26 2009-09-17 Yoshiaki Isshiki 5-Substituted-2-Phenylamino Benzamides as MEK Inhibitors
US7745663B2 (en) 2004-07-26 2010-06-29 Chugai Seiyaku Kabushiki Kaisha 5-Substituted-2-phenylamino benzamides as MEK inhibitors
US8575391B2 (en) 2004-07-26 2013-11-05 Chugai Seiyaku Kabushiki Kaisha 5-substituted-2-phenylamino benzamides as MEK inhibitors

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BE790859A (fr) 1973-04-30
DE2253748A1 (de) 1973-05-30
FR2158444A1 (enExample) 1973-06-15
GB1380095A (en) 1975-01-08
JPS5653536B2 (enExample) 1981-12-19
FR2158444B1 (enExample) 1975-10-31
JPS4861448A (enExample) 1973-08-28

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