CA1077957A - Hypolipidemic 4-(monoalkylamino) benzoic acid derivatives - Google Patents
Hypolipidemic 4-(monoalkylamino) benzoic acid derivativesInfo
- Publication number
- CA1077957A CA1077957A CA210,303A CA210303A CA1077957A CA 1077957 A CA1077957 A CA 1077957A CA 210303 A CA210303 A CA 210303A CA 1077957 A CA1077957 A CA 1077957A
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- CA
- Canada
- Prior art keywords
- compound
- formula
- benzoic acid
- ethyl
- hydrogen
- Prior art date
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Classifications
-
- 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
Abstract
ABSTRACT OF THE DISCLOSURE
4-(Monoalkylamino)benzoic acids and esters, and pharmaceutically acceptable salts thereof, which are useful for lowering serum lipids in mammals.
4-(Monoalkylamino)benzoic acids and esters, and pharmaceutically acceptable salts thereof, which are useful for lowering serum lipids in mammals.
Description
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: Rl-~-H
I
wherein Rl is an unbranched or branched alkyl group, Cn H2n~l wherein n is 8 to 19; and R2 is hydrogen, lower alkyl of from 1 to 4 carbon atoms or, dilower alkylaminoethyl; and the pharmaceutically acceptable salts thereof. Suitable lower alkyl groups contemplated by the present invention are for example, methyl, isopropyl, _-propyl, ethyl and sec-butyl.
The compounds of the invention can be prepared by reacting a compound of the formula CnHm-A II
wherein n is 7 to 18 and m is 2n~1; wherein A is CH2X or ~-X wherein X is halogen, hydroxy, alkyl sulfonate or aryl sulfonate ester, or hydrogen (except when A is CH2X), with a compound of the formula:
., ~
~ \ ~ III
"", ~
Y
wherein B is amino, acylamino or a group convertible thereinto and Y is car-boxy or a group convertible thereinto or hydrogen tin which case the carboxyl group or group convertible thereinto is introduced as a final s~ep) and when X
is halogen it may be interchanged with B, and where necessary converting the product obtained from the reaction of II with III to the desired I or a phar-maceutically acceptable salt thereof by oxidation, reduction, or hydrolysis of the appropriate functional groups and/or reaction with salt-forming acids or bases.
With reference to the above formula I, the invention contemplates as novel compounds per se those acids, esters and pharmaceutically acceptable "`~
F
salts thereof wherein n is 8 to l9. Compounds wherein n is 4 to 7 are known in the art, infra. The invention also contemplates a method for lowering serum lipids in mammals by administration of said acids and esters wherein n is 8 to 19, and the use of pharmaceutically acceptable salts and pharmaceutical compos-itions employing said acids, esters and salts to lower serum lipids.
Compounds of the present invention were shown to possess hypolipide-mic activity as determined by animal experiments. Compounds represented by the above formula wherein n is 8 to l9 have been found to possess hypolipide-mic activity in animals, namely serum triglyceride lowering, with cholesterol ' .1~
1~77957 :,:
lowering when n is 14 to 17, Of the active compounds, the pre-ferred 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 R2 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 car-boxyl group or a trifluoroacetic or citric acid salt o~
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 hy- -perlipidemia, 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 chol-esterol, phospholipid and triglyceride blood levels are termed ;~ hypolipidemic drugs. Presently three ma~or lipid-lowering ~ agents are available; clofibrate, D-thyroxine, and nicotinic .,.,;
; 25 acid. [R.I. Levy and D.S. Fredrickson, Postgraduate Medicine,Vol. 47, pps. 130-1~6 (1970).] The class of compounds encom-passed by the present invention may be termed 4-(monoalkyl-:, ~ amino)benzoic acids, esters and salts thereof.
: .
,.~
;
, ~
., .
f - 2 -. . .
.
, . . .
-As pointed out heretofore, 4-(monoalkyl)benzoic acids and/or esters wherein n in the above formula is 4 to 7 are known~l Also ~lcnown are such acids and/or esters wherein n in the above formula is 1 to 3.2 Moreover, certain 4-(mono-alkylamino)benzoi~ acid esters, i.e., those wherein n in the above formula is 3 to 7, have been disclosed as having local anesthetic activity. 3 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); J. Gen. Chem.
(U.S.S.R.), 16, 1033 (1946 ; for C4 methyl ester, J. Am.
Chem. Soc., ~, 2127 (1944 ; for C5 acid, J. Amer. Chem.
Soc., 71, 33~ (1949?; for C5 ethyl ester, J. Amer. Chem.
Soc., 71, 3366 (1949); for CB acid, J. Microbial Seral, 20 285-98 (1954); for C6 ethyl ester, Chem. Abstracts, 52:
P11928f, Chem. Abstracts 53: P5203e; for C7 ethyl ester, Chem. Abstracts 52: P11929b (Brit. Patent 788,100), Chem.
Abstracts 53: P5203e (Swiss Patent 331,982).
2References for Cl acid, J. Amer. Chem. Soc., 73, 1299 (1955), Chem. Ber., 80, 310 (ly47), J. Amer. Chem. Soc., 71, 2933 (1949); for C2 acid, J. Amer. Chem. Soc. 66, ~I27 (1944), Chem. Ber. 80, 479 (1947), J. Sci. In~
Research, 14B, 624 (1955~ Chem. Abstracts 38:12165 (Ber.
75B, 1911 TI~42); for C3 acid, J. Amer. Chem. Soc. 65, 2281 (1943), Chem. Abstracts, 38, P23461 (Ger. 716,~8, Dec. 24, 1941).
3References to polyethylene glycol and dialkylaminoethyl ; esters: for C7 Chem. Abstracts, 52, P119296 (Brit. Patent 788,100, Dec. ~3, 1957); for CB Chem. Abstracts, 53, P5203e (Swiss Patent 331,982, Sept. 30, 1958), Chem.
; Abstracts, 52, P11928f (Brit. Patent 788,100, Dec. 23, 1957~; for C5 Chem. Abstracts, 47, P5965e (U.S. Patent
I
wherein Rl is an unbranched or branched alkyl group, Cn H2n~l wherein n is 8 to 19; and R2 is hydrogen, lower alkyl of from 1 to 4 carbon atoms or, dilower alkylaminoethyl; and the pharmaceutically acceptable salts thereof. Suitable lower alkyl groups contemplated by the present invention are for example, methyl, isopropyl, _-propyl, ethyl and sec-butyl.
The compounds of the invention can be prepared by reacting a compound of the formula CnHm-A II
wherein n is 7 to 18 and m is 2n~1; wherein A is CH2X or ~-X wherein X is halogen, hydroxy, alkyl sulfonate or aryl sulfonate ester, or hydrogen (except when A is CH2X), with a compound of the formula:
., ~
~ \ ~ III
"", ~
Y
wherein B is amino, acylamino or a group convertible thereinto and Y is car-boxy or a group convertible thereinto or hydrogen tin which case the carboxyl group or group convertible thereinto is introduced as a final s~ep) and when X
is halogen it may be interchanged with B, and where necessary converting the product obtained from the reaction of II with III to the desired I or a phar-maceutically acceptable salt thereof by oxidation, reduction, or hydrolysis of the appropriate functional groups and/or reaction with salt-forming acids or bases.
With reference to the above formula I, the invention contemplates as novel compounds per se those acids, esters and pharmaceutically acceptable "`~
F
salts thereof wherein n is 8 to l9. Compounds wherein n is 4 to 7 are known in the art, infra. The invention also contemplates a method for lowering serum lipids in mammals by administration of said acids and esters wherein n is 8 to 19, and the use of pharmaceutically acceptable salts and pharmaceutical compos-itions employing said acids, esters and salts to lower serum lipids.
Compounds of the present invention were shown to possess hypolipide-mic activity as determined by animal experiments. Compounds represented by the above formula wherein n is 8 to l9 have been found to possess hypolipide-mic activity in animals, namely serum triglyceride lowering, with cholesterol ' .1~
1~77957 :,:
lowering when n is 14 to 17, Of the active compounds, the pre-ferred 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 R2 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 car-boxyl group or a trifluoroacetic or citric acid salt o~
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 hy- -perlipidemia, 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 chol-esterol, phospholipid and triglyceride blood levels are termed ;~ hypolipidemic drugs. Presently three ma~or lipid-lowering ~ agents are available; clofibrate, D-thyroxine, and nicotinic .,.,;
; 25 acid. [R.I. Levy and D.S. Fredrickson, Postgraduate Medicine,Vol. 47, pps. 130-1~6 (1970).] The class of compounds encom-passed by the present invention may be termed 4-(monoalkyl-:, ~ amino)benzoic acids, esters and salts thereof.
: .
,.~
;
, ~
., .
f - 2 -. . .
.
, . . .
-As pointed out heretofore, 4-(monoalkyl)benzoic acids and/or esters wherein n in the above formula is 4 to 7 are known~l Also ~lcnown are such acids and/or esters wherein n in the above formula is 1 to 3.2 Moreover, certain 4-(mono-alkylamino)benzoi~ acid esters, i.e., those wherein n in the above formula is 3 to 7, have been disclosed as having local anesthetic activity. 3 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); J. Gen. Chem.
(U.S.S.R.), 16, 1033 (1946 ; for C4 methyl ester, J. Am.
Chem. Soc., ~, 2127 (1944 ; for C5 acid, J. Amer. Chem.
Soc., 71, 33~ (1949?; for C5 ethyl ester, J. Amer. Chem.
Soc., 71, 3366 (1949); for CB acid, J. Microbial Seral, 20 285-98 (1954); for C6 ethyl ester, Chem. Abstracts, 52:
P11928f, Chem. Abstracts 53: P5203e; for C7 ethyl ester, Chem. Abstracts 52: P11929b (Brit. Patent 788,100), Chem.
Abstracts 53: P5203e (Swiss Patent 331,982).
2References for Cl acid, J. Amer. Chem. Soc., 73, 1299 (1955), Chem. Ber., 80, 310 (ly47), J. Amer. Chem. Soc., 71, 2933 (1949); for C2 acid, J. Amer. Chem. Soc. 66, ~I27 (1944), Chem. Ber. 80, 479 (1947), J. Sci. In~
Research, 14B, 624 (1955~ Chem. Abstracts 38:12165 (Ber.
75B, 1911 TI~42); for C3 acid, J. Amer. Chem. Soc. 65, 2281 (1943), Chem. Abstracts, 38, P23461 (Ger. 716,~8, Dec. 24, 1941).
3References to polyethylene glycol and dialkylaminoethyl ; esters: for C7 Chem. Abstracts, 52, P119296 (Brit. Patent 788,100, Dec. ~3, 1957); for CB Chem. Abstracts, 53, P5203e (Swiss Patent 331,982, Sept. 30, 1958), Chem.
; Abstracts, 52, P11928f (Brit. Patent 788,100, Dec. 23, 1957~; for C5 Chem. Abstracts, 47, P5965e (U.S. Patent
2,608,574, Aug. 26, 1952), Chem. Abstracts, 44, 9376e, J. Am. Chem. Soc., 71, 3366 (1949); for ,C4, Chem. Abstracts,
3 52, P8197d (Japan Patent 7511, Aug, 30, 1956), Current Research, Anesth. Analg. 30, 1, 76 (1951), Chemical Abstract, 56, 6585h, J. Applied Chem. (USSR), 17, 588 (1944) (Chem. Abstracts, 40, 22682), J. S~oc. Chem. Ind., 64, 177 (1945) (Chem. Abstracts, 39, 4857Y); for C3 J.
Am. Chem. Soc., 66, 2127 (1944) (Chem. Abstracts 39, 11527).
' - . . ~ . . . -.
. . : : . . :
~77957 No disclosure is known reporting on, or concerned with, hypolipidemic activity for any of the known n = 1-7 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 DESCRI_TION 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. mey are soluble in organic solvents such as chloroform, benzene, dichloromethane, N,N-dimethylformamide, dimethylsulfoxide and lower alkanols. mey 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. m ose compounds wherein R2 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-, di- or tri(lower alkyl)amines such as methylamine, diethylamine, trimethylamine, dibutylamine, N,N'--dimethylethylenediamine, and the like to obtain the corres-` 25 ponding carboxylic acid salts.
; The lower alkyl 4-(monoalkylamino)benzoates of this invention are prepared by reaction of lower alkyl ~-aminobenzo-; ates with suitable alkylating agents such as alkyl halides, sulfates, tosylates or trifluoromethylsulfonates with or with-3o out solvent at 50C. - 150C. Suitable solvents are lower alkanols, chloroform, N,N-dimethylformamide, N,N-dimethylacet-amide, diglyme, dimethylsul~oxide, acetonitrile, toluene, ben-zene, hexamethylphosphoramide and the like. The reaction may - . .~ - .
1~779S7 be carried out with an equivalent of base such as an alkali carbonate or bicarbonate or with a catalytic amount o copper powder when alkyl halides are used as the alkylating agent. Alternatively, the lower alkyl 4-~monoalkyl-amino)benzoates are prepared by reaction of a lower alkyl aminobenzoate with an alkyl halide of 8 to 19 carbon atoms in the presence of an equivalent of sodium hydride in an inert solvent such as N,N-dimethylformlamide, N,N-dimethylacetamide, and diglyme at 50C. - 150C.
Alternative methods of preparation are by reductive alkylation of a
Am. Chem. Soc., 66, 2127 (1944) (Chem. Abstracts 39, 11527).
' - . . ~ . . . -.
. . : : . . :
~77957 No disclosure is known reporting on, or concerned with, hypolipidemic activity for any of the known n = 1-7 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 DESCRI_TION 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. mey are soluble in organic solvents such as chloroform, benzene, dichloromethane, N,N-dimethylformamide, dimethylsulfoxide and lower alkanols. mey 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. m ose compounds wherein R2 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-, di- or tri(lower alkyl)amines such as methylamine, diethylamine, trimethylamine, dibutylamine, N,N'--dimethylethylenediamine, and the like to obtain the corres-` 25 ponding carboxylic acid salts.
; The lower alkyl 4-(monoalkylamino)benzoates of this invention are prepared by reaction of lower alkyl ~-aminobenzo-; ates with suitable alkylating agents such as alkyl halides, sulfates, tosylates or trifluoromethylsulfonates with or with-3o out solvent at 50C. - 150C. Suitable solvents are lower alkanols, chloroform, N,N-dimethylformamide, N,N-dimethylacet-amide, diglyme, dimethylsul~oxide, acetonitrile, toluene, ben-zene, hexamethylphosphoramide and the like. The reaction may - . .~ - .
1~779S7 be carried out with an equivalent of base such as an alkali carbonate or bicarbonate or with a catalytic amount o copper powder when alkyl halides are used as the alkylating agent. Alternatively, the lower alkyl 4-~monoalkyl-amino)benzoates are prepared by reaction of a lower alkyl aminobenzoate with an alkyl halide of 8 to 19 carbon atoms in the presence of an equivalent of sodium hydride in an inert solvent such as N,N-dimethylformlamide, 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 exarnple, n-hexadecanol and methyl 4-aminobenzoate are reduced under 1-10 atmospheres of hydrogen using an activated metal catalyst, forming 4-(n-hexadecylsmino)benzoic acid methyl eSteT. 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-amino-benzoate in the presence of an activated Raney Nickel catalyst to give methyl 4-~n-hexadecylamino)benzoate. Diborane reduction of ethyl 4-ln-hexadecanoylamino)benzoate at room temperature or above for 1-6 hours yields the ethyl analog of the above ester.
Preferred compounds are 4-(n-hexadecylamine)benzoic ~cid and its pharmaceutically acceptable alkali metal salts. They may be prepared by reacting n-hexadecylbromide with ethyl 4-aminobenzoate at a temperature of from 50 to 150C for rom 8 to 20 hours at a pressure of 1 from 1 to 5 atmospheres and recovering the product as the carboxylic acid or its alksli metal salt after hydrolysis with aqueous alcoholic alkali. They may also be prepared by reacting n-hexadecanol or some other source of hexadecyl aldehyde with 4-aminobenzoate in the presence of a Raney nickel catalyst at a tempera-ture of from 50 to 150C for a period of from 8 to 20 hours at a pressure of from 1 to 5 atmospheres and recovering the product as the carboxylic acid or its alkali metal salt after hydTolysis with aqueous alcoholic alkall.
.
1~
_ 5 _ ;-... .
., . ~., .:1 :~377957 Two types of substitution reactions also yield the desired 4-(alkylamino)benzoic acids or esters, namely, reaction of ethyl 3,4-didehydro-benzoate with an alkylamine (or its alkali me~al salt) and Friedel-Crafts acylation of an N-alkyl-aniline or N-acyl-N-alkylaniline. The for~er type of : reaction is carried out by treating a 4-halobenzoate ester such as ethyl 4-bromobenzoa~e 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-n-hexadecylaniline and the like or its N-acetyl ;; - 5a -1 ., ~ :' ` ' ' "
~0779~;7 .
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, wa~er or an aqueous lower alkanol at 25C. to 150C. Alternatively, the ~-(alkylamino)benzoic acids may be prepared by hydrolysis of the lower alkyl 4-(mono-alkylamino)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 f a lower alkyl 4-(monoalkylamino)benzoate with an appropriate alkylating agent to give the lower alkyl esters with subsequeht hydrolysis to give the acids. Suitable alkylating agents are 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. m e alkyla-tion reactions may be carried out with or without a solvent at 20C. to 150C. Suitable solvents are chloroform, dichloro-methane, 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 100C. - 150C. 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. m e lower -- : : . .
1~77957 alkylamino benzoic acid derivatives may be converted to their potassium, sodium or lithium salts and alkylated to give dial-kylaminobenzoate esters - alkylation occurring on both the amino group and on the oxygen of the acid salt. Representative di-alkylaminobenzoic acids and esters which have been prepared areethyl 4-(dodecylmethylamino)benzoate, 4-(dodecylmethylamino)-benzolc acid, 4-(dodecylethylamino)benzoic acid, 4-(methyl-; tetradecylamino)benzoic acidJ 4-(ethyltetradecylamino)benzoic acid, ethyl 4-(methylpentadecylamino)benzoateJ 4-(methylpenta-decylamino)benzoic acidJ 4-(ethylpentadecylamino)benzoic acidJ
ethyl 4-(methylhexadecylamino)benzoate, 4-(methylhexadecylamino)-benzoic acid, ethyl 4-(ethylhexadecylamino)benzoate, 4-(ethyl-hexadecylamino)benzoic acid, 4-(methylheptadecylamino)benzoic acid, 4-(ethylheptadecylamino)benzoic acid, 4-(methyloctadecyl-amino)benzoic acid, and 4-(ethyloctadecylamino)benzoic acid.
In animal tests these compounds have shown inferior hypolipide-mic activity.
Lower alkyl acylmonoalkylaminobenzoates can be pre-pared by acylation of the lower alkyl monoalkylaminobenzoates with acyl halides or anhydrides such as acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, succinic an-hydride, 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 condi-tions gives the acylmonoalkylaminobenzoic acid derivatives.m e 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-~0 -tetradecylamino)benzoate, 4-(N-acetyl-n-tetr,adecylamino)-benzoic acid, 4-(N-benzoyl-n-hexadecylamino)benzoic acid, 4--(N-acetyl-n-hexadecylamino)benzoic acid Such compounds have been prepared by acylation of ethyl 4-(tetradecylamino)-.
..
1~77957 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-(hexadecylamino)benzoic acid with acetyl chloride, benzoyl chloride, acetic anhydride or succinic anhydride in the pre-sence of a suitable base such as pyridine. In animal tests these compo~nds showed hypolipidemic activity inferior to the compounds of the present invention.
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 experi-ments 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 ~ity~ New York. A control ; group of 6-8 rats was maintained on the diet alone; test groupswere 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 o~ P. Trinder, Analyst 77, 321 (1952) and the colorimetric determination ~ ZlatkisJ
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 ~latkis (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, 1965l p. 341]. ~he 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 15~ or more below that of the controls, and/or depresses triglyceride levels by 25% or more below controls, Table I shows certain of the known compounds and several of the compounds of the present invention and the degree to which they depress serum sterols and triglyceride levels after a l-week and 4-week dosing period and phospholipids after a 4-week dosing period.
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Preferred compounds are 4-(n-hexadecylamine)benzoic ~cid and its pharmaceutically acceptable alkali metal salts. They may be prepared by reacting n-hexadecylbromide with ethyl 4-aminobenzoate at a temperature of from 50 to 150C for rom 8 to 20 hours at a pressure of 1 from 1 to 5 atmospheres and recovering the product as the carboxylic acid or its alksli metal salt after hydrolysis with aqueous alcoholic alkali. They may also be prepared by reacting n-hexadecanol or some other source of hexadecyl aldehyde with 4-aminobenzoate in the presence of a Raney nickel catalyst at a tempera-ture of from 50 to 150C for a period of from 8 to 20 hours at a pressure of from 1 to 5 atmospheres and recovering the product as the carboxylic acid or its alkali metal salt after hydTolysis with aqueous alcoholic alkall.
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., . ~., .:1 :~377957 Two types of substitution reactions also yield the desired 4-(alkylamino)benzoic acids or esters, namely, reaction of ethyl 3,4-didehydro-benzoate with an alkylamine (or its alkali me~al salt) and Friedel-Crafts acylation of an N-alkyl-aniline or N-acyl-N-alkylaniline. The for~er type of : reaction is carried out by treating a 4-halobenzoate ester such as ethyl 4-bromobenzoa~e 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-n-hexadecylaniline and the like or its N-acetyl ;; - 5a -1 ., ~ :' ` ' ' "
~0779~;7 .
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, wa~er or an aqueous lower alkanol at 25C. to 150C. Alternatively, the ~-(alkylamino)benzoic acids may be prepared by hydrolysis of the lower alkyl 4-(mono-alkylamino)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 f a lower alkyl 4-(monoalkylamino)benzoate with an appropriate alkylating agent to give the lower alkyl esters with subsequeht hydrolysis to give the acids. Suitable alkylating agents are 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. m e alkyla-tion reactions may be carried out with or without a solvent at 20C. to 150C. Suitable solvents are chloroform, dichloro-methane, 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 100C. - 150C. 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. m e lower -- : : . .
1~77957 alkylamino benzoic acid derivatives may be converted to their potassium, sodium or lithium salts and alkylated to give dial-kylaminobenzoate esters - alkylation occurring on both the amino group and on the oxygen of the acid salt. Representative di-alkylaminobenzoic acids and esters which have been prepared areethyl 4-(dodecylmethylamino)benzoate, 4-(dodecylmethylamino)-benzolc acid, 4-(dodecylethylamino)benzoic acid, 4-(methyl-; tetradecylamino)benzoic acidJ 4-(ethyltetradecylamino)benzoic acid, ethyl 4-(methylpentadecylamino)benzoateJ 4-(methylpenta-decylamino)benzoic acidJ 4-(ethylpentadecylamino)benzoic acidJ
ethyl 4-(methylhexadecylamino)benzoate, 4-(methylhexadecylamino)-benzoic acid, ethyl 4-(ethylhexadecylamino)benzoate, 4-(ethyl-hexadecylamino)benzoic acid, 4-(methylheptadecylamino)benzoic acid, 4-(ethylheptadecylamino)benzoic acid, 4-(methyloctadecyl-amino)benzoic acid, and 4-(ethyloctadecylamino)benzoic acid.
In animal tests these compounds have shown inferior hypolipide-mic activity.
Lower alkyl acylmonoalkylaminobenzoates can be pre-pared by acylation of the lower alkyl monoalkylaminobenzoates with acyl halides or anhydrides such as acetyl chloride, acetic anhydride, benzoyl chloride, benzoic anhydride, succinic an-hydride, 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 condi-tions gives the acylmonoalkylaminobenzoic acid derivatives.m e 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-~0 -tetradecylamino)benzoate, 4-(N-acetyl-n-tetr,adecylamino)-benzoic acid, 4-(N-benzoyl-n-hexadecylamino)benzoic acid, 4--(N-acetyl-n-hexadecylamino)benzoic acid Such compounds have been prepared by acylation of ethyl 4-(tetradecylamino)-.
..
1~77957 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-(hexadecylamino)benzoic acid with acetyl chloride, benzoyl chloride, acetic anhydride or succinic anhydride in the pre-sence of a suitable base such as pyridine. In animal tests these compo~nds showed hypolipidemic activity inferior to the compounds of the present invention.
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 experi-ments 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 ~ity~ New York. A control ; group of 6-8 rats was maintained on the diet alone; test groupswere 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 o~ P. Trinder, Analyst 77, 321 (1952) and the colorimetric determination ~ ZlatkisJ
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 ~latkis (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, 1965l p. 341]. ~he 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.
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In these tests, a compound is considered to have hypolipidemic activity if it depresses serum sterol levels 15~ or more below that of the controls, and/or depresses triglyceride levels by 25% or more below controls, Table I shows certain of the known compounds and several of the compounds of the present invention and the degree to which they depress serum sterols and triglyceride levels after a l-week and 4-week dosing period and phospholipids after a 4-week dosing period.
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~ ~ l ~ ,n _ ' ~077957 The data in Table I indicate that the 4-(monoalkyl-amino)benzoic acids and derivatives tested are all effective hypolipidemic agents i.eO, 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 ma~or 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 ma~or lipid moiety in blood.
m e effects of one of the compounds [4-(n-hexadecyl-amino)benzoic acid] of this invention on serum lipid levels were determined in mice and gerbils (Table II) after one week of treatment. Mice (CF-l strain) were obtained from Carworth Farms, New City, New York and gerbils were purchased from Chick . Line Co., Vineland, New Jersey. The methods used for lipid ~ analysis were the same as those indicated above for Table I.
; 20 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 _ .''~ ,.
~0 The 4-(monoalkylamino)ben~oic acids and derivatives of this invention have potencies similar to or greater than l-methyl-4-piperidyl bis(p-chlorophenoxy)acetate and clofi-brate, and thus are useful as hypolipidemic compounds in mammals when adminis~ered in amounts ranging from about .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 dire~tly 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 con-tains between about 10 and 500 milligrams of active compound.
The tablets, troches, pills, capsule's and the like may also contain the following: a binder such as gum traga-canth, 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 a~ sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil Or 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 in-~tance, tablets, pills or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active com-pounds, sucrose as a sweetening agent, methyl and propyl para- -bens 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 substan-tially non toxic in the amounts employed.
In addition, the active ingredients may be incorpor- --ated into sustained release preparations. Preparations of this type would contain greater quantities of the active ingredi-ents.
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 20 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 3 hydroxide in 100 ml. of water and refluxing for 24 hours. The acid was precipitated by adding 160 ml. of concentrated hydro-chloric acid followed by 200 ml. of water and chilling. The filtered material was slurried in chloro~orm to give a white _ 14 -solid which was recrystallized from 95,~ aqueous ethanol to give 2.95 g. of 4-(n-dodecylamino)benzoic acid as white crystals, m.p. 111.5-113; 125-125.5C.
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-dodecylamino)benzoic acid as off-white 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-(n-dodecylamino)benzoic acid, m.p. same as above.
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 (130C.) under nitrogen for 24 hours. The reac~tion 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.
4-(n-Tridecylamino)benzoic acid A mixture OI 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 t80 ml.) was added to the hot mixture, which was thbn cooled, diluted with water and filtered. Recrystal-lization from absolute ethanol and from ethanol-benzene (1:1) gave 16.5 g. of 4-(n-tridecylamino)benzoic ac'id as white crystals, m.p. 106-9; 112-~C.
., EX~MPLE 4 Ethyl 4-tn-Tetradecylamino)benzoate A mixture of 16.5 g. of ethyl 4-aminobenzoate and ~0 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-~odium 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 gi~ e 1.7 g. of crystals. The two crops were recrystallized from ethanol to give 8.75 g. of white ethyl 4-(n-tetradecyl-amino)benzoate, m.p. 81-82C.
4-(n~etradecylamino)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 l-bromotetradecane.
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 reactedJ 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. 81-82C.
A mixture of 29 g. ~f 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. 108-111C.
3 EXA~IPLE 6 Ethyl 4-(n-pentadecylamino)benzoate A mixture of 49.5 g. of ethyl 4-aminobenzoate, . .
, i ~ .
10~77957 87.3 g. of l-bromopentadecane and 41.4 g. of potassium car-bonate in 550 ml. of NJN-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. o~ white ethyl 4-(n-pentadecyl-amino)benzoate,m.p. 73-74.5C.
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 recrystal-lized from benzene-ethanol (1:1) to give 42.5 g. of white 4-(n-pentadecylamino)benzoic acid, m.p. 107-8C., 126-126.5C.
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.
Ethyl 4-(n-hexadecylamino)benzoate -; A mixture of 3~.0 g. of ethyl 4-aminobenzoate, 61.0 g.of 1-bromohexadccane, 21.2 g. of sodium carbonate and 300 ml.
of ethanol was refluxed for 24 hours. The mixture was chilled and filtere~. 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.
.
- .
' Ethyl 4-(n-hexadecylamino)benzoate A mixture of 3~.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 mix-ture 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. 80-83C.
4-(n-Hexadecylamino)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. Concentrated 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. 107-110C., 124-127.5C.) of white 4-(n-hexadecylamino)benzoic acid.
; 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 90,~ aqueous ethanol was added 33.6 ml. of l-bromo-hexadecane and the mix-.. : .
~ ture was refluxed for 25 hours. A solution of 28 g. of , ~ .
, potassium hydroxide in 150 ml. of 90~ aqueous ethanol and 100 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 produc,t which was washed with water and dried. Recrystallization from benzene yielded 10.7 g. of 4-(n-hcxadecylamlno)benzoic acid, m.p.
106-108C., complete melt 125-127C.
.
' . ' , ' : .' ' .
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 car-bonate in 700 ml. of absolute ethanol was refluxed for 24 hours.me reaction was then chilled, filtered and the solid washed with cold absolute ethanol, and then with water until it was neutral. me product was pure ethyl 4-(n-heptadecylamino)-benzoate.
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 carbon-ate in 700 ml of absolute ethanol was refluxed for 24 hours.
m e 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 hydro-chloric acid. m e mixture was diluted with 400 ml. of water, chilled and filtered to give 25.2 g. of white crystals. Re-crystallization from 300 ml. of benzene-ethanol (1:1) gave ; 21.7 g. of 4-(n-heptadecylamino)benzoic acid, m.p. 105-108C.;
128-128.5C.
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 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 .` .~
~77957 67 g. of ethyl 4-(n-octadecylamino)benzoate as white crystals m.p. 88-89C.
~XAMPLE 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 acîd 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. 103-106C., complete melt 123-126C.
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 car-bonate 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 ~hen with water. The product was recrystallized from absolute ethanol to give 791. g. of white ethyl 4-(n-nonadecylamino)-benzoate.
4-(n-Nonadecylamino)benzoic acid A mixture of 79.1 g. of ethyl 4-(n-non~decylamino)-benzoate and 103 g. of potassium hydroxide in 1200 ml. of 50~0 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-nona-decylamino)benzoic acid, m.p, 104-6C., 120-4C.
Ethyl 4-[(l-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 distilla-tion under high vacuum. Water and ethanol were added and the mixture was chilled. me 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 y~eld was 15.0 g. of ethyl 4-~(1-Methylundecyl)amino]benzoate.
4-~(1-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 mix-ture 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.
76.5-78.5C.
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 car-bonate in 250 ml. of N,N-dimethylacetamide was heated at 125-135C. for 24 hours. The mixture was then chilled, _ 21 -~' ~
-filtered and the solid washed with water and dried. The yield was 49.7 g. of ethyl 3-(n-hexadecylamino)benzoate.
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. oP white 3(n-hexa-decylamino)benzoic acid, m.p. 107.5-109.5C.
,- EXA.~LE 23 Dime~hylaminoethyl 4-(n-hexadecylamino)benzoate hydrochloride ,.
To 90 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 100 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 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. 162-165C. with previous sintering.
Ethyl 4-(n-oct~lamino)benzoate A mixture of 33 g. (0.20 mole) of ethyl 4-aminoben-3 zoate, 44 ml. of l-bromo~octane 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 1~77957 neu~ralized 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 1 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. m e 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.
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 ethanol-water (9:1) was refluxed for ~ hours. The mixture was acidified with concentrated hydrochloric acid, diluted with water and filtered.
The solid was washed thoroughly with water and recrystallized ; 20 from ethanol to give 2.1 g. of 4-(n-octylamino)benzoic acid as white crystals, m.p. 117-118C.
4-(n-Hexylamino)benzoic acid A mixture of 4.98 g. of ethyl 4-(n-hexylamino)ben-zoate, 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. 121.5-123.5C. and 127-128C.
:.
i :' .' ~ .. . :
.
~0779~;7 Ethyl 4-(n-hexylamino)benzoate A mixture of 54.4 g. of ethyl 4-aminobenzoate, 54.4 g. of 1-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 flltered to give solid which was washed with cold ethanol and with water lQ to give 44 g. of pale yellow crystals. A sample was recrystal-lized from ethanol-benzene (95:5) to give ethyl 4-hexylamino-benzoate, m.p. gl-94oc.
The present compounds can be dispensed in dosage unit form such as hard shell capsules or soft shell capsules. A
representative formulation of su~ch 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 T~e above formulation is to be thoroughly mixed and placed in equal quantities in 100 capsules.
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 ; 3 amount of active material. The following formulation is re-presentative.
.
Per tablet, mg.
4-(n-Hexadecylamino)-benzoic acid/ 500 Corn starch 210 Methylcellulose 400 ~50 Magnesium stearate 1% 182 Total 1242 The active ingredient, corn starch and methyl-cellulose 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 ~0 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.
(70~ N.F.) Sodium benzoate 150 mg.
Sacchari~ 10 mg.
Red dye (F.D. & C.
; No. 2) 10 mg.
Cherry flavor 50 mg.
Distilled water, q.s. ad 100 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 ad~usted i to 100 ml. with distilled water. Each ml. of syrup contains 50 mg. of drug.
. .
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IO IO IO ~IO
~ N C: N ~:: N a~ .C N
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~ ~ l ~ ,n _ ' ~077957 The data in Table I indicate that the 4-(monoalkyl-amino)benzoic acids and derivatives tested are all effective hypolipidemic agents i.eO, 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 ma~or 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 ma~or lipid moiety in blood.
m e effects of one of the compounds [4-(n-hexadecyl-amino)benzoic acid] of this invention on serum lipid levels were determined in mice and gerbils (Table II) after one week of treatment. Mice (CF-l strain) were obtained from Carworth Farms, New City, New York and gerbils were purchased from Chick . Line Co., Vineland, New Jersey. The methods used for lipid ~ analysis were the same as those indicated above for Table I.
; 20 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 _ .''~ ,.
~0 The 4-(monoalkylamino)ben~oic acids and derivatives of this invention have potencies similar to or greater than l-methyl-4-piperidyl bis(p-chlorophenoxy)acetate and clofi-brate, and thus are useful as hypolipidemic compounds in mammals when adminis~ered in amounts ranging from about .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 dire~tly 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 con-tains between about 10 and 500 milligrams of active compound.
The tablets, troches, pills, capsule's and the like may also contain the following: a binder such as gum traga-canth, 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 a~ sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil Or 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 in-~tance, tablets, pills or capsules may be coated with shellac, sugar, or both. A syrup or elixir may contain the active com-pounds, sucrose as a sweetening agent, methyl and propyl para- -bens 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 substan-tially non toxic in the amounts employed.
In addition, the active ingredients may be incorpor- --ated into sustained release preparations. Preparations of this type would contain greater quantities of the active ingredi-ents.
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 20 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 3 hydroxide in 100 ml. of water and refluxing for 24 hours. The acid was precipitated by adding 160 ml. of concentrated hydro-chloric acid followed by 200 ml. of water and chilling. The filtered material was slurried in chloro~orm to give a white _ 14 -solid which was recrystallized from 95,~ aqueous ethanol to give 2.95 g. of 4-(n-dodecylamino)benzoic acid as white crystals, m.p. 111.5-113; 125-125.5C.
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-dodecylamino)benzoic acid as off-white 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-(n-dodecylamino)benzoic acid, m.p. same as above.
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 (130C.) under nitrogen for 24 hours. The reac~tion 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.
4-(n-Tridecylamino)benzoic acid A mixture OI 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 t80 ml.) was added to the hot mixture, which was thbn cooled, diluted with water and filtered. Recrystal-lization from absolute ethanol and from ethanol-benzene (1:1) gave 16.5 g. of 4-(n-tridecylamino)benzoic ac'id as white crystals, m.p. 106-9; 112-~C.
., EX~MPLE 4 Ethyl 4-tn-Tetradecylamino)benzoate A mixture of 16.5 g. of ethyl 4-aminobenzoate and ~0 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-~odium 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 gi~ e 1.7 g. of crystals. The two crops were recrystallized from ethanol to give 8.75 g. of white ethyl 4-(n-tetradecyl-amino)benzoate, m.p. 81-82C.
4-(n~etradecylamino)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 l-bromotetradecane.
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 reactedJ 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. 81-82C.
A mixture of 29 g. ~f 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. 108-111C.
3 EXA~IPLE 6 Ethyl 4-(n-pentadecylamino)benzoate A mixture of 49.5 g. of ethyl 4-aminobenzoate, . .
, i ~ .
10~77957 87.3 g. of l-bromopentadecane and 41.4 g. of potassium car-bonate in 550 ml. of NJN-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. o~ white ethyl 4-(n-pentadecyl-amino)benzoate,m.p. 73-74.5C.
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 recrystal-lized from benzene-ethanol (1:1) to give 42.5 g. of white 4-(n-pentadecylamino)benzoic acid, m.p. 107-8C., 126-126.5C.
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.
Ethyl 4-(n-hexadecylamino)benzoate -; A mixture of 3~.0 g. of ethyl 4-aminobenzoate, 61.0 g.of 1-bromohexadccane, 21.2 g. of sodium carbonate and 300 ml.
of ethanol was refluxed for 24 hours. The mixture was chilled and filtere~. 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.
.
- .
' Ethyl 4-(n-hexadecylamino)benzoate A mixture of 3~.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 mix-ture 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. 80-83C.
4-(n-Hexadecylamino)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. Concentrated 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. 107-110C., 124-127.5C.) of white 4-(n-hexadecylamino)benzoic acid.
; 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 90,~ aqueous ethanol was added 33.6 ml. of l-bromo-hexadecane and the mix-.. : .
~ ture was refluxed for 25 hours. A solution of 28 g. of , ~ .
, potassium hydroxide in 150 ml. of 90~ aqueous ethanol and 100 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 produc,t which was washed with water and dried. Recrystallization from benzene yielded 10.7 g. of 4-(n-hcxadecylamlno)benzoic acid, m.p.
106-108C., complete melt 125-127C.
.
' . ' , ' : .' ' .
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 car-bonate in 700 ml. of absolute ethanol was refluxed for 24 hours.me reaction was then chilled, filtered and the solid washed with cold absolute ethanol, and then with water until it was neutral. me product was pure ethyl 4-(n-heptadecylamino)-benzoate.
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 carbon-ate in 700 ml of absolute ethanol was refluxed for 24 hours.
m e 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 hydro-chloric acid. m e mixture was diluted with 400 ml. of water, chilled and filtered to give 25.2 g. of white crystals. Re-crystallization from 300 ml. of benzene-ethanol (1:1) gave ; 21.7 g. of 4-(n-heptadecylamino)benzoic acid, m.p. 105-108C.;
128-128.5C.
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 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 .` .~
~77957 67 g. of ethyl 4-(n-octadecylamino)benzoate as white crystals m.p. 88-89C.
~XAMPLE 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 acîd 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. 103-106C., complete melt 123-126C.
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 car-bonate 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 ~hen with water. The product was recrystallized from absolute ethanol to give 791. g. of white ethyl 4-(n-nonadecylamino)-benzoate.
4-(n-Nonadecylamino)benzoic acid A mixture of 79.1 g. of ethyl 4-(n-non~decylamino)-benzoate and 103 g. of potassium hydroxide in 1200 ml. of 50~0 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-nona-decylamino)benzoic acid, m.p, 104-6C., 120-4C.
Ethyl 4-[(l-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 distilla-tion under high vacuum. Water and ethanol were added and the mixture was chilled. me 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 y~eld was 15.0 g. of ethyl 4-~(1-Methylundecyl)amino]benzoate.
4-~(1-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 mix-ture 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.
76.5-78.5C.
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 car-bonate in 250 ml. of N,N-dimethylacetamide was heated at 125-135C. for 24 hours. The mixture was then chilled, _ 21 -~' ~
-filtered and the solid washed with water and dried. The yield was 49.7 g. of ethyl 3-(n-hexadecylamino)benzoate.
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. oP white 3(n-hexa-decylamino)benzoic acid, m.p. 107.5-109.5C.
,- EXA.~LE 23 Dime~hylaminoethyl 4-(n-hexadecylamino)benzoate hydrochloride ,.
To 90 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 100 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 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. 162-165C. with previous sintering.
Ethyl 4-(n-oct~lamino)benzoate A mixture of 33 g. (0.20 mole) of ethyl 4-aminoben-3 zoate, 44 ml. of l-bromo~octane 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 1~77957 neu~ralized 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 1 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. m e 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.
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 ethanol-water (9:1) was refluxed for ~ hours. The mixture was acidified with concentrated hydrochloric acid, diluted with water and filtered.
The solid was washed thoroughly with water and recrystallized ; 20 from ethanol to give 2.1 g. of 4-(n-octylamino)benzoic acid as white crystals, m.p. 117-118C.
4-(n-Hexylamino)benzoic acid A mixture of 4.98 g. of ethyl 4-(n-hexylamino)ben-zoate, 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. 121.5-123.5C. and 127-128C.
:.
i :' .' ~ .. . :
.
~0779~;7 Ethyl 4-(n-hexylamino)benzoate A mixture of 54.4 g. of ethyl 4-aminobenzoate, 54.4 g. of 1-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 flltered to give solid which was washed with cold ethanol and with water lQ to give 44 g. of pale yellow crystals. A sample was recrystal-lized from ethanol-benzene (95:5) to give ethyl 4-hexylamino-benzoate, m.p. gl-94oc.
The present compounds can be dispensed in dosage unit form such as hard shell capsules or soft shell capsules. A
representative formulation of su~ch 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 T~e above formulation is to be thoroughly mixed and placed in equal quantities in 100 capsules.
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 ; 3 amount of active material. The following formulation is re-presentative.
.
Per tablet, mg.
4-(n-Hexadecylamino)-benzoic acid/ 500 Corn starch 210 Methylcellulose 400 ~50 Magnesium stearate 1% 182 Total 1242 The active ingredient, corn starch and methyl-cellulose 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 ~0 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.
(70~ N.F.) Sodium benzoate 150 mg.
Sacchari~ 10 mg.
Red dye (F.D. & C.
; No. 2) 10 mg.
Cherry flavor 50 mg.
Distilled water, q.s. ad 100 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 ad~usted i to 100 ml. with distilled water. Each ml. of syrup contains 50 mg. of drug.
. .
., .
.. . , : ,. , . : -- . ~ , - , .
Claims (24)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process of preparing a 4-(monoalkylamino)benzoic acid derivative of the formula:
I
wherein R1 is a branched or unbranched alkyl group of from 8 to 19 carbon atoms, R2 is hydrogen, lower alkyl of from 1 to 4 carbon atoms, or dilower alkylaminoethyl, and the pharmaceutically acceptable salts thereof, character-ized by reacting a compound of the formula:
II
wherein n is 7 to 18 and m is 2n+1; wherein A is CH2X or wherein X is halogen, hydroxy, alkyl sulfonate or aryl sulfonate ester, or hydrogen (ex-cept when A is CH2X), with a compound of the formula:
III
wherein B is amino, acylamino or a group convertible thereinto and Y is car-boxy or a group convertible thereinto or hydrogen (in which case the carboxyl group or group convertible thereinto is introduced as a final step) and when X is halogen it may be interchanged with B, and where necessary converting the product obtained from the reaction of II with III to the desired I or a phar-maceutically acceptable salt thereof by oxidation, reduction, or hydrolysis of the appropriate functional groups and/or reaction with salt-forming acids or bases.
I
wherein R1 is a branched or unbranched alkyl group of from 8 to 19 carbon atoms, R2 is hydrogen, lower alkyl of from 1 to 4 carbon atoms, or dilower alkylaminoethyl, and the pharmaceutically acceptable salts thereof, character-ized by reacting a compound of the formula:
II
wherein n is 7 to 18 and m is 2n+1; wherein A is CH2X or wherein X is halogen, hydroxy, alkyl sulfonate or aryl sulfonate ester, or hydrogen (ex-cept when A is CH2X), with a compound of the formula:
III
wherein B is amino, acylamino or a group convertible thereinto and Y is car-boxy or a group convertible thereinto or hydrogen (in which case the carboxyl group or group convertible thereinto is introduced as a final step) and when X is halogen it may be interchanged with B, and where necessary converting the product obtained from the reaction of II with III to the desired I or a phar-maceutically acceptable salt thereof by oxidation, reduction, or hydrolysis of the appropriate functional groups and/or reaction with salt-forming acids or bases.
2. A 4-(monoalkylamino)benzoic acid derivative of the formula:
wherein R1 is an unbranched or branched alkyl group of from 8 to 19 carbon atoms; and R2 is hydrogen, lower alkyl, dilower alkylaminoethyl; and the pharmaceutically acceptable salts thereof whenever prepared by the process of Claim 1 or by an obvious chemical equivalent thereof.
wherein R1 is an unbranched or branched alkyl group of from 8 to 19 carbon atoms; and R2 is hydrogen, lower alkyl, dilower alkylaminoethyl; and the pharmaceutically acceptable salts thereof whenever prepared by the process of Claim 1 or by an obvious chemical equivalent thereof.
3. A process according to claim 1 wherein in the compound of formula II the integer n has the value 15 and the alkyl group R1 is a straight chain alkyl group, and the product is converted into a pharmaceutically acceptable salt.
4. A process according to claim 3 wherein the pharmaceutically accep-table salt is the sodium salt.
5. A process according to claim 1 of preparing a 4-(mono alkylamino) benzoic acid derivative of the formula:
I
wherein R1 is a branched or unbranched alkyl group of 8 to 19 carbon atoms, R2 is hydrogen, lower alkyl of from 1 to 4 carbon atoms, or, dilower alkyl-aminoethyl and the pharmaceutically acceptable salts thereof, characterized by reacting a compound of the formula:
II
wherein n is 7 to 18 and wherein X is halogen, hydroxy or alkyl sulfonate or aryl sulfonate ester with a compound of the formula:
III
wherein R3 is H or acyl and Y is carboxy or the groups carboalkoxy or cyano convertible by hydrolysis to carboxyl as a final step which also removes the N-acyl group and, when X is fluorine, chlorine or bromine, X may be inter-changed with and if required, converting the product into a pharm-aceutically acceptable salt.
I
wherein R1 is a branched or unbranched alkyl group of 8 to 19 carbon atoms, R2 is hydrogen, lower alkyl of from 1 to 4 carbon atoms, or, dilower alkyl-aminoethyl and the pharmaceutically acceptable salts thereof, characterized by reacting a compound of the formula:
II
wherein n is 7 to 18 and wherein X is halogen, hydroxy or alkyl sulfonate or aryl sulfonate ester with a compound of the formula:
III
wherein R3 is H or acyl and Y is carboxy or the groups carboalkoxy or cyano convertible by hydrolysis to carboxyl as a final step which also removes the N-acyl group and, when X is fluorine, chlorine or bromine, X may be inter-changed with and if required, converting the product into a pharm-aceutically acceptable salt.
6. A process according to claim 1 for preparing a 4-(monoalkylamino) benzoic acid derivative of the formula:
I
wherein R is a branched or unbranched alkyl group of 8 to 19 carbon atoms, R2 is hydrogen, lower alkyl of from 1 to 4 carbon atoms, or, dilower alkyl-aminoethyl and the pharmaceutically acceptable salts thereof, characterized by reacting a compound of the formula:
II
wherein n is 7 to 18 and wherein X is halogen, hydroxy or alkyl sulfonate or aryl sulfonate ester with a compound of the formula:
III
III
wherein R3 is H or acyl and Y is carboxy or the groups carboalkoxy or cyano convertible by hydrolysis to carboxyl as a final step which also removes the N-acyl group and if required, converting the product into a pharmaceutically acceptable salt.
I
wherein R is a branched or unbranched alkyl group of 8 to 19 carbon atoms, R2 is hydrogen, lower alkyl of from 1 to 4 carbon atoms, or, dilower alkyl-aminoethyl and the pharmaceutically acceptable salts thereof, characterized by reacting a compound of the formula:
II
wherein n is 7 to 18 and wherein X is halogen, hydroxy or alkyl sulfonate or aryl sulfonate ester with a compound of the formula:
III
III
wherein R3 is H or acyl and Y is carboxy or the groups carboalkoxy or cyano convertible by hydrolysis to carboxyl as a final step which also removes the N-acyl group and if required, converting the product into a pharmaceutically acceptable salt.
7. A process of preparing a compound according to claim 1 character-ized by reacting n-hexadecylbromide with ethyl 4-aminobenzoate at a tempera-ture of from 50°C. to 150°C. for from 8 to 20 hours at a pressure of from 1 to 5 atmosphere and recovering said product therefrom as the carboxylic acid or its alkali metal salt after hydrolysis with aqueous alcoholic alkali, to obtain 4-(n-hexadecylamino)benzoic acid or its alkali metal salt.
8. A process of preparing a compound according to claim 1 charac-terized by reacting n-hexadecanol or some other source of hexadecyl aldehyde with ethyl 4-aminobenzoate in the presence of a Raney Nickel catalyst at a temperature of from 50°C. to 150°C. for a period of from 8 to 20 hours at a pressure of from 1 to 5 atmospheres and recovering said product therefrom as the carboxylic acid or its alkali metal salt after hydrolysis with aqueous alcoholic alkali, to obtain 4-(n-hexadecylamino)benzoic acid or its alkali metal salt.
9. A process of preparing a compound according to claim 1 charac-terized by reacting n-hexadecylbromide with 4-aminobenzonitrile followed by hydrolysis to convert the cyano group to a carboxyl group and obtain 4(n-hexadecylamino)benzoic acid.
10. A process of preparing a compound according to claim 1 charac-terized by reacting n-hexadecylbromide with ethyl 4-acetylaminobenzoate anion followed by hydrolysis to obtain 4-(n-hexadecylamino)benzoic acid or its alkali metal salt.
11. A process according to claim 1 of preparing a 4-(monoalkylamino) benzoic acid derivative of the formula:
I
wherein R1 is a branched or unbranched alkyl group of 8 to 19 carbon atoms, R2 is hydrogen, lower alkyl of from 1 to 4 carbon atoms or dilower alkylamino ethyl and the pharmaceutically acceptable salts thereof, characterized by reductively reacting a compound of the formula:
II
wherein n is 7 to 18 and wherein Z is halogen, alkyl sulfonate or aryl sul-fonate or hydrogen with a compound of the formula:
III
wherein Y is carboxy, carboalkoxy or hydrogen (in which case the carboxyl group is introduced as a final step), and reducing the product obtained from the reaction of II with III to the desired I or a pharmaceutically acceptable salt thereof by reaction with a base.
I
wherein R1 is a branched or unbranched alkyl group of 8 to 19 carbon atoms, R2 is hydrogen, lower alkyl of from 1 to 4 carbon atoms or dilower alkylamino ethyl and the pharmaceutically acceptable salts thereof, characterized by reductively reacting a compound of the formula:
II
wherein n is 7 to 18 and wherein Z is halogen, alkyl sulfonate or aryl sul-fonate or hydrogen with a compound of the formula:
III
wherein Y is carboxy, carboalkoxy or hydrogen (in which case the carboxyl group is introduced as a final step), and reducing the product obtained from the reaction of II with III to the desired I or a pharmaceutically acceptable salt thereof by reaction with a base.
12. A process of preparing a compound according to claim 1 character-ized by reacting n-hexadecanoyl chloride with ethyl 4-aminobenzoate at a temperature of from 80°C. to 200°C. for a period of from 8 to 20 hours at a pressure of from 1 to 5 atmospheres followed by catalytic hydrogenation or reaction with a reducing agent to obtain 4-(n-hexadecylamino)benzoic acid.
13. A process according to claim 12 wherein the reducing agent is diborane.
14. 4-(n-Hexadecylamino)benzoic acid and its alkali metal salts when made by a process according to claim 7, 8 or 10 or by an obvious chemical equivalent thereof.
15. 4-(n-Hexadecylamino)benzoic acid when made by a process according to claim 9, 12 or 13 or an obvious chemical equivalent thereof.
16. A process according to claim 1 wherein in the compound of formula II n is 13 and the alkyl group is a straight chain alkyl group and in the compound of formula III, if Y is other than a carboxyl group, the product of reaction of the compound of formula II with the compound of formula III is hydrolysed to yield a compound of formula I in which R2 is hydrogen.
17. A process according to claim 1 which comprises reacting ethyl 4-aminobenzoate with 1-bromo-n-tetradecane to obtain ethyl 4-(n-tetradecylamino) benzoate and hydrolysing the product to 4-(n-tetradecylamino)benzoic acid.
18. 4-n-(tetradecylamino)benzoic acid when made by a process accord ing to claim 17 or an obvious chemical equivalent thereof.
19. A process according to claim 1 wherein in the compound of formula II n is 14 and the alkyl group is a straight chain alkyl group and in the compound of formula III, if Y is other than a carboxyl group, the pro-duct of reaction of the compound of formula II with the compound of formula III is hydrolysed to yield a compound in which R2 is hydrogen.
20. A process according to claim 1 which comprises reacting ethyl 4-aminobenzoate with 1-bromo-n-pentadecane to obtain ethyl 4-(n-pentadecylamino) benzoate and hydrolysing the product to 4-(n-pentadecylamino)benzoic acid.
21. 4-(n-Pentadecylamino)benzoic acid when made by a process accord-ing to claim 20 or an obvious chemical equivalent thereof.
22. A process according to claim 1 wherein in the compound of formula II n is 16 and the alkyl group is a straight chain alkyl group and in the compound of formula III, if Y is other than a carboxyl group, the product of reaction of the compound of formula II with the compound of formula III is hydrolysed to yield a compound in which R2 is hydrogen.
23. A process according to claim 1 which comprises reacting ethyl-4-aminobenzoate with 1-bromo-n-heptadecane to obtain ethyl 4-(n-heptadecylamino) benzoate and hydrolysing the product to 4-(n-heptadecylamino)benzoic acid.
24. 4-(n-Heptadecylamino)benzoic acid when made by a process accord-ing to claim 23 or an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US402212A US3868416A (en) | 1973-10-01 | 1973-10-01 | Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1077957A true CA1077957A (en) | 1980-05-20 |
Family
ID=23590998
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA210,303A Expired CA1077957A (en) | 1973-10-01 | 1974-09-30 | Hypolipidemic 4-(monoalkylamino) benzoic acid derivatives |
Country Status (22)
| Country | Link |
|---|---|
| US (2) | US3868416A (en) |
| JP (1) | JPS5747901B2 (en) |
| AR (1) | AR211687A1 (en) |
| AT (1) | AT338250B (en) |
| BE (1) | BE820542A (en) |
| CA (1) | CA1077957A (en) |
| CH (1) | CH609676A5 (en) |
| DD (1) | DD116031A5 (en) |
| DE (1) | DE2446010C2 (en) |
| DK (1) | DK141844B (en) |
| ES (1) | ES430574A1 (en) |
| FR (1) | FR2246267B1 (en) |
| GB (1) | GB1488674A (en) |
| GT (1) | GT197851174A (en) |
| HU (1) | HU175875B (en) |
| IE (1) | IE40527B1 (en) |
| IL (1) | IL45643A (en) |
| NL (1) | NL179725C (en) |
| SE (1) | SE410595B (en) |
| SU (1) | SU590311A1 (en) |
| YU (1) | YU262274A (en) |
| ZA (1) | ZA745732B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1471431A (en) * | 1974-04-30 | 1977-04-27 | Science Union & Cie | Alkanolamine derivatives processes for their preparation and pharmaceutical compositions containing them |
| US4350822A (en) * | 1975-03-12 | 1982-09-21 | American Cyanamid Company | Antilipidemicpara-[aryl(alkyl or alkenyl)amino]benzoic acid derivatives |
| US4185115A (en) * | 1975-03-12 | 1980-01-22 | American Cyanamid Company | Antilipidemic para-[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 |
| US4182776A (en) * | 1975-12-09 | 1980-01-08 | American Cyanamid Company | Method of treating lipidemia with aryloxyalkylaminobenzoic acids and esters |
| AU500881B2 (en) * | 1976-01-19 | 1979-06-07 | Dow Chemical Company, The | Hypolipidemic p-aminobenzoic acids |
| GB1576007A (en) * | 1976-02-11 | 1980-10-01 | Beecham Group Ltd | Hypolipidaemic compositions |
| US4105791A (en) * | 1976-03-22 | 1978-08-08 | The Dow Chemical Company | Hypolipidemic cycloalkylaminobenzoic acids |
| 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 |
| US4117158A (en) * | 1977-09-27 | 1978-09-26 | American Cyanamid Company | 4-(monoalkylamino)benzonitriles useful as anti-atherosclerotic agents |
| 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 |
| US4154756A (en) * | 1977-12-15 | 1979-05-15 | American Cyanamid Company | 2-Substituted-4'-(monoalkylamino)-acetophenones |
| US4136256A (en) * | 1977-09-27 | 1979-01-23 | American Cyanamid Company | 4-(monoalkylamino)benzoic acid imidates |
| US4245120A (en) * | 1977-09-27 | 1981-01-13 | American Cyanamid Company | 4-(Monoalkylamino)benzene polycarboxylic acids |
| 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 |
| US4272546A (en) * | 1977-12-19 | 1981-06-09 | American Cyanamid Company | Esters of 4-(monoalkylamino)benzoic hydroxyalkanoic acids |
| US4254138A (en) * | 1977-12-19 | 1981-03-03 | American Cyanamid Company | Esters of 4-(monoalkylamino)benzoic hydroxyalkanoic acids |
| US4230878A (en) * | 1978-03-08 | 1980-10-28 | American Cyanamid Company | Hypolipidemic and antiatherosclerotic 4-[(cyclopropyl alkyl)amino]benzoic acids and derivatives |
| US4245097A (en) * | 1978-02-27 | 1981-01-13 | American Cyanamid Company | 4-[(Monosubstituted-alkyl) amino] benzoic acids and analogs as hypolipidemic and antiatherosclerotic agents |
| IL56517A0 (en) * | 1978-02-02 | 1979-03-12 | American Cyanamid Co | Novel 4-(cycloalkyl or cyclalkenyl substituted) amino, alkylamino or alkenylamino benzoic acids, salts and derivatives |
| US4205085A (en) * | 1978-03-09 | 1980-05-27 | American Cyanamid Company | Hypolipidemic and antiatherosclerotic 4-(polyfluoroalkylamino)phenyl compounds |
| US4230628A (en) * | 1978-04-12 | 1980-10-28 | American Cyanamid Company | 4-[(Carboxyl- and sulfamyl-substituted alkyl)-amino] benzoic acids and analogs |
| 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 |
| US4311846A (en) * | 1978-02-27 | 1982-01-19 | American Cyanamid Company | 4-[(Monosubstituted-alkyl) amino]benzoic acids and analogs as hypolipidemic and antiatherosclerotic agents |
| US4178385A (en) * | 1978-03-03 | 1979-12-11 | The Dow Chemical Company | Method for treating hyperlipidemia in primates using 4-((4-fluorophenylmethyl)amino)benzoic acid |
| US4310545A (en) * | 1978-03-09 | 1982-01-12 | American Cyanamid Company | Hypolipidemic and antiatherosclerotic 4-(polyfluoroalkylamino) phenyl compounds |
| US4305959A (en) * | 1978-03-09 | 1981-12-15 | American Cyanamid Company | Hypolipidemic and antiatherosclerotic 4-(polyfluoro-alkylamino)phenyl compounds |
| US4318914A (en) * | 1978-03-09 | 1982-03-09 | American Cyanamid Company | Hypolipidemic and antiatherosclerotic 4-(polyfluoro-alkylamino)phenyl compounds |
| 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 |
| YU57979A (en) * | 1979-03-09 | 1982-10-31 | Lek Tovarna Farmacevtskih | Process for preparing 4-9n-hexadecylamino0-benzoic acid |
| US4263320A (en) * | 1979-06-04 | 1981-04-21 | The Dow Chemical Company | Hypoglycemic phenylpropynylamino benzoic acids |
| US4311694A (en) * | 1979-12-31 | 1982-01-19 | American Cyanamid Company | Amorphous coprecipitates of 4-(monoalkylamino) benzoic acid and derivatives and certain water-soluble materials |
| US4375478A (en) * | 1982-03-02 | 1983-03-01 | Abbott Laboratories | Aminobenzoic acid derivatives |
| JP2659488B2 (en) * | 1992-01-22 | 1997-09-30 | 川崎重工業株式会社 | Sliding door device |
| 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 |
| US6080428A (en) * | 1993-09-20 | 2000-06-27 | Bova; David J. | Nicotinic acid compositions for treating hyperlipidemia and related methods therefor |
| US6676967B1 (en) | 1993-09-20 | 2004-01-13 | Kos Pharmaceuticals, Inc. | Methods for reducing flushing in individuals being treated with nicotinic acid for hyperlipidemia |
| US6129930A (en) * | 1993-09-20 | 2000-10-10 | Bova; David J. | Methods and sustained release nicotinic acid compositions for treating hyperlipidemia at night |
| US20080045573A1 (en) * | 1993-09-20 | 2008-02-21 | Bova David J | Methods and Sustained Release Nicotinic Acid Compositions for Treating Hyperlipidemia |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3758561A (en) * | 1968-10-18 | 1973-09-11 | Merck & Co Inc | 2-loweralkylamino-4-amino benzoic acids, their salts and esters, and acid addition salts thereof |
| US3716644A (en) * | 1971-07-15 | 1973-02-13 | American Cyanamid Co | Hypolipidemic agents |
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- 1973-10-01 US US402212A patent/US3868416A/en not_active Expired - Lifetime
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- 1974-09-09 ZA ZA00745732A patent/ZA745732B/en unknown
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- 1974-09-27 YU YU02622/74A patent/YU262274A/en unknown
- 1974-09-30 FR FR7432894A patent/FR2246267B1/fr not_active Expired
- 1974-09-30 SE SE7412307A patent/SE410595B/en not_active IP Right Cessation
- 1974-09-30 DK DK515474AA patent/DK141844B/en not_active IP Right Cessation
- 1974-09-30 CA CA210,303A patent/CA1077957A/en not_active Expired
- 1974-09-30 BE BE149073A patent/BE820542A/en not_active IP Right Cessation
- 1974-10-01 NL NLAANVRAGE7412956,A patent/NL179725C/en not_active IP Right Cessation
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- 1974-10-01 HU HU74AE427A patent/HU175875B/en unknown
- 1974-10-01 DD DD181444A patent/DD116031A5/xx unknown
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- 1974-10-01 AT AT788574A patent/AT338250B/en not_active IP Right Cessation
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1978
- 1978-03-01 GT GT197851174A patent/GT197851174A/en unknown
Also Published As
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|---|---|
| AT338250B (en) | 1977-08-10 |
| IL45643A0 (en) | 1974-11-29 |
| US3924001A (en) | 1975-12-02 |
| YU262274A (en) | 1982-02-25 |
| DK141844C (en) | 1980-11-10 |
| JPS5747901B2 (en) | 1982-10-13 |
| NL7412956A (en) | 1975-04-03 |
| NL179725C (en) | 1986-11-03 |
| AR211687A1 (en) | 1978-02-28 |
| HU175875B (en) | 1980-11-28 |
| ATA788574A (en) | 1976-12-15 |
| ES430574A1 (en) | 1977-02-16 |
| GT197851174A (en) | 1979-08-23 |
| ZA745732B (en) | 1975-09-24 |
| IL45643A (en) | 1979-09-30 |
| DE2446010A1 (en) | 1975-04-03 |
| DK141844B (en) | 1980-06-30 |
| US3868416A (en) | 1975-02-25 |
| IE40527B1 (en) | 1979-06-20 |
| JPS5059347A (en) | 1975-05-22 |
| SE7412307L (en) | 1975-04-02 |
| NL179725B (en) | 1986-06-02 |
| GB1488674A (en) | 1977-10-12 |
| FR2246267A1 (en) | 1975-05-02 |
| DD116031A5 (en) | 1975-11-05 |
| FR2246267B1 (en) | 1977-10-28 |
| DK515474A (en) | 1975-06-09 |
| SE410595B (en) | 1979-10-22 |
| IE40527L (en) | 1975-04-01 |
| SU590311A1 (en) | 1978-01-30 |
| DE2446010C2 (en) | 1985-05-15 |
| CH609676A5 (en) | 1979-03-15 |
| BE820542A (en) | 1975-04-01 |
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