US3868416A - Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives - Google Patents

Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives Download PDF

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US3868416A
US3868416A US402212A US40221273A US3868416A US 3868416 A US3868416 A US 3868416A US 402212 A US402212 A US 402212A US 40221273 A US40221273 A US 40221273A US 3868416 A US3868416 A US 3868416A
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benzoic acid
ethyl
mixture
ethanol
benzoate
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US402212A
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Jay Donald Albright
Stephen Joseph Riggi
Robert Gordon Shepherd
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Wyeth Holdings LLC
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American Cyanamid Co
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Priority to US402212A priority Critical patent/US3868416A/en
Priority to ZA00745732A priority patent/ZA745732B/en
Priority to IL45643A priority patent/IL45643A/en
Priority to GB40539/74A priority patent/GB1488674A/en
Priority to AR255678A priority patent/AR211687A1/en
Priority to DE2446010A priority patent/DE2446010C2/en
Priority to YU02622/74A priority patent/YU262274A/en
Priority to IE2015/74A priority patent/IE40527B1/en
Priority to BE149073A priority patent/BE820542A/en
Priority to CA210,303A priority patent/CA1077957A/en
Priority to FR7432894A priority patent/FR2246267B1/fr
Priority to DK515474AA priority patent/DK141844B/en
Priority to SE7412307A priority patent/SE410595B/en
Priority to CH1321774A priority patent/CH609676A5/xx
Priority to AT788574A priority patent/AT338250B/en
Priority to NLAANVRAGE7412956,A priority patent/NL179725C/en
Priority to SU742065154A priority patent/SU590311A1/en
Priority to DD181444A priority patent/DD116031A5/xx
Priority to JP49113271A priority patent/JPS5747901B2/ja
Priority to HU74AE427A priority patent/HU175875B/en
Priority to ES430574A priority patent/ES430574A1/en
Priority to US518022A priority patent/US3924001A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions

Definitions

  • R is an unbranched or branched alkyl group, C,, H wherein n is 4 to 19; and R is hydrogen, lower alkyl, benzyl, dilower alkylaminoethyl, lower alkoxyethyl, 1-methyl-4-piperidyl, 2-pyridylmethyl, 4- pyridylmethyl; and the pharmaceutically acceptable salts thereof.
  • Suitable lower alkyl groups contemplated by the present invention are those having up to six carbon atoms such as, for example, methyl, isopropyl, npropyl, ethyl, sec-butyl, tert-amyl and n-hexyl.
  • the invention contemplates as novel compounds per se only those acids, esters and pharmaceutically acceptable salts thereof wherein n is 8 to 19.
  • Compounds wherein n is 4 to 7 are known in the art, infra.
  • the invention contemplates a method for lowering serum lipids in mammals by administration of said acids and esters wherein n is 4 to 19, and the use of pharmaceutically acceptable salts and pharmaceutical compositions employing said acids, esters and salts to lower serum lipids.
  • n 14 to 17
  • R in the above formula is hydrogen
  • the compounds of the present invention may be utilized either as the free acids or in the form of a pharmaceutically acceptable salt. Since the compounds are amphoteric, the salts can involve either the acidic or the basic moiety.
  • the salts may be either of an inorganic nature, such as the ammonium salt, sodium salt, potassium salt, etc., of the carboxyl group or the hydrochloric or sulfuric acid salts of the amino group, or of an organic type, such as an organic amine salt of the carboxyl group or a trifluoroacetic or citric acid salt of the amino group.
  • the 4-(monoalkylamino)benzoic acids and esters of the present invention are, in general, colorless or tan crystalline solids (some being colorless or tan oils) having characteristic melting points and spectral properties. They are soluble in organic solvents such as chloroform, benzene, dichloromethane, N,N-dimethylformamide, dimethylsulfoxide and lower alkanols. They are, however, generally insoluble in water.
  • the 4-(monoalkylamino)benzoic acids and esters of the present invention are bases and may be converted to their non-toxic acid-addition salts by treatment with acids such as sulfuric, hydrochloric, phosphoric, succinic, citric, and the like.
  • acids such as sulfuric, hydrochloric, phosphoric, succinic, citric, and the like.
  • Those compounds wherein R is hydrogen may be reacted with alkali bases such as sodium hydroxide, potassium hydroxide and calcium hydroxide or with organic bases such as ammonium hydroxide or lower mono-, dior tri(lower alkyl)amines such as methylamine, diethylamine, trimethylamine, dibutylamine, N,N'-dimethylethylenediamine, and the like to obtain the corresponding carboxylic acid salts.
  • the lower alkyl 4-(monoalkylamino)benzoates of this invention are prepared by reaction of loweralkyl p-aminobenzoates with suitable alkylating agents such as alkyl halides, sulfates, tosylates or trifluoromethylsulfonates with or without solvent at 50C. l50C.
  • suitable alkylating agents such as alkyl halides, sulfates, tosylates or trifluoromethylsulfonates with or without solvent at 50C. l50C.
  • suitable alkylating agents such as alkyl halides, sulfates, tosylates or trifluoromethylsulfonates with or without solvent at 50C. l50C.
  • suitable solvents are lower alkanols, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, diglyme, dimethylsulfoxide, acetonitrile, toluen
  • the reaction may be carried out with an equivalent of base such as an alkali carbonate or bicarbonate or with a catalytic amount of copper powder when alkyl halides are used as the alkylating agent.
  • base such as an alkali carbonate or bicarbonate
  • catalytic amount of copper powder when alkyl halides are used as the alkylating agent.
  • the lower alkyl 4-(monoalkylamino)benzoates are prepared by reaction of a lower alkyl aminobenzoate with an alkyl halide of4 to 19 carbon atoms in the presence of an equivalent of sodium hydride in an inert solvent such as N,N-dimethylformamide, N,N- dimethylacetamide, and diglyme at 50C.l50C.
  • Alternative methods of prepartion are by reductive alkylation of a 4-aminobenzoate ester or by a metal hydride reduction of a 4-(acylamino)benzoate ester or acid.
  • n-hexadecanal and methyl 4- aminobenzoate are reduced under 1-10 atmospheresof hydrogen using an activated metal catalyst, forming 4-(n-hexadecylamino)benzoic acid methyl ester.
  • the aldehyde appears to be formed in small amounts in situ in the synthetic procedure comprising heating at an elevated temperature and pressure n-hexadecanol and methyl 4-aminobenzoate in the presence of an activated Rancy nickel catalyst to give methyl 4-(n-hexadecylamino)benzoate.
  • Diboranc reduction of ethyl 4-(n-hexadecanoylamino)benzoate at room temperature or above for l-6 hours yields the ethyl analog of the above ester.
  • Two types of substitution reactions also yield the de sired 4-(alkylamino)benzoic acids or esters, namely, reaction of ethyl 3,4-didehydrobenzoate with an alkylamine (or its alkali metal salt) and Friedel-Crafts acylation of an N-alkylaniline or N-acyl-N-alkylaniline.
  • the former type of reaction is carried out by treating a 4- halobenzoate ester such as ethyl 4-bromobenzoate with the lithium, potassium, or sodium salt of an alkylamine (in excess) such as n-hexadecylamine in ether or other aprotic solvent.
  • the latter type comprises reacting N-nhexadecylaniline and the like or its N'acetyl derivative with oxalyl chloride and anhydrous aluminum chloride in dry ether, halocarbon or hydrocarbon medium.
  • the 4-(alkylamino)benzoic acids of this invention are prepared by hydrolysis of the corresponding benzoate esters by reacting with an alkali hydroxide such as sodium or potassium hydroxide in a lower alkanol,
  • the 4-(alkylamino)benzoic acids maybe prepared by hydrolysis of the lower alkyl 4-(monoalkylamino)benzoates with mineral acids such as hydrochloric, hydrobromic and sulfuric acid in water or aqueous lower alkanols.
  • lower alkyl 4-(dialkylamino)benzoates or the 4-(dialkylamino)benzoic acids which can be prepared by reaction of a lower alkyl 4 (monoalkylamino)benzoate with an appropriate alkylating agent to give the lower alkyl esters with subsequent hydrolysis to give the acids.
  • Suitable alkylating agents are lower alkyltosylates, lower dialkylsulfates (such as di methyl sulfate, diethyl sulfate and dipropyl sulfate), tri- (lower alkyl)oxonium tetrafluoroborates (such as trimethyloxonium and triethyloxonium tetrafluoroborates), lower alkyl halides, methyl fluorosulfonate and ethyl fluorosulfonate.
  • the alkylation reactions may 'be carried out with or without a solvent at 20C. to
  • Suitable solvents are chloroform, dichloromethane, carbontetrachloride, benzene, xylene and the like.
  • methylations are conveniently carried out with methyl fluorosulfonate in dichloromethane at 25C. for 2-20 hours while ethylations are conveniently carried out with excess diethyl sulfate at C.-l50C. without solvent.
  • Alkylations with alkyl halides may be carried out by first reacting the lower alkyl monoalkylaminobenzoate in a suitable solvent with sodium hydride or butyl lithium to give the amine anion and then reacting with the alkyl halide.
  • the lower alkylamino benzoic acid derivatives may be converted to their potassium, sodium or lithium salts and alkylated to give dialkylaminobenzoate esters alkylation occurring on both the amino group and on the oxygen of the acid salt.
  • Representative dialkylaminobenzoic acids and esters which have been prepared are ethyl 4-(dodecylmethylamino)benzoate, 4-(dodecylmethylamino)-benzoic acid, 4-(dodecylethylamino)benzoic acid, 4-(methyltetradecylamino)benzoic acid, 4-(ethyltetradecylamino)benzoic acid, ethyl 4-(methylpentadecylamino)benzoate, 4-(methylpentadecylamino)- benzoic acid, 4-(ethylpentadecylamino)benzoic acid, ethyl 4-(methylhexadecyla
  • Lower alkyl acylmonoalkylaminobenzoates can be prepared by acylation of the lower alkyl monoalkylaminobenzoates with acyl halides or anhydrides such as acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, succinic anhydride, etc. in the presence of a suitable base as pyridine, triethylamine and the like with or without an organic solvent.
  • a suitable base as pyridine, triethylamine and the like with or without an organic solvent.
  • Acylation of monoalkylaminobenzoic acids under similar conditions gives the acylmonoalkylaminobenzoic acid derivatives.
  • the N-acyl derivatives were prepared for testing for their activity per se and for the activity generated by their de-acylation.
  • N- benzoyl, N-acetyl, and N-succinoyl derivatives for example, ethyl 4-(N-acetyl-n-tetradecylamino)benzoate, 4-(N-acetyl-n-tetradecylamino)-benzoic acid, 4-(N- benzoyl-n-hexadecylamino)benzoic acid, 4-(N-acetyln-hexadecylamino)benzoic acid.
  • Such compounds have been prepared by acylation of ethyl 4-(tetradecylamino)-benzoate with acetyl chloride or acetic anhydridein presence of a suitable base such as pyridine or 4-dimethylamin'opyridine or by the acylation of 4-(tetradecylamino)benzoic acid and 4- (hexadecylamino)benzoic acid with acetyl chloride, benzoyl chloride, acetic anhydride or succinic anhydride in the presence of a suitable base such as pyritrols.
  • Table I shows several of the compounds of the present invention and the degree to which they depress serum sterolsand triglyceride levels after a 1-week and 4-week dosing period and phospholipids after a 4-weck dosing period.
  • the compounds of the present invention were shown to possess hypolipidemic activity as determined by animal experiments as follows: the compounds studied were administered orally admixed with the diet to groups of 4-6 male rats, CFE strain from Carworth Farms, New City, N.Y. A control group of 6-8 rats was maintained on the diet alone; test groups were maintained on the diet plus the indicated percentage of compound by weight. After 6 days or 2-4 weeks treatment, serum sterol concentrations were determined either (1) according to the saponification and extraction method of P. Trinder, Analyst 77, 321 (1952) and the colorimetric determination of Zlatkis, et al., J. Lab. Clin. Med. 44, t
  • Serum triglycerides were estimated by the automated procedure of Kessler and Lederer [Automation in Analytical Chemistry (monoalkylamino)benzoic acids and derivatives tested are all effective hypolipidemic agents, i.e., they reduce serum triglyceride and/or sterol levels. Reduction of serum sterol is highly desirable clinically since essentially all major studies reported in the literature indicate that elevated serum sterol concentration is directly related to the development of other atherosclerosis.
  • the major lipids found in abnormal levels are sterol and triglycerides.
  • the preferred compounds of this invention are capable of decreasing both of these blood lipid fractions as well as phospholipids, the third major lipid moiety in blood.
  • mice and gerbils were determined in mice and gerbils (Table 11) after 1 week of treatment.
  • Mice CF-l strain
  • gerbils were purchased from Chick Line Co., Vineland, NJ.
  • the methods used for lipid analysis were the same as those indicated above for Table I.
  • the 4-(monoalkylamino)benzoic acids and derivatives of this invention have potencies similar to or greater than 1-methy1-4-piperidyl bis( pchlorophenoxy)acetate and clofibrate, and thus are useful as hypolipidemic compounds in mammals when administered in amounts ranging from about 0.5 mg. per kg. to about 40 mg. per kg. of body weight per day.
  • a preferred dosage regimen for optimum results would be from about 2 mg. per kg. to about 29 mg. per kg.
  • the daily dosage employed for a subject of about 70 kg. of body weight is about 35 mg. to about 2.8 g., and preferably about 140 mg. to about 2.0 g.
  • the active compounds of the present invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet.
  • the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like.
  • Such compositions and preparations should contain at least 0.1% of active compound.
  • the percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5% to about 75% or more of the weight of the unit.
  • the amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained.
  • Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about and 500 milligrams of active compound.
  • the tablets, troches, pills, capsules and the like may i also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as
  • any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non toxic in the amounts employed.
  • the active ingredients may be incorporated into sustained release preparations. Preparations of this type would contain greater quantities of the active ingredients.
  • the crude product was freed of ester by adding 31.2 g. of potassium hydroxide in ml. of water and refluxing for 24 hours.
  • the acid was precipitated by adding 160 ml. of concentrated hydrochloric acid followed by 200 ml. of water and chilling.
  • the filtered material was slurried in chloroform to give a white solid which was recrystallized from 95% aqueous ethanol to give 2.95 g. of 4-(ndodecylamino)benzoic acid as white crystals, m.p. l11.5-l13C, 125.5C.
  • EXAMPLE 2 Ethyl 4-(n-tridecylamino)benzoate
  • EXAMPLE3 4-(n-Tridecylamino)benzoic acid
  • a mixture of 27.7 g. of ethyl 4-(ntridecylamino)benzoate, and 44.7 g. of potassium hydroxide in 450 ml. of water-ethanol (1:1) was refluxed for 6 hours.
  • Concentrated hydrochloric acid 80 ml.
  • was added to the hot mixture which was then cooled, diluted with water and filtered. Recrystallization from absolute ethanol and from ethanol-benzene (1:1) gave 16.5 g. of 4-(n-tridecylamino)benzoic acid as white crystals, m.p. l()6109C: 112-1l3C.
  • EXAMPLE 4 Ethyl 4-(n-Tetradecylamino)benzoate A mixture of 16.5 g. of ethyl 4-aminobenzoate and 30 g. of l-bromotetradecane was heated on a steam bath for 19 hours. Ethanol was added and the mixture filtered. The solid was washed with ethanol, water, 0.1 N
  • EXAMPLE 4-(n-Tetradecylamino)benzoic acid To a solution of 16.5 g. of ethyl 4-aminobenzoate in 150 ml. of dry N,N-dimethylformamide was added 4.12 g. of sodium hydride (56% in oil) and 27.7 g. of lbromotetradecane. The mixture was heated on a steam bath until hydrogen evolution began and then chilled briefly to control the reaction. After the sodium hydride had reacted. the mixture was heated on a steam bath under nitrogen for 6 hours. The mixture was chilled, filtered and the solid washed with ethanol and with water to give 21.75 g. (59%) of ethyl 4-(n-tetradecylamino)benzoate, m.p. 8l-82C.
  • EXAMPLE 7 4-(n-Pentadecylamino)benzoic acid
  • a mixture of 58.8 g. of ethyl 4-(n-pentadecylamino)- benzoate and 87.5 g. of potassium hydroxide in 900 ml. of water-ethanol (1:1) was refluxed for 6 hours.
  • Concentrated hydrochloric acid 140 ml. was added to the hot solution followed by 600 ml. of water and the mixture was chilled. The product was collected, washed well with water, and recrystallized from benzeneethanol (1:1) to give 42.5 g. of white 4-(npentadecylamino)benzoic acid, m.p. 107l08C., 126-126.5C.
  • EXAMPLE 8 Ethyl 4-(n-hexadecylamino)benzoate A solution of 49.5 g. of ethyl 4-aminobenzoate and 45.8 ml. of l-bromohexadecane in 525 ml. of absolute ethanol was refluxed overnight. The reaction mixture was chilled and the filtered product recrystallized from 750 ml. of absolute ethanol to give 16.5 g. of ethyl 4-(n-hexadecylamino)benzoate as white crystals, m.p. 84-86.5C.
  • EXAMPLE 9 Ethyl 4-(n-hexadecylamino)benzoate A mixture of 33.0 g. of ethyl 4-aminobenzoate, 61.0 g. of l-bromohexadecane, 21.2 g. of sodium carbonate and 300 ml. of ethanol was refluxed for 24 hours. The mixture was chilled and filtered. The solid was washed with 250 ml. of cold ethanol and with one liter of water to give 20 g. of white ethyl 4-(n-hexadecylamino)benzoate, m.p. 81-84C.
  • EXAMPLE l0 Ethyl 4-(n-hexadecylamino)benzoate A mixture of 33.0 g. of ethyl 4-aminobenzoate. 61.0 g. of l-bromohexadecane, 27.6 g. of potassium carbonate and 400 ml. of dry ethanol was refluxed for 23 hours. An additional 61 g. of l-bromohexadecane was added and the mixture refluxed for an additional 32 hours. The mixture was chilled, filtered and the solid washed with 250 ml. of cold ethanol and with 1 liter of water. to give 30.6 g. of white ethyl 4(n-hcxadecylamino)benzoate, m.p. 83C.
  • EXAMPLE 1 1 4-(n-Hexadecylamino)benzoic acid
  • EXAMPLE 12 4-(n-Hexadecylamino)benzoic acid
  • To a mixture of 13.7 g. of 4-aminobenzoic acid and 5.61 g. of potassium hydroxide in 150 ml. of aqueous ethanol was added 33.6 ml. of l-bromohexadecane and the mixture was refluxed for 25 hours.
  • a solution of 28 g. of potassium hydroxide in 150 ml. of 90% aqueous ethanol and ml. water was added. The mixture was refluxed for 24 hours and 35 ml of concentrated hydrochloric acid was added to the hot solution.
  • EXAMPLE 13 Ethyl 4-(n-heptadecylamino)benzoate A mixture of 48.3 g. of ethyl 4-aminobenzoate, 93.4 g. of l-bromoheptadecane and 40.4 g. of potassium carbonate in 700 ml. of absolute ethanol was refluxed for 24 hours. The reaction was then chilled, filtered and the solid washed with cold absolute ethanol, and then with water until it was neutral. The product was pure ethyl 4-(n-heptadecylamino)benzoate EXAMPLE l4 4-(n-l-leptadecylamino)benzoic acid A mixture of 48.3 g.
  • EXAMPLE Ethyl 4-(n-octadecylamino)benzoate A mixture of 66 g. of ethyl 4-aminobenzoate, 133.4 g. of l-bromooctadecane, 55 g. of potassium carbonate and 550 ml. of N,N-dimethylacetamide was heated at 135C. for hours. The mixture was chilled, filtered and the solid washed with cold ethanol. Recrystallized from ethanol to give 98 g. of product. Recrystallization from benzene-ethanol (1:1) gave 67 g. of ethyl 4-(noctadecylamino)benzoate as white crystals m.p. 88-89C.
  • EXAMPLE 16 4-(n-Octadecylamino)benzoic acid A mixture of 33 g. of ethyl 4-aminobenzoate, 67 g. of l-bromooctadecane, 27.6 g. of potassium carbonate and 400 ml. of N,N-dimethylacetamide was heated at 130-155C. for 18 hours. The mixture was chilled, filtered and the solid washed with water and slurried in 100 ml. of ethanol to give 38 g. of white crystals.
  • EXAMPLE 17 Ethyl 4-( n-nonadecylamino )benzoate A mixture of 40.4 g. of ethyl 4-aminobenzoate, 85.2 g. of l-bromononadecane, and 33.8 g. of potassium carbonate in 400 ml. of dry N,N-dimethylacetamide was heated under nitrogen at 130C. for 24 hours. The mixture was chilled, filtered, and the solid washed with cold absolute ethanol and then with water. The product was recrystallized from absolute ethanol to give 791. g.
  • EXAMPLE 18 4'(n-Nonadecylamino)benzoic acid A mixture of 79.1 g. of ethyl 4-(n- EXAMPLE 19 Ethyl 4-[(1-methylundecyl)amino]benzoate A mixture of 49.6 g. of ethyl 4-aminobenzoate, 74.9 g. of 2-bromododecane, and 41.5 g. of potassium carbonate in 550 ml.
  • EXAMPLE 21 Ethyl 3-(n-hexadecylamino)benzoate A mixture of 24.8 g. of ethyl 3-aminobenzoate, 45.8 ml. of l-bromohexadecane and 20.7 g. of potassium carbonate in 250 m1. of N,N-dimethylacetamide was heated at 125135C. for 24 hours. The mixture was then chilled, filtered and the solid washed with water and dried. The yield was 49.7 g. of ethyl 3-(n-hexadecylamino)benzoate.
  • EXAMPLE 22 3-(n-Hexadecylamino)benzoic acid A mixture of 49.7 g. of ethyl 3-(n-hexadecylamino)- benzoatc and 71.3 g. of potassium hydroxide in 700 ml.
  • EXAMPLE 23 Dimethylaminoethyl 4 (n-hexadecylamino)benzoate hydrochloride To ml. of thionyl chloride cooled to 0C. was added portionwise, 21.7 g. (0.060 mole) of 4-(nhexadecylamino)-benzoic acid. To the viscous mass was added ml. of toluene. After stirring overnight (16.5 hour), the solvent was removed in vacuo. Toluene (50 ml.) was added the solvent removed in vacuo. Nitrogen was bubbled through the residual oil, 100 m1. of toluene added and the solution cooled. To the mixture was added 6.24 g.
  • EXAMPLE 24 Ethyl 4-(n-octylamino)benzoate A mixture of 33 g. (0.20 mole) of ethyl 4- aminobenzoate, 44 ml. of l-bromooctane and 0.50 g. of cooper powder was heated on a steam bath for 19 hours. The mixture was chilled, diluted with ethanol, filtered and the solid washed with cold ethanol and with water to give tan crystals. The filtrate was neutralized with N potassium hydroxide, chilled and filtered and the solid washed with water and with ethanol to give tan crystals. The two crops of crystals were combined to give 16 g. of product.
  • the mother liquors from the two crops of crystals were combined, diluted with water and extracted with ether.
  • the ether extracts were washed with water,'with l N hydrochloric acid and with water.
  • the ether extracts were dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was diluted with ethanol, chilled and filtered to give 3.7 g. of product.
  • the two crops of product (19.7 g.) were combined and recrystallized from ethanol to give 15.] g. of white crystals, m.p. 7980C.
  • EXAMPLE 25 4-(n-Octylamino)benzoic acid
  • a mixture of 3.0 g. of ethyl 4-(noctylamino)benzoate, 3 g. of potassium hydroxide and 50 ml. of ethanol-water (9:1 was refluxed for 3 hours.
  • the mixture was acidified with concentrated hydrochloric acid, diluted with water and filtered.
  • the solid was washed thoroughly with water and recrystallized from ethanol to give 2.1 g. of 4-(n-octylamino)benzoic acid as white crystals, m.p. ll7-l 18C.
  • EXAMPLE 26 4-(n-Hexylamino)benzoic acid A mixture of 4.98 g. of ethyl 4-(n-hexylamino)benzoate, 11.2 g. of potassium hydroxide and 50 ml. of ethanol-water (1:1) was refluxed for 6 hours. To the hot solution was added 16.6 ml. of concentrated hydrochloric acid. The mixture was diluted with 100 ml. of water, chilled, filtered and the solid washed with water. The solid was recrystallized from ethanol-water (3:1) to give 3.85 g. of 4-(n-hexylamino)benzoic acid, m.p. l2l.5-123.5C. and l27-128C.
  • EXAMPLE 27 Ethyl 4-(n-hexylamino)benzoate A mixture of 54.4 g. of ethyl 4-aminobenzoate, 54.4 g. of l-bromohexane and 45.6 g. of potassium carbonate in 660 ml. of hexamethylphosphoramide was stirred and heated at 120C. for 24 hours. The mixture was chilled, diluted with 60 ml. of water, chilled and filtered. An additional 140 ml. of water was added and the mixture chilled and filtered to give solid which was washed with cold ethanol and with water to give 44 g. of pale yellow crystals. A sample was recrystallized from ethanol-benzene (95:5) to give ethyl 4- hexylaminobenzoate, m.p. 9l-94C.
  • EXAMPLE 28 The present compounds can be dispensed in dosage unit form such as hard shell capsules or soft shell capsules.
  • dosage unit form such as hard shell capsules or soft shell capsules.
  • a representative formulation of such capsules is as follows:
  • the above formulation is to be thoroughly mixed and placed in equal quantities in 100 capsules.
  • EXAMPLE 29 The following example represents a formulation useful in preparing tablets. Larger tablets can be scored and divided in halves to be given once or twice a day. Obviously smaller tablets can be used in multiple doses to obtain the daily amount of active material. The following formulation is representative.
  • EXAMPLE 30 The following example represents a formulation for preparing an oral syrup.

Abstract

4-(Monoalkylamino)benzoic acids and esters, pharmaceutically acceptable salts thereof, and a method for lowering serum lipids in mammals by administration of said acids, esters and salts; and pharmaceutical compositions thereof.

Description

United States Patent Albright et al.
[4 1 Feb. 25, 1975 American Cyanamid Company, Stamford, Conn.
Filed: Oct. 1, 1973 Appl. No.: 402,212
Assignee:
U.S. Cl..... 260/518 R, 260/293.78, 260/295 R, 260/47] R, 260/472, 260/50l.11, 424/263, 424/267, 424/310, 424/319 Int. Cl. C07c 101/60 Field of Search 260/471 R, 472, 518 R, 260/501.11
[56] References Cited UNITED STATES PATENTS 9/1973 Rogers et al. 260/518 R Primary Examiner-Lorraine A. Weinberger Assistant Examiner-L. A. Thaxton Attorney, Agent, or FirmJack W. Richards [57] ABSTRACT 4-(Monoalkylamino)benzoic acids and esters, pharm aceutically acceptable salts thereof, and a method for lowering serum lipids in mammals by administration of said acids, esters and salts; and pharmaceutical compositions thereof.
7 Claims, No Drawings HYPOLIPIDEMIC 4-(MONOALKYLAMINO)BENZOIC ACID DERIV ATIVES SUMMARY OF THE INVENTION This invention relates to organic compounds and more particularly it is concerned with 4- (monoalkylamino)benzoic acids and 4- (monoalkylamino)benzoic acid esters which may be represented by the following structural formula:
wherein R is an unbranched or branched alkyl group, C,, H wherein n is 4 to 19; and R is hydrogen, lower alkyl, benzyl, dilower alkylaminoethyl, lower alkoxyethyl, 1-methyl-4-piperidyl, 2-pyridylmethyl, 4- pyridylmethyl; and the pharmaceutically acceptable salts thereof. Suitable lower alkyl groups contemplated by the present invention are those having up to six carbon atoms such as, for example, methyl, isopropyl, npropyl, ethyl, sec-butyl, tert-amyl and n-hexyl.
With reference to the above formula, the invention contemplates as novel compounds per se only those acids, esters and pharmaceutically acceptable salts thereof wherein n is 8 to 19. Compounds wherein n is 4 to 7 are known in the art, infra. However,'the invention contemplates a method for lowering serum lipids in mammals by administration of said acids and esters wherein n is 4 to 19, and the use of pharmaceutically acceptable salts and pharmaceutical compositions employing said acids, esters and salts to lower serum lipids.
Compounds of the present invention were shown to possess hypolipidemic activity as determined by animal experiments. Compounds represented by the above formula wherein n is 4 to 19 have been found to possess hypolipidemic activity in animals, namely, serum triglyceride lowering, with cholesterol lowering when n is 14 to 17. Of the active compounds, the preferred group comprises those compounds where n is 14 to 17, i.e., wherein the straight-chain alkyl group contains 14 to 17 carbon atoms and R in the above formula is hydrogen. The compounds of the present invention may be utilized either as the free acids or in the form of a pharmaceutically acceptable salt. Since the compounds are amphoteric, the salts can involve either the acidic or the basic moiety. The salts may be either of an inorganic nature, such as the ammonium salt, sodium salt, potassium salt, etc., of the carboxyl group or the hydrochloric or sulfuric acid salts of the amino group,,or of an organic type, such as an organic amine salt of the carboxyl group or a trifluoroacetic or citric acid salt of the amino group.
BACKGROUND OF THE INVENTION Considerable effort has been directed in recent years to obtain substances which are useful in the treatment of hyperlipidemia, a condition associated with elevated cholesterol, phospholipid and/or triglyceride blood levels. This condition is associated with a number of discases, one of the most serious being atherosclerosis. Medicaments used to lower cholesterol, phospholipid and triglyceride blood levels are termed hypolipidemic drugs. Presently three major lipid-lowering agents are available; clofibrate, D-thyroxine, and nicotinic acid. [R]. Levy and D.S. Fredrickson, Postgraduate Medicine, Vol. 47, pps. 130-136 (1970).] The class of compoundsencompassed by the present invention may be termed 4-(monoalkylamino)benzoic acids, esters and salts thereof.
As pointed out heretofore, 4-(monoalky1)benzoic acids and/or esters wherein n in the above formula is 4 to 7 are known. Also known are such acids and/or esters wherein n in the above formula is l to 3. Moreover, certain 4-(monoa1kylamino)benzoic acid esters, i.e., those wherein n in the above formula is 3 to 7, have been disclosed as having local anesthetic activity. However, there is no known disclosure of even local anesthetic activity for the acids or esters of'this invention. References for C4 acid, J. Soc. Chem. Ind., 64, 177 (1945); J. Applied Chem. (U.S.S.R.), 17, 588 1944);]. Gen. Chem. (U.S.S.R.), 16, 1033 (1946); for C. methyl ester, J. Am. Chem. Soc., 66, 2127 (1944); for C5 acid, J. Amer. Chem. Soc., 71, 3366 (1949); for C5 ethyl ester, J. Amer. Chem. Soc., 71, 3366 (1949); for C5 acid, J. Microbial Seral, 20 285-98 (1954); for C5 ethyl ester, Chem. Abstracts, 52: P119281", Chem. Abstracts 53: P5203e; for C1 eth l ester, Chem. Abstracts 52: P119291) (British Pat. No. 788,100), hem. Abstracts 53: P5203e (Swiss Pat. No. 331,982). References for C acid, J. Amer. Chem. Soc., 73, 1299 (1955), Chemv Ber., 80, 310 (1947), J. Amer. Chem. Soc., 71, 2933 (1949); for C2 acid, J. Amer. Chem. Soc. 66, 2127 (1944), Chem. Ber. 80, 479 (1947), J. Sci. 1nd. Research, 14B, 624 (1955); Chem. Abstracts 38:1216 (Ber. B, 1911 (1942); for C -,acid,J. Amer. Chem. Soc. 65,
2231 (1943), Chem. Abstracts, 38, P2346 (Ger. 716,668, Dec. 24, 19 1).
References to polyethylene glycol and dialkylaminoethyl esters: for C Chem. Abstracts, 52, P119296 (British Pat. No. 788,100, Dec. 23, 1957); for C Chem. Abstracts, 53, P5203e (Swiss Pat. No. 331,982, Sept. 30, 1958), Chem. Abstracts, 52, Pll928f (British Pat. No. 788,100, Dec. 23, 1957); for C Chem. Abstracts. 47, P5965e (US Pat. No. 2,608,574, Au 26, 1952), Chem. Abstracts, 44, 9367c, J. Am. Chem. Soc., 71, 3366 (1949); for C Chem. Abstracts, 52, P8197d (Japan Pat. No. 7511, Aug. 30, 1956), Chem. Abstracts, 52, P8197d (Japan Pat. No. 7511, Aug. 30, 1956), Current Research, Anesth.Ana1g. 30, 1, 76(1951), Chemical Abstract, 56, 6585h, J. Applied Chem. (USSR), 17, 588 (1944)-(Chem. Abstracts, 40, 2268 J. Soc. Chem. Ind., 64, 177 1945) (Chem. Abstracts, 39, 4857 for C J. Am. Chem. Soc., 66, 2127 (1944) (Chem. Abstracts 39, 1152 No disclosure is known reporting on, or concerned with, hypolipidemic activity for any of the known n l-7 compounds. It has now, unexpectedly, been found that both the known n 4-7 and the heretofore unknown n 8-19 compounds all possess hypolipidemic activity. No pharmaceutical activity has been reported for any of the. n 8-19 compounds herein.
DETAILED DESCRIPTION OF THE INVENTION The 4-(monoalkylamino)benzoic acids and esters of the present invention are, in general, colorless or tan crystalline solids (some being colorless or tan oils) having characteristic melting points and spectral properties. They are soluble in organic solvents such as chloroform, benzene, dichloromethane, N,N-dimethylformamide, dimethylsulfoxide and lower alkanols. They are, however, generally insoluble in water.
The 4-(monoalkylamino)benzoic acids and esters of the present invention are bases and may be converted to their non-toxic acid-addition salts by treatment with acids such as sulfuric, hydrochloric, phosphoric, succinic, citric, and the like. Those compounds wherein R is hydrogen may be reacted with alkali bases such as sodium hydroxide, potassium hydroxide and calcium hydroxide or with organic bases such as ammonium hydroxide or lower mono-, dior tri(lower alkyl)amines such as methylamine, diethylamine, trimethylamine, dibutylamine, N,N'-dimethylethylenediamine, and the like to obtain the corresponding carboxylic acid salts. The lower alkyl 4-(monoalkylamino)benzoates of this invention are prepared by reaction of loweralkyl p-aminobenzoates with suitable alkylating agents such as alkyl halides, sulfates, tosylates or trifluoromethylsulfonates with or without solvent at 50C. l50C. Suitable solvents are lower alkanols, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, diglyme, dimethylsulfoxide, acetonitrile, toluene, benzene, hexamethylphosphoramide and the like. The reaction may be carried out with an equivalent of base such as an alkali carbonate or bicarbonate or with a catalytic amount of copper powder when alkyl halides are used as the alkylating agent. Alternatively, the lower alkyl 4-(monoalkylamino)benzoates are prepared by reaction of a lower alkyl aminobenzoate with an alkyl halide of4 to 19 carbon atoms in the presence of an equivalent of sodium hydride in an inert solvent such as N,N-dimethylformamide, N,N- dimethylacetamide, and diglyme at 50C.l50C.
Alternative methods of prepartion are by reductive alkylation of a 4-aminobenzoate ester or by a metal hydride reduction of a 4-(acylamino)benzoate ester or acid. For example, n-hexadecanal and methyl 4- aminobenzoate are reduced under 1-10 atmospheresof hydrogen using an activated metal catalyst, forming 4-(n-hexadecylamino)benzoic acid methyl ester. The aldehyde appears to be formed in small amounts in situ in the synthetic procedure comprising heating at an elevated temperature and pressure n-hexadecanol and methyl 4-aminobenzoate in the presence of an activated Rancy nickel catalyst to give methyl 4-(n-hexadecylamino)benzoate. Diboranc reduction of ethyl 4-(n-hexadecanoylamino)benzoate at room temperature or above for l-6 hours yields the ethyl analog of the above ester.
Two types of substitution reactions also yield the de sired 4-(alkylamino)benzoic acids or esters, namely, reaction of ethyl 3,4-didehydrobenzoate with an alkylamine (or its alkali metal salt) and Friedel-Crafts acylation of an N-alkylaniline or N-acyl-N-alkylaniline. The former type of reaction is carried out by treating a 4- halobenzoate ester such as ethyl 4-bromobenzoate with the lithium, potassium, or sodium salt of an alkylamine (in excess) such as n-hexadecylamine in ether or other aprotic solvent. The latter type comprises reacting N-nhexadecylaniline and the like or its N'acetyl derivative with oxalyl chloride and anhydrous aluminum chloride in dry ether, halocarbon or hydrocarbon medium.
The 4-(alkylamino)benzoic acids of this invention are prepared by hydrolysis of the corresponding benzoate esters by reacting with an alkali hydroxide such as sodium or potassium hydroxide in a lower alkanol,
water or an aqueous lower alkanol at 25C. to 150C.
Alternatively, the 4-(alkylamino)benzoic acids maybe prepared by hydrolysis of the lower alkyl 4-(monoalkylamino)benzoates with mineral acids such as hydrochloric, hydrobromic and sulfuric acid in water or aqueous lower alkanols.
Of lower activity than the compounds of the present invention are the lower alkyl 4-(dialkylamino)benzoates or the 4-(dialkylamino)benzoic acids, which can be prepared by reaction of a lower alkyl 4 (monoalkylamino)benzoate with an appropriate alkylating agent to give the lower alkyl esters with subsequent hydrolysis to give the acids. Suitable alkylating agents are lower alkyltosylates, lower dialkylsulfates (such as di methyl sulfate, diethyl sulfate and dipropyl sulfate), tri- (lower alkyl)oxonium tetrafluoroborates (such as trimethyloxonium and triethyloxonium tetrafluoroborates), lower alkyl halides, methyl fluorosulfonate and ethyl fluorosulfonate. The alkylation reactions may 'be carried out with or without a solvent at 20C. to
150C. Suitable solvents are chloroform, dichloromethane, carbontetrachloride, benzene, xylene and the like. For example, methylations are conveniently carried out with methyl fluorosulfonate in dichloromethane at 25C. for 2-20 hours while ethylations are conveniently carried out with excess diethyl sulfate at C.-l50C. without solvent. Alkylations with alkyl halides may be carried out by first reacting the lower alkyl monoalkylaminobenzoate in a suitable solvent with sodium hydride or butyl lithium to give the amine anion and then reacting with the alkyl halide. The lower alkylamino benzoic acid derivatives may be converted to their potassium, sodium or lithium salts and alkylated to give dialkylaminobenzoate esters alkylation occurring on both the amino group and on the oxygen of the acid salt. Representative dialkylaminobenzoic acids and esters which have been prepared are ethyl 4-(dodecylmethylamino)benzoate, 4-(dodecylmethylamino)-benzoic acid, 4-(dodecylethylamino)benzoic acid, 4-(methyltetradecylamino)benzoic acid, 4-(ethyltetradecylamino)benzoic acid, ethyl 4-(methylpentadecylamino)benzoate, 4-(methylpentadecylamino)- benzoic acid, 4-(ethylpentadecylamino)benzoic acid, ethyl 4-(methylhexadecylamino)benzoate, 4-(methylhexadecylamino)-benzoic acid, ethyl 4-(ethylhexadecylamino)benzoate, 4-(ethylhexadecylamino)benzoic acid, 4-(methylheptadecylamino)benzoic acid, 4- (ethylheptadecylamino)benzoic acid, 4-(methyloctadecylamino)benzoic acid, and 4- (ethyloctadecylamino)benzoic acid. In animal tests these compounds have shown inferior hypolipidemic activity.
Lower alkyl acylmonoalkylaminobenzoates can be prepared by acylation of the lower alkyl monoalkylaminobenzoates with acyl halides or anhydrides such as acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, succinic anhydride, etc. in the presence of a suitable base as pyridine, triethylamine and the like with or without an organic solvent. Acylation of monoalkylaminobenzoic acids under similar conditions gives the acylmonoalkylaminobenzoic acid derivatives. The N-acyl derivatives were prepared for testing for their activity per se and for the activity generated by their de-acylation. The compounds studied were N- benzoyl, N-acetyl, and N-succinoyl derivatives, for example, ethyl 4-(N-acetyl-n-tetradecylamino)benzoate, 4-(N-acetyl-n-tetradecylamino)-benzoic acid, 4-(N- benzoyl-n-hexadecylamino)benzoic acid, 4-(N-acetyln-hexadecylamino)benzoic acid. Such compounds have been prepared by acylation of ethyl 4-(tetradecylamino)-benzoate with acetyl chloride or acetic anhydridein presence of a suitable base such as pyridine or 4-dimethylamin'opyridine or by the acylation of 4-(tetradecylamino)benzoic acid and 4- (hexadecylamino)benzoic acid with acetyl chloride, benzoyl chloride, acetic anhydride or succinic anhydride in the presence of a suitable base such as pyritrols. Table I shows several of the compounds of the present invention and the degree to which they depress serum sterolsand triglyceride levels after a 1-week and 4-week dosing period and phospholipids after a 4-weck dosing period.
TABLE I HYPOLIPIDEMIC ACTIVITY OF 4-(MONOALKYLAMINO)BENZOIC ACIDS AND DERIVATIVES I-Week test, 7c Lowering of Serum 4-Week test. 7r Lowering of Serum Compound Compound in Diet Sterol Triglyceride Sterol Triglyceride Phospholipid 4-( Butylamino-benzoic Acid 0.1 16 39 4-(n-Hexylamino)benzoic Acid 0.1 16 35 4-(n-Octylamino)benzoic Acid 0.1 11 32 4-(n-Dodecylamino)henzoic Acid 0.1 67 4 (n-Tridecylamino)benzoic Acid 8 0.1 16 39 4-(n-Tetradecylamino)- benzoic Acid O.l 1O 47 4-(n-Pentadecylamino)- benzoic Acid 0.! I9 39 46 Ethyl 4-(n-hexadecylaminobenzoate 0.1 I 31 4-(n-Hexadecylamino)benzoic Acid 0.1 30 v 48 37 68 39 4-(n-Heptadecylamino)- benzoic Acid 0.1 12 42 24 65 33 4-(n-Octadecylamino)- benzoic Acid 0.1 18 15 50 21 4-(n-Nonadec lamino)- benzoic Acid y 0 5 4; 1Q 44 w l8 Dimethylaminoethyl 4-(n-hexadecylamino)- 0.1 9 41 benzoate hydrochloride vention is not known and the inventors do not WlSh to The data in Table 1 indicate that the 4- be limited to any particular mechanism. However, the compounds of the present invention were shown to possess hypolipidemic activity as determined by animal experiments as follows: the compounds studied were administered orally admixed with the diet to groups of 4-6 male rats, CFE strain from Carworth Farms, New City, N.Y. A control group of 6-8 rats was maintained on the diet alone; test groups were maintained on the diet plus the indicated percentage of compound by weight. After 6 days or 2-4 weeks treatment, serum sterol concentrations were determined either (1) according to the saponification and extraction method of P. Trinder, Analyst 77, 321 (1952) and the colorimetric determination of Zlatkis, et al., J. Lab. Clin. Med. 44, t
486 (1953) or (2) by the extraction method of H. H. Leffler, Amer. J. Clin. Path. 31, 310 (l959),'and the colorimetric determination of Zlatkis (vide supra), the overall method appropriately modified for use with an automatic mechanical analyzer. Serum triglycerides were estimated by the automated procedure of Kessler and Lederer [Automation in Analytical Chemistry (monoalkylamino)benzoic acids and derivatives tested are all effective hypolipidemic agents, i.e., they reduce serum triglyceride and/or sterol levels. Reduction of serum sterol is highly desirable clinically since essentially all major studies reported in the literature indicate that elevated serum sterol concentration is directly related to the development of other atherosclerosis. Of the clinical types of hyperlipoproteinemias described to date, the major lipids found in abnormal levels are sterol and triglycerides. The preferred compounds of this invention are capable of decreasing both of these blood lipid fractions as well as phospholipids, the third major lipid moiety in blood.
The effects of one of the compounds [4-(nhexadecylamino)benzoic acid] of this invention on serum lipid levels were determined in mice and gerbils (Table 11) after 1 week of treatment. Mice (CF-l strain) were obtained from Carworth Farms, New City, NY. and gerbils were purchased from Chick Line Co., Vineland, NJ. The methods used for lipid analysis were the same as those indicated above for Table I.
TABLE II HYPOLIPIDEMIC ACTIVITY OF 4-(n-HEXADECYLAMINO)- BENZOIC ACID IN MICE AND GERBILS Mice Serum Phospholipid, 7o 28 Lowering The 4-(monoalkylamino)benzoic acids and derivatives of this invention have potencies similar to or greater than 1-methy1-4-piperidyl bis( pchlorophenoxy)acetate and clofibrate, and thus are useful as hypolipidemic compounds in mammals when administered in amounts ranging from about 0.5 mg. per kg. to about 40 mg. per kg. of body weight per day. A preferred dosage regimen for optimum results would be from about 2 mg. per kg. to about 29 mg. per kg. Thus the daily dosage employed for a subject of about 70 kg. of body weight is about 35 mg. to about 2.8 g., and preferably about 140 mg. to about 2.0 g.
The active compounds of the present invention may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft gelatin capsules, or they may be compressed into tablets, or they may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage in the compositions and preparations may, of course, be varied and may conveniently be between about 5% to about 75% or more of the weight of the unit. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about and 500 milligrams of active compound.
The tablets, troches, pills, capsules and the like may i also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as afatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active compounds, sucrose-as a sweetening agent, tives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non toxic in the amounts employed.
In addition, the active ingredients may be incorporated into sustained release preparations. Preparations of this type would contain greater quantities of the active ingredients.
methyl and propyl parabens as perserva-' lized from benzene EXAMPLE 1 4-(n-Dodecylamino)benzoic Acid A solution of 10.4 g. of potassium hydroxide in 200 ml. of aqueous ethanol was added to a solution of 25.4 g. of 4-aminobenzoic acid in 200 ml. of 90% ethanol. After all the solid material had dissolved, 44.3 ml. of l-bromododecane and 25.5 g. of potassium carbonate were added and the mixture refluxed for 25 hrs. An additional 44 ml. of l-bromododecane was then added and heating was continued for 30 hrs. The crude product was freed of ester by adding 31.2 g. of potassium hydroxide in ml. of water and refluxing for 24 hours. The acid was precipitated by adding 160 ml. of concentrated hydrochloric acid followed by 200 ml. of water and chilling. The filtered material was slurried in chloroform to give a white solid which was recrystallized from 95% aqueous ethanol to give 2.95 g. of 4-(ndodecylamino)benzoic acid as white crystals, m.p. l11.5-l13C, 125.5C.
The chloroform filtrate was taken to dryness and the resulting solid washed with pentane. The insoluble material was recrystallized from 95% aqueous ethanol to give 3.10 g. of 4-(n-dodecy1amino)benzoic acid as offwhite flakes, m.p. same as above. The pentane filtrate was taken to dryness and the resulting solid recrystalto give 9.40 g. of 4-(ndodecylamino)benzoic acid, m.p. same as above.
EXAMPLE 2 Ethyl 4-(n-tridecylamino)benzoate EXAMPLE3 4-(n-Tridecylamino)benzoic acid A mixture of 27.7 g. of ethyl 4-(ntridecylamino)benzoate, and 44.7 g. of potassium hydroxide in 450 ml. of water-ethanol (1:1) was refluxed for 6 hours. Concentrated hydrochloric acid (80 ml.) was added to the hot mixture, which was then cooled, diluted with water and filtered. Recrystallization from absolute ethanol and from ethanol-benzene (1:1) gave 16.5 g. of 4-(n-tridecylamino)benzoic acid as white crystals, m.p. l()6109C: 112-1l3C.
EXAMPLE 4 Ethyl 4-(n-Tetradecylamino)benzoate A mixture of 16.5 g. of ethyl 4-aminobenzoate and 30 g. of l-bromotetradecane was heated on a steam bath for 19 hours. Ethanol was added and the mixture filtered. The solid was washed with ethanol, water, 0.1 N
sodium hydroxide and with water to give 9.0 g. of white crystals. The filtrate was basified, filtered and the solid was washed with ethanol to give 1.7 g. of crystals. The two crops were recrystallized from ethanol to give 8.75 g. of white ethyl 4-(n-tetradecylamino)benzoate, m.p. 8182C.
EXAMPLE 4-(n-Tetradecylamino)benzoic acid To a solution of 16.5 g. of ethyl 4-aminobenzoate in 150 ml. of dry N,N-dimethylformamide was added 4.12 g. of sodium hydride (56% in oil) and 27.7 g. of lbromotetradecane. The mixture was heated on a steam bath until hydrogen evolution began and then chilled briefly to control the reaction. After the sodium hydride had reacted. the mixture was heated on a steam bath under nitrogen for 6 hours. The mixture was chilled, filtered and the solid washed with ethanol and with water to give 21.75 g. (59%) of ethyl 4-(n-tetradecylamino)benzoate, m.p. 8l-82C.
A mixture of 29 g. of ethyl 4-(ntetradecylaminobenzoate, 28 g. of potassium hydroxide and 500 ml. of 50% ethanol was refluxed for 6 hours. The mixture was acidified with concentrated hydrochloric acid, chilled and filtered to give tan crystals. Recrystallization from ethanol gave 15.1 g. of white 4-(n-tetradecylamino)benzoic acid, m.p. 108-1llC.
EXAMPLE 6 Ethyl 4-(n-pentadecylamino)benzoate A mixture of 49.5 g. of ethyl 4-aminobenzoate, 87.3
g. of l-bromopentadecane and 41.4 g. of potassium I carbonate in 550 ml. of N,N-dimethylacetamide was heated 135C.) under nitrogen for 24 hours. The reaction mixture was chilled, filtered and the solid washed with cold absolute ethanol, with water and dried in air. Recrystallization from absolute ehtanol gave 58.8 g. of white ethyl 4-(n-pentadecylamino)benzoate, m.p. 7374.5C.
EXAMPLE 7 4-(n-Pentadecylamino)benzoic acid A mixture of 58.8 g. of ethyl 4-(n-pentadecylamino)- benzoate and 87.5 g. of potassium hydroxide in 900 ml. of water-ethanol (1:1) was refluxed for 6 hours. Concentrated hydrochloric acid (140 ml.) was added to the hot solution followed by 600 ml. of water and the mixture was chilled. The product was collected, washed well with water, and recrystallized from benzeneethanol (1:1) to give 42.5 g. of white 4-(npentadecylamino)benzoic acid, m.p. 107l08C., 126-126.5C.
EXAMPLE 8 Ethyl 4-(n-hexadecylamino)benzoate A solution of 49.5 g. of ethyl 4-aminobenzoate and 45.8 ml. of l-bromohexadecane in 525 ml. of absolute ethanol was refluxed overnight. The reaction mixture was chilled and the filtered product recrystallized from 750 ml. of absolute ethanol to give 16.5 g. of ethyl 4-(n-hexadecylamino)benzoate as white crystals, m.p. 84-86.5C.
EXAMPLE 9 Ethyl 4-(n-hexadecylamino)benzoate A mixture of 33.0 g. of ethyl 4-aminobenzoate, 61.0 g. of l-bromohexadecane, 21.2 g. of sodium carbonate and 300 ml. of ethanol was refluxed for 24 hours. The mixture was chilled and filtered. The solid was washed with 250 ml. of cold ethanol and with one liter of water to give 20 g. of white ethyl 4-(n-hexadecylamino)benzoate, m.p. 81-84C.
EXAMPLE l0 Ethyl 4-(n-hexadecylamino)benzoate A mixture of 33.0 g. of ethyl 4-aminobenzoate. 61.0 g. of l-bromohexadecane, 27.6 g. of potassium carbonate and 400 ml. of dry ethanol was refluxed for 23 hours. An additional 61 g. of l-bromohexadecane was added and the mixture refluxed for an additional 32 hours. The mixture was chilled, filtered and the solid washed with 250 ml. of cold ethanol and with 1 liter of water. to give 30.6 g. of white ethyl 4(n-hcxadecylamino)benzoate, m.p. 83C.
EXAMPLE 1 1 4-(n-Hexadecylamino)benzoic acid EXAMPLE 12 4-(n-Hexadecylamino)benzoic acid To a mixture of 13.7 g. of 4-aminobenzoic acid and 5.61 g. of potassium hydroxide in 150 ml. of aqueous ethanol was added 33.6 ml. of l-bromohexadecane and the mixture was refluxed for 25 hours. A solution of 28 g. of potassium hydroxide in 150 ml. of 90% aqueous ethanol and ml. water was added. The mixture was refluxed for 24 hours and 35 ml of concentrated hydrochloric acid was added to the hot solution. Chilling and filtering gave product which was washed with water and dried. Recrystallization from benzene yielded 10.7 g. of 4-(nhexadecylamino)benzoic acid, m.p. 106108C., complete melt 127C.
EXAMPLE 13 Ethyl 4-(n-heptadecylamino)benzoate A mixture of 48.3 g. of ethyl 4-aminobenzoate, 93.4 g. of l-bromoheptadecane and 40.4 g. of potassium carbonate in 700 ml. of absolute ethanol was refluxed for 24 hours. The reaction was then chilled, filtered and the solid washed with cold absolute ethanol, and then with water until it was neutral. The product was pure ethyl 4-(n-heptadecylamino)benzoate EXAMPLE l4 4-(n-l-leptadecylamino)benzoic acid A mixture of 48.3 g. of ethyl 4-aminobenzoate, 93.4 g. of l-bromoheptadecane, and 40.4 g. of potassium carbonate in 700 ml. of absolute ethanol was refluxed for 24 hours. The reaction mixture was chilled, filtered and the solid washed with cold absolute ethanol and with water to give 27.9 g. of ethyl 4-(n-heptadecylamino)benzoate as white flakes. A mixture of 27.9 g. of this ester, 38.8 g. of potassium hydroxide and 400 ml. of ethanol-water (1:1) was refluxed for 6.5 hours. To the hot solution was added 65 ml. of concen- 1 1 trated hydrochloric acid. The mixture was diluted with 400 ml. of water, chilled and filtered to give 25.2 g. of white crystals. Recrystallization from 300 ml. of benzene-ethanol (1:1) gave 21.7 g. of 4-(nheptadecylamino)benzoic acid, m.p. l05108C.; 128-128.5C.
EXAMPLE Ethyl 4-(n-octadecylamino)benzoate A mixture of 66 g. of ethyl 4-aminobenzoate, 133.4 g. of l-bromooctadecane, 55 g. of potassium carbonate and 550 ml. of N,N-dimethylacetamide was heated at 135C. for hours. The mixture was chilled, filtered and the solid washed with cold ethanol. Recrystallized from ethanol to give 98 g. of product. Recrystallization from benzene-ethanol (1:1) gave 67 g. of ethyl 4-(noctadecylamino)benzoate as white crystals m.p. 88-89C.
EXAMPLE 16 4-(n-Octadecylamino)benzoic acid A mixture of 33 g. of ethyl 4-aminobenzoate, 67 g. of l-bromooctadecane, 27.6 g. of potassium carbonate and 400 ml. of N,N-dimethylacetamide was heated at 130-155C. for 18 hours. The mixture was chilled, filtered and the solid washed with water and slurried in 100 ml. of ethanol to give 38 g. of white crystals.
The crystals were combined with 56 g. of potassium hydroxide, 1000 m1. of ethanol-water (1:1) and the mixture refluxed for 7 hours. While hot, 100 ml. of concentrated hydrochloric acid was slowly added to the mixture followed by adding 200 ml. of water, cooling and filtering to give 40 g. of white crystals. Recrystallization from benzene and then from ethanol gave 22.6
g. of 4-(n-octadecylamino)benzoic acid, m.p. 103106C., complete melt 123-126C.
EXAMPLE 17 Ethyl 4-( n-nonadecylamino )benzoate A mixture of 40.4 g. of ethyl 4-aminobenzoate, 85.2 g. of l-bromononadecane, and 33.8 g. of potassium carbonate in 400 ml. of dry N,N-dimethylacetamide was heated under nitrogen at 130C. for 24 hours. The mixture was chilled, filtered, and the solid washed with cold absolute ethanol and then with water. The product was recrystallized from absolute ethanol to give 791. g. of white ethyl 4-n-nonadecylamino)benzoate EXAMPLE 18 4'(n-Nonadecylamino)benzoic acid A mixture of 79.1 g. of ethyl 4-(n- EXAMPLE 19 Ethyl 4-[(1-methylundecyl)amino]benzoate A mixture of 49.6 g. of ethyl 4-aminobenzoate, 74.9 g. of 2-bromododecane, and 41.5 g. of potassium carbonate in 550 ml. of N,N-dimethylacetamide was EXAMPLE 20 4-[( l-methylundecyl)amino]benzoic acid A mixture of 15.0 g. of ethyl 4-[( l-methylundecyl)- amino]benzoate and 25.2 g. of potassium hydroxide in 175 m1. of 50% aqueous ethanol was refluxed for 6 hours. Concentrated hydrochloric acid (37 ml.) was added to the hot reaction mixture and the product precipitated upon chilling. The filtered product was recrystallized from absolute ethanol to give 7.70 g. of 4- [(1-methylundecyl)amino]benzoic acid, m .p. 76.578.5C.
EXAMPLE 21 Ethyl 3-(n-hexadecylamino)benzoate A mixture of 24.8 g. of ethyl 3-aminobenzoate, 45.8 ml. of l-bromohexadecane and 20.7 g. of potassium carbonate in 250 m1. of N,N-dimethylacetamide was heated at 125135C. for 24 hours. The mixture was then chilled, filtered and the solid washed with water and dried. The yield was 49.7 g. of ethyl 3-(n-hexadecylamino)benzoate.
EXAMPLE 22 3-(n-Hexadecylamino)benzoic acid A mixture of 49.7 g. of ethyl 3-(n-hexadecylamino)- benzoatc and 71.3 g. of potassium hydroxide in 700 ml.
of water-ethanol (1:1) was refluxed for 6 hours. Con-' centrated hydrochloric acid was added to the hot solution followed by 500 ml. of water and chilling. The product was recrystallized from ethanol-benzene (3:1) yielding 28.4 g. of white 3(n-hexadecylamino)benzoic acid, m.p. 107.5109.5C.
EXAMPLE 23 Dimethylaminoethyl 4 (n-hexadecylamino)benzoate hydrochloride To ml. of thionyl chloride cooled to 0C. was added portionwise, 21.7 g. (0.060 mole) of 4-(nhexadecylamino)-benzoic acid. To the viscous mass was added ml. of toluene. After stirring overnight (16.5 hour), the solvent was removed in vacuo. Toluene (50 ml.) was added the solvent removed in vacuo. Nitrogen was bubbled through the residual oil, 100 m1. of toluene added and the solution cooled. To the mixture was added 6.24 g. (0.070 mole) of 2- dimethylaminoethanol. The mixture was stirred at room temperature for 4.5 hours, diluted with ether, stirred 1.0 hour. Chilling and filtering gave solid which was washed with ether and with water to give 7.0 g. of tan crystals. Recrystallization (twice) from ethanol gave 5.2 g. of tan crystals, m.p. 162165C. with previous sintering.
EXAMPLE 24 Ethyl 4-(n-octylamino)benzoate A mixture of 33 g. (0.20 mole) of ethyl 4- aminobenzoate, 44 ml. of l-bromooctane and 0.50 g. of cooper powder was heated on a steam bath for 19 hours. The mixture was chilled, diluted with ethanol, filtered and the solid washed with cold ethanol and with water to give tan crystals. The filtrate was neutralized with N potassium hydroxide, chilled and filtered and the solid washed with water and with ethanol to give tan crystals. The two crops of crystals were combined to give 16 g. of product. The mother liquors from the two crops of crystals were combined, diluted with water and extracted with ether. The ether extracts were washed with water,'with l N hydrochloric acid and with water. The ether extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was diluted with ethanol, chilled and filtered to give 3.7 g. of product. The two crops of product (19.7 g.) were combined and recrystallized from ethanol to give 15.] g. of white crystals, m.p. 7980C.
EXAMPLE 25 4-(n-Octylamino)benzoic acid A mixture of 3.0 g. of ethyl 4-(noctylamino)benzoate, 3 g. of potassium hydroxide and 50 ml. of ethanol-water (9:1 was refluxed for 3 hours. The mixture was acidified with concentrated hydrochloric acid, diluted with water and filtered. The solid was washed thoroughly with water and recrystallized from ethanol to give 2.1 g. of 4-(n-octylamino)benzoic acid as white crystals, m.p. ll7-l 18C.
EXAMPLE 26 4-(n-Hexylamino)benzoic acid A mixture of 4.98 g. of ethyl 4-(n-hexylamino)benzoate, 11.2 g. of potassium hydroxide and 50 ml. of ethanol-water (1:1) was refluxed for 6 hours. To the hot solution was added 16.6 ml. of concentrated hydrochloric acid. The mixture was diluted with 100 ml. of water, chilled, filtered and the solid washed with water. The solid was recrystallized from ethanol-water (3:1) to give 3.85 g. of 4-(n-hexylamino)benzoic acid, m.p. l2l.5-123.5C. and l27-128C.
EXAMPLE 27 Ethyl 4-(n-hexylamino)benzoate A mixture of 54.4 g. of ethyl 4-aminobenzoate, 54.4 g. of l-bromohexane and 45.6 g. of potassium carbonate in 660 ml. of hexamethylphosphoramide was stirred and heated at 120C. for 24 hours. The mixture was chilled, diluted with 60 ml. of water, chilled and filtered. An additional 140 ml. of water was added and the mixture chilled and filtered to give solid which was washed with cold ethanol and with water to give 44 g. of pale yellow crystals. A sample was recrystallized from ethanol-benzene (95:5) to give ethyl 4- hexylaminobenzoate, m.p. 9l-94C.
EXAMPLE 28 The present compounds can be dispensed in dosage unit form such as hard shell capsules or soft shell capsules. A representative formulation of such capsules is as follows:
per I00 capsules, 0
grams 4-(n-Pentadecylamino)- benzoic acid 50.0 Lactose, USP 300.0 Magnesium stearate (0.5%) 3.1 Total 353.1
The above formulation is to be thoroughly mixed and placed in equal quantities in 100 capsules.
EXAMPLE 29 The following example represents a formulation useful in preparing tablets. Larger tablets can be scored and divided in halves to be given once or twice a day. Obviously smaller tablets can be used in multiple doses to obtain the daily amount of active material. The following formulation is representative.
Per tablet, mg.
4-(n-Hexadecylamino)- benzoic acid 500 Corn starch 210 Methyleellulose 400 350 Magnesium stearate 7a 182 Total 1242 The active ingredient, corn starch and methylcellulose are to be blended together. The mixture, after drying, is to be lubricated with 1% magnesium stearate and compressed into tablets in a suitable tableting machine.
EXAMPLE 30 The following example represents a formulation for preparing an oral syrup.
Ingredient Amount dimethylaminoethyl 4-(n-hexadecylam|no)- benzoate hydrochloride 5000 mg. Sorbitol solution 40 ml. NF.) Sodium benzoate 150 mg. Saccharin 10 mg. Red dye (FD. & C. No. 2) 10 mg. Cherry flavor 50 mg. Distilled water, q.s. ad ml.
4. 4-(n-Hexadecylamino)benzoic acid. 5. 4-(n-Heptadecylamino)benzoic acid. 6. Pharmaceutically acceptable salts of 4-(n- Hexadecylamin0)benzoic acid.
7. Sodium salt of 4-(n-Hexadecylamino)benzoic acid.

Claims (7)

1. 4-(MONOALKYLAMINO)BENZOIC ACID DERIVATIVES OF THE FORMULA:
2. 4-(n-Tetradecylamino)benzoic acid.
3. 4-(n-Pentadecylamino)benzoic acid.
4. 4-(n-Hexadecylamino)benzoic acid.
5. 4-(n-Heptadecylamino)benzoic acid.
6. Pharmaceutically acceptable salts of 4-(n-Hexadecylamino)benzoic acid.
7. Sodium salt of 4-(n-Hexadecylamino)benzoic acid.
US402212A 1973-10-01 1973-10-01 Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives Expired - Lifetime US3868416A (en)

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IL45643A IL45643A (en) 1973-10-01 1974-09-11 Hypolipidemic 4-(monoalkylamino)-benzoic acid derivatives,their preparation and pharmaceutical compositions comprising them
GB40539/74A GB1488674A (en) 1973-10-01 1974-09-17 Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives
AR255678A AR211687A1 (en) 1973-10-01 1974-09-23 PROCEDURE FOR PREPARING DERIVATIVES OF 4- (MONOALKYLAMINE) BENZOIC ACID
DE2446010A DE2446010C2 (en) 1973-10-01 1974-09-26 4- (Monoalkylamino) benzoic acid derivatives and therapeutic preparation containing them
IE2015/74A IE40527B1 (en) 1973-10-01 1974-09-27 Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives
YU02622/74A YU262274A (en) 1973-10-01 1974-09-27 Process for obtaining 4-(monoalkylamino) benzoic acid derivatives
SE7412307A SE410595B (en) 1973-10-01 1974-09-30 PROCEDURE FOR THE PREPARATION OF 4- (MONOALKYLAMINO) BENZOIC ACID DERIVATIVES
CA210,303A CA1077957A (en) 1973-10-01 1974-09-30 Hypolipidemic 4-(monoalkylamino) benzoic acid derivatives
FR7432894A FR2246267B1 (en) 1973-10-01 1974-09-30
DK515474AA DK141844B (en) 1973-10-01 1974-09-30 Analogous process for preparing a 4- (monoalkylamino) benzoic acid derivative.
BE149073A BE820542A (en) 1973-10-01 1974-09-30 NEW MONOALKYLAMINO-4-BENZOIC ACIDS
AT788574A AT338250B (en) 1973-10-01 1974-10-01 PROCESS FOR THE PRODUCTION OF NEW 4- (MONOALKYLAMINO) -BENZOIC ACIDS AND THEIR ESTERS
NLAANVRAGE7412956,A NL179725C (en) 1973-10-01 1974-10-01 METHOD FOR PREPARING AND / OR MANUFACTURING A PHARMACEUTICAL PREPARATION FOR THE TREATMENT OF HYPERLIPIDEMIA IN HOT BLOODS BASED ON A BENZOIC ACID DERIVATIVE; METHOD FOR PREPARING A BENZOIC ACID DERIVATIVE TO BE USED THEREIN
SU742065154A SU590311A1 (en) 1973-10-01 1974-10-01 4-(monoalkylamino)-benzoic acid derivatives or their salts possessing hypolipidemic activity
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HU74AE427A HU175875B (en) 1973-10-01 1974-10-01 Process for producing 4-bracket-monoalkyl-amino-bracket closed-benzoic acids, esters and pharmaceutically acceptable salts thereof, and pharmaceutical compositions of hypolipidemic activity containing them as active agents
CH1321774A CH609676A5 (en) 1973-10-01 1974-10-01
ES430574A ES430574A1 (en) 1973-10-01 1974-10-02 Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives
US518022A US3924001A (en) 1973-10-01 1974-10-25 Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives
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US4117158A (en) * 1977-09-27 1978-09-26 American Cyanamid Company 4-(monoalkylamino)benzonitriles useful as anti-atherosclerotic agents
US4133890A (en) * 1977-01-05 1979-01-09 The Dow Chemical Company Hypolipidemic compositions and method employing derivatives of 4-(((1,3-benzodioxol-5-yl)methyl)amino)benzoic acid
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US4181737A (en) * 1978-05-18 1980-01-01 The Dow Chemical Company 4-((3-Methoxyphenyl)amino)benzoic acid, a method for treating hyperlipidemia, and compositions thereof
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US4245097A (en) * 1978-02-27 1981-01-13 American Cyanamid Company 4-[(Monosubstituted-alkyl) amino] benzoic acids and analogs as hypolipidemic and antiatherosclerotic agents
US4245119A (en) * 1977-09-27 1981-01-13 American Cyanamid Company 4-(Monoalkylamino) benzene polycarboxylic acids
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US4272546A (en) * 1977-12-19 1981-06-09 American Cyanamid Company Esters of 4-(monoalkylamino)benzoic hydroxyalkanoic acids
US4304929A (en) * 1979-03-09 1981-12-08 Lek Tovarna Farmacevtskih In Kemicnih Izdelkov, N.Sol.O. Process for preparing 4-(n-hexadecylamino)-benzoic acid
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US4307113A (en) * 1978-04-20 1981-12-22 Sandoz, Inc. Anthranilic acid derivatives
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US4311846A (en) * 1978-02-27 1982-01-19 American Cyanamid Company 4-[(Monosubstituted-alkyl) amino]benzoic acids and analogs as hypolipidemic and antiatherosclerotic agents
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US4185115A (en) * 1975-03-12 1980-01-22 American Cyanamid Company Antilipidemic para-[aryl(alkyl or alkenyl)amino]-benzoic acid derivatives
US4350822A (en) * 1975-03-12 1982-09-21 American Cyanamid Company Antilipidemicpara-[aryl(alkyl or alkenyl)amino]benzoic acid derivatives
US4058550A (en) * 1975-10-28 1977-11-15 American Cyanamid Company Polysubstituted-alkyl esters of 4-alkylaminobenzoic acids
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US4245119A (en) * 1977-09-27 1981-01-13 American Cyanamid Company 4-(Monoalkylamino) benzene polycarboxylic acids
US4242273A (en) * 1977-09-27 1980-12-30 American Cyanamid Company 4-(Monoalkylamino)benzoic acid amides and imidates
US4245120A (en) * 1977-09-27 1981-01-13 American Cyanamid Company 4-(Monoalkylamino)benzene polycarboxylic acids
US4117158A (en) * 1977-09-27 1978-09-26 American Cyanamid Company 4-(monoalkylamino)benzonitriles useful as anti-atherosclerotic agents
US4154756A (en) * 1977-12-15 1979-05-15 American Cyanamid Company 2-Substituted-4'-(monoalkylamino)-acetophenones
US4272546A (en) * 1977-12-19 1981-06-09 American Cyanamid Company Esters of 4-(monoalkylamino)benzoic hydroxyalkanoic acids
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US4348399A (en) * 1978-02-02 1982-09-07 American Cyanamid Company Antiatherosclerotic and hypolipidemic 4-(monoalkylamino)phenyl alkane, alkene and alkyne carbinols, aldehydes, carboxylic acids and derivatives
US4333940A (en) * 1978-02-02 1982-06-08 American Cyanamid Company Ring-fluorinated 4-(monosubstituted-amino) phenyl compounds in inhibiting atherosclerotic lesion development
US4243609A (en) * 1978-02-02 1981-01-06 American Cyanamid Company Ring-fluorinated 4-(hexadecyl-amino) N-substituted benzamide compounds
US4245097A (en) * 1978-02-27 1981-01-13 American Cyanamid Company 4-[(Monosubstituted-alkyl) amino] benzoic acids and analogs as hypolipidemic and antiatherosclerotic agents
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IE40527L (en) 1975-04-01
DK141844C (en) 1980-11-10
IE40527B1 (en) 1979-06-20
DK515474A (en) 1975-06-09
NL179725C (en) 1986-11-03
JPS5059347A (en) 1975-05-22
HU175875B (en) 1980-11-28
AR211687A1 (en) 1978-02-28
SE7412307L (en) 1975-04-02
DD116031A5 (en) 1975-11-05
DK141844B (en) 1980-06-30
SE410595B (en) 1979-10-22
US3924001A (en) 1975-12-02
CA1077957A (en) 1980-05-20
GB1488674A (en) 1977-10-12
DE2446010C2 (en) 1985-05-15
GT197851174A (en) 1979-08-23
ZA745732B (en) 1975-09-24
AT338250B (en) 1977-08-10
FR2246267B1 (en) 1977-10-28
NL179725B (en) 1986-06-02
DE2446010A1 (en) 1975-04-03
ES430574A1 (en) 1977-02-16
SU590311A1 (en) 1978-01-30
FR2246267A1 (en) 1975-05-02
IL45643A (en) 1979-09-30
IL45643A0 (en) 1974-11-29
JPS5747901B2 (en) 1982-10-13
ATA788574A (en) 1976-12-15
NL7412956A (en) 1975-04-03
YU262274A (en) 1982-02-25
BE820542A (en) 1975-04-01
CH609676A5 (en) 1979-03-15

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