US3924001A - Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives - Google Patents

Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives Download PDF

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US3924001A
US3924001A US518022A US51802274A US3924001A US 3924001 A US3924001 A US 3924001A US 518022 A US518022 A US 518022A US 51802274 A US51802274 A US 51802274A US 3924001 A US3924001 A US 3924001A
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benzoic acid
ethyl
benzoate
mixture
ethanol
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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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    • 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

  • 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:
  • R is an unbranched or branched alkyl group, C,, H n wherein n is 4 to 19; and R is hydrogen, lower alkyl, benzyl, dilower alkylaminoethyl, lower alkoxyethyl, l-methyl-4-pipen'dyl, 2-pyridylmethyl, 4- pyridylmethyl; and the pharrnaceutically 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 tn'fluoroacetic'or citric acid salt of the amino group.
  • 4-(monoalkyl)benzoic acids and/or esters wherein n in the above fomiula is 4 to 7 are known. Also known are such acids and/or esters wherein n in the above formula is 1 to 3. Moreover, certain 4-(monoalkylamino)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 C acid, J. Soc. Chem. Ind., 64, 177 (1945); J. Applied Chem.
  • Chem. Abstracts, 38, P2346 (Ger. 716,668, Dec. 24, 1941 3 References to polyethylene glycol and dialkylaminoethyl esters: for C Chem. Abstracts, 52. P119296 (Brit. Pat. No. 788,100, Dec. 23, 1957); for C Chem. Abstracts, 53, P5203e (Swiss Pat. No. 331,982, Sept. 30, 1958), Chem. Abstracts, 52, P1 l928f(Brit. Pat. No. 788,100, Dec. 23, 1957); for C Chem. Abstracts, 47, P5965e (US. Pat. No. 2,608,574, Aug. 26, 1952), Chem.
  • 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.
  • the lower alkyl 4-(monoalkylamino)benzoates of this invention are prepared by reaction of lower alkyl p-aminobenzoates with suitable alkylating agents such as alkyl halides, sulfates, tosylates or trifluoromethylsulfonates with or without solvent at 50C. 150C.
  • suitable alkylating agents such as alkyl halides, sulfates, tosylates or trifluoromethylsulfonates with or without solvent at 50C. 150C.
  • suitable alkylating agents such as alkyl halides, sulfates, tosylates or trifluoromethylsulfonates
  • suitable alkylating agents such as alkyl halides, sulfates, tosylates or trifluoromethylsulfonates
  • solvents are lower alkanols, chloroform, N,l ldimethylformamide, N,N-dimethylacetamide,
  • the reaction may be carried out with an equivalent of base suchas an alkali carbonate or bicarbonate or with a catalytic amount ofcopper. 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 hal ide of 4 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. 150C.
  • Alternative methods of preparation 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 atmospheres of 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 Raney nickel catalyst to give methyl 4-(n-hexadecylamino)benzoate.
  • Diborane reduction of ethyl 4-(n-hexadecanoylamino)benzoate at room temperature or above for 16 hours yields the ethyl analog of the above ester.
  • Two types of substitution reactions also yield the desired 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 l ⁇ l-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.
  • an alkali hydroxide such as sodium or potassium hydroxide
  • the 4--(alkylamino)benzoic acids may be prepared by hydrolysis of the lower alkyl 4-(monoalkylarnino)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 adids which can be prepared by reaction of a lower alkyl 4-(monoalkylamino)benzoate with an appropriatealkylating agent to give the lower alkyl esters with subsequent hydrolysis to give the acids.
  • Suitable alkylating agents are 4,.
  • lower alkyltosylates lower dialkylsulfates (such as dimethyl 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.
  • 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-(dodecy1methylamino)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-( methylhexadecy
  • Lower alkyl acylmonalkylaminobenzoates can be prepared by acylation of the lower alkyl monoalkylaminobenzoates with acyl halides or anhydrides such as acetyl chloride, acetic anhydride, benzoyl chloride, ben zoic anhydride, succinic anhydride, etc. in the presence of a suitable base as puridine, 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,
  • Such compounds have been prepared by acylation of ehtyl 4-(tetradecylamino)- benzoate with acetyl chloride or acetic anhydride in presence of a suitable base such as pyridine or 4-dimethylaminopyridine or by the acylation of 4-(tetradecylamino)benzoic acid and 4-(hex-'
  • a suitable base such as pyridine or 4-dimethylaminopyridine
  • 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, New York. 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 (I) according to the saponification and extraction method of P. Trinder, Analyst 77, 321 (1952) and the colorimetric determination of Ziatkis, et. al., J. Lab. Clin. Med. 44, 486 (1953) or (2) by the extraction method of H. H. Leffler, Amer.
  • a compound is considered to have hypolipidemic activity if it depresses serum sterol levels or more below that of the controls, and/or depresses triglyceride levels by 25% or more below controls.
  • Table I shows several of the compounds of the present invention and the degree to which they depress serum sterols and triglyceride levels after a 1-week and 4-week dosing period and phospholipids after a 4-week dosing period.
  • TABLE 1 evated 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 II) after one week of treatment.
  • Mice CF-1 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 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 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 10 and 500 milligrams of active compound.
  • the tablets, troches, pills, capsules and the like may 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 peppermin
  • any material 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, methyl and propyl parabens as perservatives, a dye and a flavoring such as cherry or orange flavor.
  • 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.
  • EXAMPLE 1 4-(n-Dodecylamino)benzoic Acid A solution of 10.4 g. of potassium hydroxide in 200 ml. of 90% 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 hrs. An additional 44 ml. of l-bromododecane was then added and heating was continued for hrs. The crude product was freed of ester by adding 31.2 g. of potassium hydroxide in 100 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. 111.5-113; l25-125.5C.
  • the chloroform filtrate was taken to dryness and the resulting solid washed with pentane.
  • the insoluble material was recrystallized from aqueous ethanol to give 3.10 g. of 4-(n-dodecylamino)benzoic acid as offwhite flakes, m.p. same as above.
  • the pentane filtrate was taken to dryness and the resulting solid recrystallized from benzene to give 9.40 g. of 4-(ndodecylamino)benzoic acid, m.p. same as above.
  • EXAMPLE 2 Ethyl 4-(n-tridecylamino)benzoate A mixture of 47.0 g. of ethyl 4-aminobenzoate, 72.8 ml. of l-bromotridecane, and 39.3 g. of potassium carbonate in 500 ml. of dry N,N-dimethylacetamide was heated (C.) under nitrogen for 24 hours. The reaction mixture was then chilled, filtered, and the solid product washed once with cold absolute ethanol and with water. Additional product was obtained by adding water to the filtrate and washing it twice with absolute ethanol. The total yield of ethyl 4-(n-tridecylamino)- benzoate was 66.5 g. of white crystals.
  • EXAMPLE 3 4-(n-Tridecylamino)benzoic acid A mixture of 27.7 g. of ethyl 4-(n-tridecylamino)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-(ntridecylamino)benzoic acid as white crystals, m.p. 1069: 1 l23C. 4
  • EXAMPLE 4 Ethyl 4-(n-Tetradecylamino)benzoate To a solution of 16.5 g. of ethyl 4-aminobenzoate in 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. 8182C.
  • 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 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 ethanol gave 58.8 g. of white ethyl 4-(n-pentadecylamino)benzoate, m.p. 7374.5C.
  • EXAMPLE 7 4-( n-Pentadecylamino)benzoic acid
  • 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-(nhexadecylamino)benzoate as white crystals, m.p. 84-86.5C.
  • EXAMPLE 9 I 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 l Ethyl 4-(n-hexadecylamino)benzoate
  • 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-hexadecylamino )benzoate, m.p. 8083C.
  • EXAMPLE 11 4-( n-l-lexadecylamino)benzoic acid
  • a mixture of 5.85 g. of ethyl 4-(n-hexadecylamino)- benzoate and 4.21 g. of potassium hydroxide in 150 ml. of water-ethanol (1:1) was refluxed for 6.5 hours.
  • Con- 10 centrated hydrochloric acid (40 ml.) added to the hot solution followed by cooling, adding 100 ml. of water and chilling gave the hydrochloride salt of the product. It was recrystallized from ethanol-water (9:1) to yield 5.0 g. (m.p. 107110C., l24-l27.5C.) of white 4- (n-hexadecylamino)benzoic acid.
  • EXAMPLE l2 4-(n-l-lexadecylamino)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-bromo-hexadecane 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.
  • EXAMPLE 14 4-(n-Heptadecylamino)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.
  • EXAMPLE 15 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 C. for 20 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-(- octadecylamino)benzoate as white crystals m.p. 8889C.
  • 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 4aminobenzoate, 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-nonadecylamino )benzoate and 103 g. of potassium hydroxide in 1200 ml. of 50% ethanol was refluxed for 6 hours. Hydrochloric acid (170 ml.) was then added to the hot solution and the mixture was diluted with 300 ml. of water, chilled and filtered. Recrystallization from benzene-ethanol (1:1) gave 67.4 g. of white 4-(n-nonadecylamino)benzoic acid, m.p. 104-6C., 120-4C.
  • 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 heated at 130C. for 24 hours.
  • the reaction mixture was taken to a small volume by distillation under high vacuum. Water and ethanol were added and the mixture was chilled.
  • the product was collected, washed with water and recrystallized from absolute ethanol followed by chromatography on silica gel in chloroform solution. The fractions containing the product were combined and the solvent was removed under vacuum.
  • the yield was 15.0 g. of ethyl 4-[(1-Methy1undecyl- )amino]benzoate.
  • EXAMPLE 4-[( l-methylundecyl)amino]benzoic acid A mixture of 15.0 g. of ethyl 4-[(1-methylundecyl)amino]benzoate and 25.2 g. of potassium hydroxide in 175 ml. 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- 12 [(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 ml. 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-hexyadecylamino)benzoate.
  • EXAMPLE 22 3-(n-Hexadecylamino)benzoic acid
  • a mixture of 49.7 g. of ethyl 3-(n-hexadecylamino)- benzoate and 71.3 g. of potassium hydroxide in 700 ml. of water-ethanol (1:1) was refluxed for 6 hours.
  • Concentrated 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 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 10 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
  • EXAMPLE 25 4-(n-Octylamino)benzoic acid
  • a mixture of 3.0 g. of ethyl 4-(n'-octylamino)benzoate, 3 g. of potassium hydroxide and 50 ml. of ethanolwater (9:1) was refluxed for 3 hours.
  • the mixture was acidified with concentrated hydrochloric acid, diluted with water and f ltered.
  • the solid was washed thor oughly with water and recrystallized from ethanol to give 2.1 g. of 4-(n-octylamino) benzoic acid as white crystals, m.p. l17118C.
  • 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-waterr (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. 121.5-l23.5C. and l27l28C.
  • EXAMPLE 27 Ethyl 4-(n-hexylamino)benzoate 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:
  • the above formulation is to be thoroughly mixed and placed in equal quantities in 100 capsules.
  • 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.
  • the sorbitol solution is to be added to 40 ml. of distilled water and the active ingredient is suspended therein.
  • the saccharin, sodium benzoate, flavor and dye are to be added and dissolved in the above solution.
  • the volume is adjusted to 100 ml. with distilled water.
  • Each ml. of syrup contains 50 mg. of drug.
  • a method of treating hyperlipidemia in a mammal comprising administering to said mammal an effective serum lipid-lowering amount of a 4-(monoalkylamino) benzoic acid derivative of the formula:
  • R is an unbranched or branched alkyl group, C H H wherein n is 4 to 19; and R is hydrogen, lower alkyl, benzyl, dilower akylaminoethyl or lower alkoxymethyl or a pharmaceutically acceptable salt thereof.
  • a therepeutic composition in unit dosage form which is useful to lower serum lipids comprising a 4- (monoalkylamino) benzoic acid derivative of the formula:

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

llie tts att 1191 Alliright et al. 1 Dec. 2, 11975 HYPOLIPIDEMIC [58] Field of Search 424/310 4-(MONOALKYLAMKNO)BENZOIC ACID DERKVATIVES [56] References Cited [75] Inventors: Jay Donald Albright, Nanuet; UNITED STATES PATENTS Stephen Joseph Riggi* suffer"? $716,644 2/1973 Albers ct r11 424/302 Robert Gordon Shepherd, South Nyack all of Primary E.raminer-Stanley J. Friedman [73] Assignee: American Cyanamid Company, Attorney, Agent, or FirmJack W. Richards Stamford. Conn.
221 Filed; on. 25, 1974 ABSTRACT [21] Appl No: 518,022 4-(Monoalkylamino)benzoic acids and esters, pharmaceutically acceptable salts thereof, and a method for Related Applicat'on Data lowering serum lipids in mammals by administration of [62] Division of Ser. No. 402212, Oct. lv 1973, Pat. Nov said acids, esters and salts; and pharmaceutical com- 3,868,4l6. positions thereof.
{52] US. Cl. 424/319; 424/263; 424/267;
424/310 51 1111. e1. A61K 31/44; A61K 31/195; 7 Claims, N0 Drawmgs A61K 31/245; A61K3l/445 HYPOLIPIDEMIC 4-(MONOALKYLAMINO)BENZOIC ACID DERIVATIVES This is a division of application Ser. No. 402,212 filed Oct. 1, 1973, now US. Pat. No. 3,868,416.
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:
co a
wherein R is an unbranched or branched alkyl group, C,, H n wherein n is 4 to 19; and R is hydrogen, lower alkyl, benzyl, dilower alkylaminoethyl, lower alkoxyethyl, l-methyl-4-pipen'dyl, 2-pyridylmethyl, 4- pyridylmethyl; and the pharrnaceutically 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 tn'fluoroacetic'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 diseases, 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. I. Levy and D. S. Fredrickson, Postgraduate Medicine, Vol. 47, pps. 130-136 (1970).]The class of compounds encompassed by the present invention may be termed 4-(monoalkylamino)benzoic acids, esters and salts thereof.
As pointed out heretofore, 4-(monoalkyl)benzoic acids and/or esters wherein n in the above fomiula is 4 to 7 are known. Also known are such acids and/or esters wherein n in the above formula is 1 to 3. Moreover, certain 4-(monoalkylamino)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 C acid, J. Soc. Chem. Ind., 64, 177 (1945); J. Applied Chem. (U.S.S.R.), 17, 588 (1944); J. Gen. Chem. (U.S.S.R.), 16, 1033 (1946); for C methyl ester, J. Am. Chem. Soc., 66, 2127 (1944); for C acid, J. Amer. Chem. Soc., 71, 3366 (1949); for C,, ethyl ester, J. Amer. Chem; Soc., 71, 3366 (1949); for C acid, J. Microbial Seral, 20, 285-98 (1954); for C ethyl ester, Chem. Abstracts, 52: P11928f, Chem. Abstracts 53: P5203e; for C-, ethyl ester, Chem. Abstracts 52: Pl 1929b (Brit. Pat. No. 788,100), Chem. Abstracts 53: P5203e (Swiss Pat. No. 331,982). References for C, acid, J. Amer. Chem. Soc., 73, 1299 (1955), Chem. Ber., 80, 310 (1947), J. Amer. Chem. Soc., 71, 2933 (1949); for C acid, J. Amer. Chem. Soc. 66, 2127 (1944), Chem. Ber. 80, 479 (1947), J. Sci. Ind. Research, 148, 624 (1955); Chem. Abstracts 3811216 (Ber. B, 1911 (1942); for C acid,J. Amer. Chem. Soc. 65, 2281 (1943), Chem. Abstracts, 38, P2346 (Ger. 716,668, Dec. 24, 1941 3 References to polyethylene glycol and dialkylaminoethyl esters: for C Chem. Abstracts, 52. P119296 (Brit. Pat. No. 788,100, Dec. 23, 1957); for C Chem. Abstracts, 53, P5203e (Swiss Pat. No. 331,982, Sept. 30, 1958), Chem. Abstracts, 52, P1 l928f(Brit. Pat. No. 788,100, Dec. 23, 1957); for C Chem. Abstracts, 47, P5965e (US. Pat. No. 2,608,574, Aug. 26, 1952), Chem. Abstracts, 44, 9376c, J. Am. Chem. Soc., 71, 3366 (1949); for C Chem. Abstracts, 52, P8197d (Japan Pat. No. 7511, Aug. 30, 1956), Current Research, Anesth. Analg. 30,
l, 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, 48579); 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.
3 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 lower alkyl p-aminobenzoates with suitable alkylating agents such as alkyl halides, sulfates, tosylates or trifluoromethylsulfonates with or without solvent at 50C. 150C. Suitable solvents are lower alkanols, chloroform, N,l ldimethylformamide, N,N-dimethylacetamide, diglyme, dimethylsulfoxide, acetonitrile, toluene, benzene, hexamethylphosphoramide and the like. The reaction may be carried out with an equivalent of base suchas an alkali carbonate or bicarbonate or with a catalytic amount ofcopper. 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 hal ide of 4 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. 150C.
Alternative methods of preparation 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 atmospheres of 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 Raney nickel catalyst to give methyl 4-(n-hexadecylamino)benzoate. Diborane reduction of ethyl 4-(n-hexadecanoylamino)benzoate at room temperature or above for 16 hours yields the ethyl analog of the above ester.
Two types of substitution reactions also yield the desired 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 l\l-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 may be prepared by hydrolysis of the lower alkyl 4-(monoalkylarnino)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 adids, which can be prepared by reaction of a lower alkyl 4-(monoalkylamino)benzoate with an appropriatealkylating agent to give the lower alkyl esters with subsequent hydrolysis to give the acids. Suitable alkylating agents are 4,. lower alkyltosylates, lower dialkylsulfates (such as dimethyl 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 220 hours while ethylations are conveniently carried out with excess diethyl sulfate at C. C. 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-(dodecy1methylamino)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 acylmonalkylaminobenzoates can be prepared by acylation of the lower alkyl monoalkylaminobenzoates with acyl halides or anhydrides such as acetyl chloride, acetic anhydride, benzoyl chloride, ben zoic anhydride, succinic anhydride, etc. in the presence of a suitable base as puridine, 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- benZoyl-n-hexadecylamino )benzoic acid, 4-( N-acetyl-n-hexadecylamino )benzoic acid. Such compounds have been prepared by acylation of ehtyl 4-(tetradecylamino)- benzoate with acetyl chloride or acetic anhydride in presence of a suitable base such as pyridine or 4-dimethylaminopyridine or by the acylation of 4-(tetradecylamino)benzoic acid and 4-(hex-' The mechanism of action of the 4-(monoalkylamino)benzoic acid compounds of this invention is not known and the inventors do not wish to 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, New York. 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 (I) according to the saponification and extraction method of P. Trinder, Analyst 77, 321 (1952) and the colorimetric determination of Ziatkis, et. al., J. Lab. Clin. Med. 44, 486 (1953) or (2) by the extraction method of H. H. Leffler, Amer. J. Clin. Path. 31, 310 (1959), 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 Skeggs, L. T.'(Ed.), Mediad Inc. New York, 1965, p. 341]. The phospholipids were determined by standard methods [G. R. Bartlett, J. Biol. Chem. 234, 466 (1959)]. Changes in serum lipids are expressed as percent lowering from control.
In these tests, a compound is considered to have hypolipidemic activity if it depresses serum sterol levels or more below that of the controls, and/or depresses triglyceride levels by 25% or more below controls. Table I shows several of the compounds of the present invention and the degree to which they depress serum sterols and triglyceride levels after a 1-week and 4-week dosing period and phospholipids after a 4-week dosing period.
TABLE 1 evated 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-(n-hexadecylamino)benzoic acid] of this invention on serum lipid levels were determined in mice and gerbils (Table II) after one week of treatment. Mice (CF-1 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 Gerbils Mice Dose, percent of diet 0.1 0.1 Serum Sterol, Lowering 20 22 Serum Phospholipid, 28
Lowering ferred dosage regimen for optimum results would be HYPOLIPIDEMIC ACTIVITY OF 4-(MONOALKYLAMINO)BENZOIC ACIDS AND DERIVATIVES l-Week test, Low- 4-Week test,
Low-
Compound ering of Serum ering of Serum Compound I in Diet Sterol Triglyceride Sterol Triglyceride Phospholipid 4-(Butylamino)-ben2oic Acid 0.1 16 39 4-(n-Hexylamino)benzoic Acid 0.1 16 35 4-(n-Octylamino)benzoic Acid 0.1 I l 32 4-(n-Dodecylamino)benzoic Acid 0.1 10 67 4-(n-Tridecylamino)benzoic Acid 0.1 16 39 4-( n-Tetradecyl amino benzoic Acid 0.1 10 47 4-(n-Pentadecylamino)- I benzoic Acid 0.1 19 39 25 46 35 Ethyl 4-(n-hexadecylaminobenzoate 0. l 1 3 1 4-(nI-Iexadecylamino)benzoic Acid 0.1 30 48 37 68 39 4-(n-I-Ieptadecylamino)- benzoic Acid 0.1 12 42 24 65 33 4-(n-Octadecylamino)- benzoic Acid 0.1 18 15 21 4-(n-Nonadecylamino)- benzoic Acid 0 54 I0 44 I8 Dimethylaminoethyl 4( n-hexadecylamino)- 0.1 9 41 benzoate hydrochloride The data in Table I indicate that the 4-(monoalkylamino)benzoic acids and derivatives tested are all effrom about 2 mg. per kg. to about 29 mg. per kg. Thus the daily dosage employed for a subject of about kg. of body weight is about 35 mg. to about 2.8 g., and
7 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 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 10 and 500 milligrams of active compound.
The tablets, troches, pills, capsules and the like may 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 a fatty 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, methyl and propyl parabens as perservatives, 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.
EXAMPLE 1 4-(n-Dodecylamino)benzoic Acid A solution of 10.4 g. of potassium hydroxide in 200 ml. of 90% 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 hrs. An additional 44 ml. of l-bromododecane was then added and heating was continued for hrs. The crude product was freed of ester by adding 31.2 g. of potassium hydroxide in 100 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. 111.5-113; l25-125.5C.
The chloroform filtrate was taken to dryness and the resulting solid washed with pentane. The insoluble material was recrystallized from aqueous ethanol to give 3.10 g. of 4-(n-dodecylamino)benzoic acid as offwhite flakes, m.p. same as above. The pentane filtrate was taken to dryness and the resulting solid recrystallized from benzene to give 9.40 g. of 4-(ndodecylamino)benzoic acid, m.p. same as above.
EXAMPLE 2 Ethyl 4-(n-tridecylamino)benzoate A mixture of 47.0 g. of ethyl 4-aminobenzoate, 72.8 ml. of l-bromotridecane, and 39.3 g. of potassium carbonate in 500 ml. of dry N,N-dimethylacetamide was heated (C.) under nitrogen for 24 hours. The reaction mixture was then chilled, filtered, and the solid product washed once with cold absolute ethanol and with water. Additional product was obtained by adding water to the filtrate and washing it twice with absolute ethanol. The total yield of ethyl 4-(n-tridecylamino)- benzoate was 66.5 g. of white crystals.
EXAMPLE 3 4-(n-Tridecylamino)benzoic acid A mixture of 27.7 g. of ethyl 4-(n-tridecylamino)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-(ntridecylamino)benzoic acid as white crystals, m.p. 1069: 1 l23C. 4
EXAMPLE 4 Ethyl 4-(n-Tetradecylamino)benzoate To a solution of 16.5 g. of ethyl 4-aminobenzoate in 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. 8182C.
A mixture of 29 g. of ethyl 4-(n-tetradecylamino)benzoate, 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. 108111C.
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 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 ethanol gave 58.8 g. of white ethyl 4-(n-pentadecylamino)benzoate, m.p. 7374.5C.
EXAMPLE 7 4-( n-Pentadecylamino)benzoic acid 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-(nhexadecylamino)benzoate as white crystals, m.p. 84-86.5C.
EXAMPLE 9 I 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 l 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-hexadecylamino )benzoate, m.p. 8083C.
EXAMPLE 11 4-( n-l-lexadecylamino)benzoic acid A mixture of 5.85 g. of ethyl 4-(n-hexadecylamino)- benzoate and 4.21 g. of potassium hydroxide in 150 ml. of water-ethanol (1:1) was refluxed for 6.5 hours. Con- 10 centrated hydrochloric acid (40 ml.) added to the hot solution followed by cooling, adding 100 ml. of water and chilling gave the hydrochloride salt of the product. It was recrystallized from ethanol-water (9:1) to yield 5.0 g. (m.p. 107110C., l24-l27.5C.) of white 4- (n-hexadecylamino)benzoic acid.
EXAMPLE l2 4-(n-l-lexadecylamino)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-bromo-hexadecane 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-(n-hexadecylamino)benzoic acid, m.p. l06108C., complete melt EXAMPLE 13 Ethyl 4-(n-heptadecylamino)benzoate A mixture of 48.3 g. of ethyl 4arninobenzoate, 93.4 g. of 1-bromoheptadecane and 40.4 g. of potassium carbonate in 700 m1. 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 14 4-(n-Heptadecylamino)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 concentrated 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-(n-heptadecylamino)benzoic acid, m.p. l05108C.; 128128.5C.
EXAMPLE 15 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 C. for 20 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-(- octadecylamino)benzoate as white crystals m.p. 8889C.
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 ml. 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. 103l06C., complete melt 123126C.
EXAMPLE 17 Ethyl 4-(n-nonadecylamino)benzoate A mixture of 40.4 g. of ethyl 4aminobenzoate, 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-nonadecylamino )benzoate and 103 g. of potassium hydroxide in 1200 ml. of 50% ethanol was refluxed for 6 hours. Hydrochloric acid (170 ml.) was then added to the hot solution and the mixture was diluted with 300 ml. of water, chilled and filtered. Recrystallization from benzene-ethanol (1:1) gave 67.4 g. of white 4-(n-nonadecylamino)benzoic acid, m.p. 104-6C., 120-4C.
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 heated at 130C. for 24 hours. The reaction mixture was taken to a small volume by distillation under high vacuum. Water and ethanol were added and the mixture was chilled. The product was collected, washed with water and recrystallized from absolute ethanol followed by chromatography on silica gel in chloroform solution. The fractions containing the product were combined and the solvent was removed under vacuum. The yield was 15.0 g. of ethyl 4-[(1-Methy1undecyl- )amino]benzoate.
EXAMPLE 4-[( l-methylundecyl)amino]benzoic acid A mixture of 15.0 g. of ethyl 4-[(1-methylundecyl)amino]benzoate and 25.2 g. of potassium hydroxide in 175 ml. 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- 12 [(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 ml. 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-hexyadecylamino)benzoate.
EXAMPLE 22 3-(n-Hexadecylamino)benzoic acid A mixture of 49.7 g. of ethyl 3-(n-hexadecylamino)- benzoate and 71.3 g. of potassium hydroxide in 700 ml. of water-ethanol (1:1) was refluxed for 6 hours. Concentrated 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 hyd rochloride To ml. of thionyl chloride cooled to 0C. was added portionwise, 21.7 g. (0.060 mole) of 4-(n-hexadecylamino)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 ml. of toluene added and the solution cooled. To the mixture was added 6.24 g. (0.070 mole) of Z-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 10 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 15.1 g. of white crystals, m.p. 79-80C.
EXAMPLE 25 4-(n-Octylamino)benzoic acid A mixture of 3.0 g. of ethyl 4-(n'-octylamino)benzoate, 3 g. of potassium hydroxide and 50 ml. of ethanolwater (9:1) was refluxed for 3 hours. The mixture was acidified with concentrated hydrochloric acid, diluted with water and f ltered. The solid was washed thor oughly with water and recrystallized from ethanol to give 2.1 g. of 4-(n-octylamino) benzoic acid as white crystals, m.p. l17118C.
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-waterr (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. 121.5-l23.5C. and l27l28C.
EXAMPLE 27 Ethyl 4-(n-hexylamino)benzoate 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 100 capsules,
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 Per tablet, mg.
4-( n-H exadecylarnino)- benzoic acid 500 "-continued Per tablet. mg.
Corn starch 210 Methylcellulose 400 350 Magnesium stearate 1% 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-hexadecylamino benzoate hydrochloride 5000 mg. Sorbitol solution 40 ml. N.F.) Sodium benzoate 150 mg. Saccharin 10 mg. Red dye {F.D. & c. No 2) 10 mg. Cherry flavor 50 mg. Distilled water, q.s. ad ml.
The sorbitol solution is to be added to 40 ml. of distilled water and the active ingredient is suspended therein. The saccharin, sodium benzoate, flavor and dye are to be added and dissolved in the above solution. The volume is adjusted to 100 ml. with distilled water. Each ml. of syrup contains 50 mg. of drug.
1 claim:
1. A method of treating hyperlipidemia in a mammal comprising administering to said mammal an effective serum lipid-lowering amount of a 4-(monoalkylamino) benzoic acid derivative of the formula:
co s.
wherein R is an unbranched or branched alkyl group, C H H wherein n is 4 to 19; and R is hydrogen, lower alkyl, benzyl, dilower akylaminoethyl or lower alkoxymethyl or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 wherein said 4-(monoalkylamino)benzoic acid derivative is administered to provide a daily dosage of from about 0.5 mg. to about 40 mg. per kg. of body weight of said mammal.
3. The method of claim 2 wherein said daily dosage is about 2 mg. to about 29 mg. per kg. of body weight of said mammal.
4. The method of claim 3 wherein the compound is 4-(n-hexadecylamino)benzoic acid and pharmaceutically acceptable salt thereof.
5. A therepeutic composition in unit dosage form which is useful to lower serum lipids comprising a 4- (monoalkylamino) benzoic acid derivative of the formula:
hexadecylamino )benzoic acid.

Claims (7)

1. A METHOD OF TREATING HYPERLIPIDEMIA IN A MAMMAL COMPRISING ADMINISTERING TO SAID MAMMAL AN EFFECTIVE SERUM LIPIDLOWERING AMOUNT OF A 4-(MONOALKYLAMINO) BENZOIC ACID DERIVATIVE OF THE FORMULA:
2. The method of claim 1 wherein said 4-(monoalkylamino)benzoic acid derivative is administered to provide a daily dosage of from about 0.5 mg. to about 40 mg. per kg. of body weight of said mammal.
3. The method of claim 2 wherein said daily dosage is about 2 mg. to about 29 mg. per kg. of body weight of said mammal.
4. The method of claim 3 wherein the compound is 4-(n-hexadecylamino)benzoic acid and pharmaceutically acceptable salt thereof.
5. A therepeutic composition in unit dosage form which is useful to lower serum lipids comprising a 4-(monoalkylamino) benzoic acid derivative of the formula:
6. The composition according to claim 5 wherein the daily dosage is from about 140 mg. to about 2.0 g.
7. The composition according to claim 5 wherein the 4-(monoalkylamino)benzoic acid derivative is 4-(n-hexadecylamino)benzoic acid.
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US4242273A (en) * 1977-09-27 1980-12-30 American Cyanamid Company 4-(Monoalkylamino)benzoic acid amides and imidates
US6080428A (en) * 1993-09-20 2000-06-27 Bova; David J. Nicotinic acid compositions for treating hyperlipidemia and related methods therefor
US6129930A (en) * 1993-09-20 2000-10-10 Bova; David J. Methods and sustained release nicotinic acid compositions for treating hyperlipidemia at night
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US6746691B2 (en) 1993-09-20 2004-06-08 Kos Pharmaceuticals, Inc. Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics
US6818229B1 (en) 1993-09-20 2004-11-16 Kos Pharmaceuticals, Inc. Intermediate release nicotinic acid compositions for treating hyperlipidemia
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US4245119A (en) * 1977-09-27 1981-01-13 American Cyanamid Company 4-(Monoalkylamino) benzene polycarboxylic acids
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US4307113A (en) * 1978-04-20 1981-12-22 Sandoz, Inc. Anthranilic acid derivatives
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
US4206223A (en) * 1979-01-05 1980-06-03 The Dow Chemical Company Method for treating hyperglycemia in mammals using 4-(((1,3-benzodioxol-5-yl)methyl)amino)benzoic acid or derivatives thereof
US4281019A (en) * 1979-02-01 1981-07-28 American Cyanamid Company 4-[(Unsaturated or cyclopropylated alkyl)amino]phenyl compounds useful as hypolipidemic and antiatherosclerotic agents
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US4263320A (en) * 1979-06-04 1981-04-21 The Dow Chemical Company Hypoglycemic phenylpropynylamino benzoic acids
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US4182776A (en) * 1975-12-09 1980-01-08 American Cyanamid Company Method of treating lipidemia with aryloxyalkylaminobenzoic acids and esters
US4242273A (en) * 1977-09-27 1980-12-30 American Cyanamid Company 4-(Monoalkylamino)benzoic acid amides and imidates
US6080428A (en) * 1993-09-20 2000-06-27 Bova; David J. Nicotinic acid compositions for treating hyperlipidemia and related methods therefor
US6129930A (en) * 1993-09-20 2000-10-10 Bova; David J. Methods and sustained release nicotinic acid compositions for treating hyperlipidemia at night
US6676967B1 (en) 1993-09-20 2004-01-13 Kos Pharmaceuticals, Inc. Methods for reducing flushing in individuals being treated with nicotinic acid for hyperlipidemia
US6746691B2 (en) 1993-09-20 2004-06-08 Kos Pharmaceuticals, Inc. Intermediate release nicotinic acid compositions for treating hyperlipidemia having unique biopharmaceutical characteristics
US6818229B1 (en) 1993-09-20 2004-11-16 Kos Pharmaceuticals, Inc. Intermediate release nicotinic acid compositions for treating hyperlipidemia
US20050118257A1 (en) * 1993-09-20 2005-06-02 Bova David J. Nicotinic acid compositions for treating hyperlipidemia and related methods therefor
US20080045573A1 (en) * 1993-09-20 2008-02-21 Bova David J Methods and Sustained Release Nicotinic Acid Compositions for Treating Hyperlipidemia
US7998506B2 (en) 1993-09-20 2011-08-16 Kos Life Sciences, Inc. Nicotinic acid compositions for treating hyperlipidemia and related methods therefor

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