CA1108159A - Substituted 4-(((2-thienyl)methyl)amino) benzoic acids and a method for treating hypolipidemia - Google Patents
Substituted 4-(((2-thienyl)methyl)amino) benzoic acids and a method for treating hypolipidemiaInfo
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- CA1108159A CA1108159A CA300,577A CA300577A CA1108159A CA 1108159 A CA1108159 A CA 1108159A CA 300577 A CA300577 A CA 300577A CA 1108159 A CA1108159 A CA 1108159A
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/28—Halogen atoms
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- 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
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Abstract
ABSTRACT
The invention relates to novel substituted 4-(2--thienylmethylamino)-benzoic acid compounds, a hypolipidemic composition containing same, and a process for preparing the compounds. The compounds correspond to the formula wherein R is hydrogen or C1-3 alkyl, and X, Y, and Z
independently represent hydrogen, chloro, or bromo, with the proviso that at least one of X, Y, and Z is chloro or bromo, and pharmaceutically acceptable salts thereof. The compounds are useful for lowering serum lipid levels in mammals.
18,307-F
The invention relates to novel substituted 4-(2--thienylmethylamino)-benzoic acid compounds, a hypolipidemic composition containing same, and a process for preparing the compounds. The compounds correspond to the formula wherein R is hydrogen or C1-3 alkyl, and X, Y, and Z
independently represent hydrogen, chloro, or bromo, with the proviso that at least one of X, Y, and Z is chloro or bromo, and pharmaceutically acceptable salts thereof. The compounds are useful for lowering serum lipid levels in mammals.
18,307-F
Description
110~ 9 This invention concerns halo-substituted 4-(2-thienyl-methylamino)benzoic acids, the corresponding esters and salts thereof, a hypolipidemic composition containing same, and a pro-cess ror preparing the compounds.
4-(2-Thienylmethylamino)benzoic acid and the corres-ponding ethyl ester have been described in Izo. Akad. Nauk SSSR, Ser. Khim. 1967(9), 2049-55 (C.A. 68; 104869K). No utility for the compounds is disclosed. Belgian Patent No. 839,382 granted September 10, 1976 discloses 4[aryl(alkyl or alkenyl)-amino]benzoic acid compounds having hypolidemic activity.
The present invention provides 4-(2-thienylmethylamino)-benzoic acid compounds corresponding to the general formula ~ ~ CH2NH ~ COOR
wherein R represents hydrogen or Cl 3 alkyl, and Xl Y, and Z
independently represent hydrogen, chloro, or bromo, with the proviso that at least one of X, Y, and Z is chloro or bromo.
Pharmaceutically-acceptable salts of the p-amino-benzoic acids, i.e. when R is hydrogen, are also considered as being within the scope of this invention. Pharmaceutically-acceptable salts refer to the acid addition salts of thosebases which will form a salt with a carboxylic acid and which will not cause an adverse physiological effect when administered to an animal at dosages consistent with good pharmacological activity. Suitable bases thus include, for example, the alkali metal and alkaline earth metal hydroxides, carbonates, and bicarbonates such as sodium hydroxides, potassium hydroxide, calcium hydroxide, ~: `
15g potassium carbonate, sodium bicarbonate, or magnesium carbonate; ammonia, primary, secondary, and tertiary amines.
Also, aluminum salts may be obtained by treating the corres-ponding sodium salt with an appropriate aluminum complex S such as aluminum chloride hexahydrate.
Compounds of the present invention have shown h~polipidemic activity in animals and in particular in mammals. Hypolipidemic activity as used herein refers to the effect of lowering the blood lipid content and in particular the cholesterol and triglyceride content of the serum. The compounds are therefore suitable for use in treating serum hyperlipidemia in mammals and in particular are useful for the treatment of hypercholesterolemia and hypertriglyceridemia, that is, abnormally hish levels of lipids, cholesterol, or triglycerides, respectively, in the serum. The compounds can be administered orally or parent~
erally by subcutaneous, intravenous, or intraperitoneal injection or by implantation, oral administration being preferred.
The effective hypolipidemic amount of the p-amino-benzoic acid compounds to be administered to an animal, that ; is, the amount which is effective to significantly lower the serum lipid level, can vary depending upon such factors as the animal treated, the particular compound employed, the desired lipid level to be obtained, whether or not the animal is hyperlipidemic, the period of administratlon, and the method of administration. In general, an effective daily dosage range is from about 1 mg/kg of body weight to 20Q mg/kg of body weight, with a daily dosage range of from - 30 about 10 mg/kg to 100 mg/kg of body weight being preferred.
.
.
18,307-F -2-: ~ .
For oral administration, pharmaceutical prepar-ations of the p-aminobenzoic acids may be made by following conventional techniques. These techinques involve granu-lating and compressing, when ~ecessary, or variously mixing i and dissolving or suspending the ingredients as appropriate to the desired end product. Numerous pharmaceutical forms to carry the compounds can be used. For example, the pure compound can be used or it can be mixed with a solid carrier.
Generally, inorganic pharmaceutical carriers are preferable and particularly solid inorganic carriers. One reason for - this is the large number of inorganic materials which are known to be pharmaceutically safe and acceptable, as well as very convenient in preparing formulations. The compositions may take the form of tablets, linguets, powders, capsules, slurries, troches, or lozenges, and such compositions may be ~; prepared by stand~rd pharmaceutical techniques. Tablet compositions may be coated or uncoated, and they may be effervescent or non-effervescent. Conventional excipients for tablet formations may be used. For example, inert diluents, such as magnesium carbonate or lactose, disinte-grating agents such as maize starch or alginic acid, and lubricating agents such as magnesium stearate may be used.
~ I~ a liquid carrier is used, the preparation may ; be in the form of a soft gelatin capsule, a syrup, a liquid solution, or suspension.
The hydrocarbon solubility of most of the compounds of this invention is high enough to allow the use of pharmaceutically-acceptable oils and carriers. For example, vegetable or animal oils such as sunflower oil, safflower oil, maize oil or cod liver oil can be used. Glycerine can lg,307-F 3 also be used. With this latter solvent, from 2 to 30 percent water, may be added. When water alone is the carrier, or when the solubllity of the compound in the oil is low, the preparations can be administered in the lorm of a slurry.
Emulsion compositions may be formulated using emulsifying agents such as sorbitan trioleate, polyoxy~
ethylene sorbitan monooleate, leclthin, gum acacia, or gum tragacanth. Aqueous based suspensions may be prepared with the aid of wetting agents such as polyethylene oxide con-densation products of alkylphenols, fatty alcohols, or fatty acids with the suspending agents, for example, a hydrophilic colloid such as polyvinylpyrrolidone. The emulsions and suspensions may contain conventional excipients such as sweetening agents, coloring materials, or preservatives.
The compounds can also be incorporated in a nutritive foodstuff such as, for example, butter, margarine, edible oils, casein, or carbohydrates. Such nutritive compositions are adapted to be administered as a partial or total diet or as a supplement to the diet. Such compo-sitions preferably contain from about 0.02 to about 2.0 percent of the active ingredient when administered as the total diet. The compositions can contain higher concentra-tions of the active ingredient when administered as a supplement.
For parenteral use, the compounds can be formulated with sterile ingredients, compounded, and packaged ascepti-cally. They may be administered intravenously or intra-muscularLy. Useful solvents for formulation ~or such use are the polyhydric aliphatic alcohols and mixtures thereof.
Especially satisfactory are the pharmaceutically acceptable 18,307-F -4-;-glycols, such as propylene glycol, and mixtures thereof.
Glycerine is particularly useful. Up to 25-30 percent by volume of water may be incorporated in the vehicle, if desired. An 80 percent aqueous propylene glycol solution ls a particularly convenient solvent system. A pH of about 7.4 and isotonicity compatible with body isotonicity are desirable. Basicity may be controlled by addition of a base as required, and a particularly convenient base is monoethanolamine. It may often be desirable to incorporate a local anesthetic and such are well known to those skilled in the art.
The percentage of the compound to be used in the pharmaceutical carrier may be varied. It is necessary that the compound constitute a proportion such that a suitable dosage will be obtained and it is preferred to use pharma-ceutical compositions containing at least 10 weight percent of the compound. Activity increases with concentration of the agent in the carrier, but those compositions containing a significant amount of carrier, e.g. at least 1 percent and preferably at least 5 percent, are preferred as they allow for the easier administration of the compound.
The active compounds of the present invention are prepared by known procedures. In general, member compounds are made by reacting p-aminobenzoic acid or an ester thereof in an inert solvent with a halo-substituted 2-thiophene-carboxaldehyde. The resulting Schiff base is reduced to prepare the corresponding p-aminobenzoic acid derivative.
A convenient method of carrying out this latter procedure involves mixing the Schiff base with an excess of ethanol and water. Dilute aqueous sodium hydroxide optionally can be added to the mixture. Sodium borohydride is added at 18,307-F _5_ - '.' ~ ' room temperature and stirred until it dissolves. The mixture is then heated, poured onto ice, and acidified. The product may be filtered off as a precipitate and further purified by known procedures.
Several of the halogenated aldehydes were not readily available and were prepared by methods generally known from the literature. For example, 4-chloro-2-thio-phenecarboxaldehyde was prepared by the chlorination of 2-thiophenecarboxaldehyde using a large excess of the aluminum chloride catalyst. See J. Org. Chem., 21 381 (1955) and J Heter. Chem., 393 (1976). Using the same method 4,5-dichloro-2-thiophenecarboxaldehyde was also prepared from 5-chloro-2-thiophenecarboxaldehyde. See C.A. 57;16526i.
The followlng examples further illustrate the invention.
Example l 4-(3~5-Dichloro-2-thienylmethylamino)ben2oic acid A 50% oil dispersion (5.8 grams, 0.12 mole) of sodium hydride was washed with hexane under nitrogen. To this, 200 ml of dry dimethylformamide and 29.5 yrams (0.113 mole) of solid ethyl N-trifluoroacetyl-4-aminobenzoate was added. The reaction mass exothermed mildly. The mixture was cooled to 20C and stirred for 15 minutes. Afterwards, 27.7 grams of 3,5-dichloro-2-bromomethylthiophene was added.
The reaction mass was heated for 18 hours at 85C. At the end of that period the mixture was poured into l liter of cold water and extracted with methylene chloride. The product was dried with anhydrous sodium sulfate and the dried solution concentrated to a brown oil. The resulting oil was refluxed for 2 hours with 50 ml of ethanol and 200 ml of 5N sodium hydroxide. The cooled, ~rown solution was diluted with water and acidified with acetic acid. The ,:
18,307-F -6-crude 4-(3,5-dichloxo-2-thienylmethylamino)benzoic acid was obtained as a brown gum, and recrystallization from propylene glycol methyl ether gave 17 g. brown crystals, m.p. 169-170.5C.
Elemental analysis: C H N
Calculated 47.71 3.00 4.63 Found 47.8 3.06 4.74 Example 2 4-(5-Chloro-2-thienylmet ylamino)benzoic acid A mixture containing 46.6 grams (0.34 mole) of p-aminobenzoic acid, 50 grams (0.34 mole) of 5-chloro-2-thiophenecarboxaldehyde, and 400 ml. of toluene was heated , to reflux for about 3.5 hours. The water formed was collected in a Dean-Stark trap. The reaction mass was c0012d at the end o this period and the Schiff base collected as a tan solid. To a mixture of the intermediate Schiff base and 1.2 ~' liters of glacial acetic acid 21.2 grams (0.35 mole) of ~- dimethylaminoborane was added. The reaction mass was warmed to 40C for about 30 minutes and poured in 2 liters of ice water. The white precipitate of 4-(5-chloro-2-thienylmethyl-i 20 amino)benzoic acid was washed in water, dried, and re-crystallized from toluene. Yield, 60 g. (70%);
m.p. 177-178C.
Example 3 4-(4,5-Dichloro-2-thienylmethylamino)benzoic acid Step 1: Synthesis of 4,5-dichloro-2-thiophene-carboxaldehyde.
', ' ~ ~:
; To a mechanically stirred solution of 31.8 grams , (0.217 mole) 5-chloro-2-thiophenecarboxaldehyde in 150 ml of methylene chloride, 65 grams (0.487 mole) of anhydrous aluminum chloride was added in small portions. The mixture exothermed and turned purple. To this mixture 20.6 grams , ~ ~
, 18 , 3 0 7 -F
(0.29 mole) of chlorine in 250 ml of carbon tetrachloride was added dropwise. The reaction mass was refluxed for about 15 hours, and an additional 15 grams (0.21 mole) of chlorine in 200 ml of carbon tetrachloride was added. The mixture was refluxed for an additional 7 hours. The reaction was quenched by pouring over one liter of ice water. The aqueous layer was extracted with chloroform. The chloroform solution was washed with water and sodium bicarbonate. ~fter drying with anhydrous sodium sulfate and concentration under vacuum, a yellow-brown oil was obtained. The crude 4,5-dichloro-2-thiophenecarboxaldehyde crystallized on standing and was recrystallized from hexane.
Step 2: The product 4-(4,5-dichloro-2-thienylmethyl-amino~benzoic acid, m.p. 225-227C, was prepared from the 4,5-dichloro-2-thiophenecarboxaldehyde intermediate in essentially the same manner as described in Example 2 above;
yield, 88%.
Elemental analysis: C H N
Calculated 47.71 3.00 4.63 Found 47.6 3.09 4.80 In addition to the compounds described in the examples above, other compounds were prepared using essentially the same techniques. These compounds shown as Examples 4, 5 and 6 were as follows:
Example 4 4-(5-Chloro-2-thienylmethylamino)benzoic acid ethyl ester, m.p. 108-109C, was prepared from ethyl _-aminobenzoate and 5-chloro-2-thiophenecarboxaldehyde.
Yield, 87~.
18,307 ~:~v~
Elemental analysis: C _ ~ N
CalculatedS6.86 4.77 4.73 Found 56.7 4.87 4.85 Exam~le 5 .~
4-(5-Bromo-2-thienylmethylamino)benzoic acid, m.p. 188-190C. Yield, 61%.
Elemental analysis: C H N
Calculated46.18 3.23 4.49 Found 46.1 3.29 4.65 Example 6 4-(4-Chloro-2-thienylmethylamino)benzoic acid, m.p. 165-168C. Yield, 96%.
Elemental analysis: C H N
Calculated53.85 3.77 5.23 Found 53.6 3.80 5.38 Example 7 The hypolidemic effect of the compounds of the invention was illustratively demonstrated in rats. In this procedure, a compound was dissolved in acetone, taken up on a silica gel, and mixed with normal ground feed to yield concentrations of 0.125 percent of the compound in the animal feed. The treated feed was administered to male rats weighing 150-160 grams over a 14 day period. Following the feeding period, the rats were sacrificed, and the blood samples were collected. The liver was removed, weighed, and froæen for future analysis. The relative levels of serum cholesterol in the blood samples were determined by the Henly method. A. A. Henly, Analyst, 82, 286 (1957).
Liver cholesterol was measured by the Sperry-Webb method.
Journal of Biological Chemistry 187, 97 (1950). The 18,307-F -9-.
; relative levels of triglycerides in the blood and liversamples were determin~d by the Von Handel and Zilversmit method. J. Lab. Clin. Med. 50, 152 (1957) and Clin. Chem.
-7, 249 (1961). Taking the average levels of the control rats as standard, the mean results obtained ln the treated groups is thereby ascertained.
The data presented in Table I summarizes the results of the above studies.
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.~
.....
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i,~
,~' .~ .
18,307-F -10-i9 ~D CO ~ ~ O O
~-~ ~1 .~ 3 + + + + + +
~ S~
~ ~ o ~ ~ U'~
O-~
O
* 3 ~ U~
~ ~ +
.,, a h * ~
O S
~_1 H~) ~1~~rlco e;' O
,~a) ~t~ I + + +
* .~
U~
. ~ ~ ~ ~~O ~1 ~ O
U~ ~1 .~ ~ ~
E~ h a * ~ O
o a),l ~ IJ --~ ~ ~ ~ O ~ ~ h ~ ~ h u a~ a) l l l l l l s~
u~ ~ ~ 8 o ~ ~
Z
~ a o ~ E~
18 ~ 3 7-F -11 ' The data in Table I indicate that the compounds of the present invention are highly effective as hypolidemic agents in the lowering of serum cholesterol and serum tri-glycerides while causing only minimal changes in liver weight and overall body weight. The compounds 4-(4,5--dichloro-2-thienylmethylamino)benzoic acid (Example 3) and 4-(5-chloro-2-thienylmethylamino)benzoic acid ethyl ester (Example 4) are shown to be especially useful in lowering cholesterol levels in mammals. Likewise the compounds 4-(5-chloro-2~thienylmethylamino)benzoic acid ethyl ester (Example 4) and 4-(4-chloro-2-thienylmethylamino)benzoic acid (Example 6) were found to be particularly effective in ; lowering serum triglycerides.
. ' .
, ~ . .
~` .
13~307-F -12-
4-(2-Thienylmethylamino)benzoic acid and the corres-ponding ethyl ester have been described in Izo. Akad. Nauk SSSR, Ser. Khim. 1967(9), 2049-55 (C.A. 68; 104869K). No utility for the compounds is disclosed. Belgian Patent No. 839,382 granted September 10, 1976 discloses 4[aryl(alkyl or alkenyl)-amino]benzoic acid compounds having hypolidemic activity.
The present invention provides 4-(2-thienylmethylamino)-benzoic acid compounds corresponding to the general formula ~ ~ CH2NH ~ COOR
wherein R represents hydrogen or Cl 3 alkyl, and Xl Y, and Z
independently represent hydrogen, chloro, or bromo, with the proviso that at least one of X, Y, and Z is chloro or bromo.
Pharmaceutically-acceptable salts of the p-amino-benzoic acids, i.e. when R is hydrogen, are also considered as being within the scope of this invention. Pharmaceutically-acceptable salts refer to the acid addition salts of thosebases which will form a salt with a carboxylic acid and which will not cause an adverse physiological effect when administered to an animal at dosages consistent with good pharmacological activity. Suitable bases thus include, for example, the alkali metal and alkaline earth metal hydroxides, carbonates, and bicarbonates such as sodium hydroxides, potassium hydroxide, calcium hydroxide, ~: `
15g potassium carbonate, sodium bicarbonate, or magnesium carbonate; ammonia, primary, secondary, and tertiary amines.
Also, aluminum salts may be obtained by treating the corres-ponding sodium salt with an appropriate aluminum complex S such as aluminum chloride hexahydrate.
Compounds of the present invention have shown h~polipidemic activity in animals and in particular in mammals. Hypolipidemic activity as used herein refers to the effect of lowering the blood lipid content and in particular the cholesterol and triglyceride content of the serum. The compounds are therefore suitable for use in treating serum hyperlipidemia in mammals and in particular are useful for the treatment of hypercholesterolemia and hypertriglyceridemia, that is, abnormally hish levels of lipids, cholesterol, or triglycerides, respectively, in the serum. The compounds can be administered orally or parent~
erally by subcutaneous, intravenous, or intraperitoneal injection or by implantation, oral administration being preferred.
The effective hypolipidemic amount of the p-amino-benzoic acid compounds to be administered to an animal, that ; is, the amount which is effective to significantly lower the serum lipid level, can vary depending upon such factors as the animal treated, the particular compound employed, the desired lipid level to be obtained, whether or not the animal is hyperlipidemic, the period of administratlon, and the method of administration. In general, an effective daily dosage range is from about 1 mg/kg of body weight to 20Q mg/kg of body weight, with a daily dosage range of from - 30 about 10 mg/kg to 100 mg/kg of body weight being preferred.
.
.
18,307-F -2-: ~ .
For oral administration, pharmaceutical prepar-ations of the p-aminobenzoic acids may be made by following conventional techniques. These techinques involve granu-lating and compressing, when ~ecessary, or variously mixing i and dissolving or suspending the ingredients as appropriate to the desired end product. Numerous pharmaceutical forms to carry the compounds can be used. For example, the pure compound can be used or it can be mixed with a solid carrier.
Generally, inorganic pharmaceutical carriers are preferable and particularly solid inorganic carriers. One reason for - this is the large number of inorganic materials which are known to be pharmaceutically safe and acceptable, as well as very convenient in preparing formulations. The compositions may take the form of tablets, linguets, powders, capsules, slurries, troches, or lozenges, and such compositions may be ~; prepared by stand~rd pharmaceutical techniques. Tablet compositions may be coated or uncoated, and they may be effervescent or non-effervescent. Conventional excipients for tablet formations may be used. For example, inert diluents, such as magnesium carbonate or lactose, disinte-grating agents such as maize starch or alginic acid, and lubricating agents such as magnesium stearate may be used.
~ I~ a liquid carrier is used, the preparation may ; be in the form of a soft gelatin capsule, a syrup, a liquid solution, or suspension.
The hydrocarbon solubility of most of the compounds of this invention is high enough to allow the use of pharmaceutically-acceptable oils and carriers. For example, vegetable or animal oils such as sunflower oil, safflower oil, maize oil or cod liver oil can be used. Glycerine can lg,307-F 3 also be used. With this latter solvent, from 2 to 30 percent water, may be added. When water alone is the carrier, or when the solubllity of the compound in the oil is low, the preparations can be administered in the lorm of a slurry.
Emulsion compositions may be formulated using emulsifying agents such as sorbitan trioleate, polyoxy~
ethylene sorbitan monooleate, leclthin, gum acacia, or gum tragacanth. Aqueous based suspensions may be prepared with the aid of wetting agents such as polyethylene oxide con-densation products of alkylphenols, fatty alcohols, or fatty acids with the suspending agents, for example, a hydrophilic colloid such as polyvinylpyrrolidone. The emulsions and suspensions may contain conventional excipients such as sweetening agents, coloring materials, or preservatives.
The compounds can also be incorporated in a nutritive foodstuff such as, for example, butter, margarine, edible oils, casein, or carbohydrates. Such nutritive compositions are adapted to be administered as a partial or total diet or as a supplement to the diet. Such compo-sitions preferably contain from about 0.02 to about 2.0 percent of the active ingredient when administered as the total diet. The compositions can contain higher concentra-tions of the active ingredient when administered as a supplement.
For parenteral use, the compounds can be formulated with sterile ingredients, compounded, and packaged ascepti-cally. They may be administered intravenously or intra-muscularLy. Useful solvents for formulation ~or such use are the polyhydric aliphatic alcohols and mixtures thereof.
Especially satisfactory are the pharmaceutically acceptable 18,307-F -4-;-glycols, such as propylene glycol, and mixtures thereof.
Glycerine is particularly useful. Up to 25-30 percent by volume of water may be incorporated in the vehicle, if desired. An 80 percent aqueous propylene glycol solution ls a particularly convenient solvent system. A pH of about 7.4 and isotonicity compatible with body isotonicity are desirable. Basicity may be controlled by addition of a base as required, and a particularly convenient base is monoethanolamine. It may often be desirable to incorporate a local anesthetic and such are well known to those skilled in the art.
The percentage of the compound to be used in the pharmaceutical carrier may be varied. It is necessary that the compound constitute a proportion such that a suitable dosage will be obtained and it is preferred to use pharma-ceutical compositions containing at least 10 weight percent of the compound. Activity increases with concentration of the agent in the carrier, but those compositions containing a significant amount of carrier, e.g. at least 1 percent and preferably at least 5 percent, are preferred as they allow for the easier administration of the compound.
The active compounds of the present invention are prepared by known procedures. In general, member compounds are made by reacting p-aminobenzoic acid or an ester thereof in an inert solvent with a halo-substituted 2-thiophene-carboxaldehyde. The resulting Schiff base is reduced to prepare the corresponding p-aminobenzoic acid derivative.
A convenient method of carrying out this latter procedure involves mixing the Schiff base with an excess of ethanol and water. Dilute aqueous sodium hydroxide optionally can be added to the mixture. Sodium borohydride is added at 18,307-F _5_ - '.' ~ ' room temperature and stirred until it dissolves. The mixture is then heated, poured onto ice, and acidified. The product may be filtered off as a precipitate and further purified by known procedures.
Several of the halogenated aldehydes were not readily available and were prepared by methods generally known from the literature. For example, 4-chloro-2-thio-phenecarboxaldehyde was prepared by the chlorination of 2-thiophenecarboxaldehyde using a large excess of the aluminum chloride catalyst. See J. Org. Chem., 21 381 (1955) and J Heter. Chem., 393 (1976). Using the same method 4,5-dichloro-2-thiophenecarboxaldehyde was also prepared from 5-chloro-2-thiophenecarboxaldehyde. See C.A. 57;16526i.
The followlng examples further illustrate the invention.
Example l 4-(3~5-Dichloro-2-thienylmethylamino)ben2oic acid A 50% oil dispersion (5.8 grams, 0.12 mole) of sodium hydride was washed with hexane under nitrogen. To this, 200 ml of dry dimethylformamide and 29.5 yrams (0.113 mole) of solid ethyl N-trifluoroacetyl-4-aminobenzoate was added. The reaction mass exothermed mildly. The mixture was cooled to 20C and stirred for 15 minutes. Afterwards, 27.7 grams of 3,5-dichloro-2-bromomethylthiophene was added.
The reaction mass was heated for 18 hours at 85C. At the end of that period the mixture was poured into l liter of cold water and extracted with methylene chloride. The product was dried with anhydrous sodium sulfate and the dried solution concentrated to a brown oil. The resulting oil was refluxed for 2 hours with 50 ml of ethanol and 200 ml of 5N sodium hydroxide. The cooled, ~rown solution was diluted with water and acidified with acetic acid. The ,:
18,307-F -6-crude 4-(3,5-dichloxo-2-thienylmethylamino)benzoic acid was obtained as a brown gum, and recrystallization from propylene glycol methyl ether gave 17 g. brown crystals, m.p. 169-170.5C.
Elemental analysis: C H N
Calculated 47.71 3.00 4.63 Found 47.8 3.06 4.74 Example 2 4-(5-Chloro-2-thienylmet ylamino)benzoic acid A mixture containing 46.6 grams (0.34 mole) of p-aminobenzoic acid, 50 grams (0.34 mole) of 5-chloro-2-thiophenecarboxaldehyde, and 400 ml. of toluene was heated , to reflux for about 3.5 hours. The water formed was collected in a Dean-Stark trap. The reaction mass was c0012d at the end o this period and the Schiff base collected as a tan solid. To a mixture of the intermediate Schiff base and 1.2 ~' liters of glacial acetic acid 21.2 grams (0.35 mole) of ~- dimethylaminoborane was added. The reaction mass was warmed to 40C for about 30 minutes and poured in 2 liters of ice water. The white precipitate of 4-(5-chloro-2-thienylmethyl-i 20 amino)benzoic acid was washed in water, dried, and re-crystallized from toluene. Yield, 60 g. (70%);
m.p. 177-178C.
Example 3 4-(4,5-Dichloro-2-thienylmethylamino)benzoic acid Step 1: Synthesis of 4,5-dichloro-2-thiophene-carboxaldehyde.
', ' ~ ~:
; To a mechanically stirred solution of 31.8 grams , (0.217 mole) 5-chloro-2-thiophenecarboxaldehyde in 150 ml of methylene chloride, 65 grams (0.487 mole) of anhydrous aluminum chloride was added in small portions. The mixture exothermed and turned purple. To this mixture 20.6 grams , ~ ~
, 18 , 3 0 7 -F
(0.29 mole) of chlorine in 250 ml of carbon tetrachloride was added dropwise. The reaction mass was refluxed for about 15 hours, and an additional 15 grams (0.21 mole) of chlorine in 200 ml of carbon tetrachloride was added. The mixture was refluxed for an additional 7 hours. The reaction was quenched by pouring over one liter of ice water. The aqueous layer was extracted with chloroform. The chloroform solution was washed with water and sodium bicarbonate. ~fter drying with anhydrous sodium sulfate and concentration under vacuum, a yellow-brown oil was obtained. The crude 4,5-dichloro-2-thiophenecarboxaldehyde crystallized on standing and was recrystallized from hexane.
Step 2: The product 4-(4,5-dichloro-2-thienylmethyl-amino~benzoic acid, m.p. 225-227C, was prepared from the 4,5-dichloro-2-thiophenecarboxaldehyde intermediate in essentially the same manner as described in Example 2 above;
yield, 88%.
Elemental analysis: C H N
Calculated 47.71 3.00 4.63 Found 47.6 3.09 4.80 In addition to the compounds described in the examples above, other compounds were prepared using essentially the same techniques. These compounds shown as Examples 4, 5 and 6 were as follows:
Example 4 4-(5-Chloro-2-thienylmethylamino)benzoic acid ethyl ester, m.p. 108-109C, was prepared from ethyl _-aminobenzoate and 5-chloro-2-thiophenecarboxaldehyde.
Yield, 87~.
18,307 ~:~v~
Elemental analysis: C _ ~ N
CalculatedS6.86 4.77 4.73 Found 56.7 4.87 4.85 Exam~le 5 .~
4-(5-Bromo-2-thienylmethylamino)benzoic acid, m.p. 188-190C. Yield, 61%.
Elemental analysis: C H N
Calculated46.18 3.23 4.49 Found 46.1 3.29 4.65 Example 6 4-(4-Chloro-2-thienylmethylamino)benzoic acid, m.p. 165-168C. Yield, 96%.
Elemental analysis: C H N
Calculated53.85 3.77 5.23 Found 53.6 3.80 5.38 Example 7 The hypolidemic effect of the compounds of the invention was illustratively demonstrated in rats. In this procedure, a compound was dissolved in acetone, taken up on a silica gel, and mixed with normal ground feed to yield concentrations of 0.125 percent of the compound in the animal feed. The treated feed was administered to male rats weighing 150-160 grams over a 14 day period. Following the feeding period, the rats were sacrificed, and the blood samples were collected. The liver was removed, weighed, and froæen for future analysis. The relative levels of serum cholesterol in the blood samples were determined by the Henly method. A. A. Henly, Analyst, 82, 286 (1957).
Liver cholesterol was measured by the Sperry-Webb method.
Journal of Biological Chemistry 187, 97 (1950). The 18,307-F -9-.
; relative levels of triglycerides in the blood and liversamples were determin~d by the Von Handel and Zilversmit method. J. Lab. Clin. Med. 50, 152 (1957) and Clin. Chem.
-7, 249 (1961). Taking the average levels of the control rats as standard, the mean results obtained ln the treated groups is thereby ascertained.
The data presented in Table I summarizes the results of the above studies.
, " .
' ' .... ~
.~
.....
"
,,',.~ ' .
i,~
,~' .~ .
18,307-F -10-i9 ~D CO ~ ~ O O
~-~ ~1 .~ 3 + + + + + +
~ S~
~ ~ o ~ ~ U'~
O-~
O
* 3 ~ U~
~ ~ +
.,, a h * ~
O S
~_1 H~) ~1~~rlco e;' O
,~a) ~t~ I + + +
* .~
U~
. ~ ~ ~ ~~O ~1 ~ O
U~ ~1 .~ ~ ~
E~ h a * ~ O
o a),l ~ IJ --~ ~ ~ ~ O ~ ~ h ~ ~ h u a~ a) l l l l l l s~
u~ ~ ~ 8 o ~ ~
Z
~ a o ~ E~
18 ~ 3 7-F -11 ' The data in Table I indicate that the compounds of the present invention are highly effective as hypolidemic agents in the lowering of serum cholesterol and serum tri-glycerides while causing only minimal changes in liver weight and overall body weight. The compounds 4-(4,5--dichloro-2-thienylmethylamino)benzoic acid (Example 3) and 4-(5-chloro-2-thienylmethylamino)benzoic acid ethyl ester (Example 4) are shown to be especially useful in lowering cholesterol levels in mammals. Likewise the compounds 4-(5-chloro-2~thienylmethylamino)benzoic acid ethyl ester (Example 4) and 4-(4-chloro-2-thienylmethylamino)benzoic acid (Example 6) were found to be particularly effective in ; lowering serum triglycerides.
. ' .
, ~ . .
~` .
13~307-F -12-
Claims (7)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a 4-(2-thienylmethyl-amino)benzoic acid compound corresponding to the formula wherein R represents hydrogen or C1-3 alkyl, and X, Y, and Z independently represent hydrogen, chloro, or bromo with the proviso that at least one of X, Y, and Z is chloro or bromo, which process comprises reacting a 4-aminobenzoic acid compound corresponding to the formula wherein R is as defined above, with a 2-thiophenecarboxalde-hyde corresponding to the formula wherein X, Y, and Z are as defined above, followed by reduction of the Schiff base thus formed.
2. A process for preparing 4-(3,5-dichloro-2--thienylmethylamino)benzoic acid which comprises reacting 4-aminobenzoic acid with 3,5-dichloro-2-thiophenecarboxalde-hyde followed by reduction of the Schiff base thus formed.
3. A process for preparing 4-(5-chloro-2-thienyl-methylamino)benzoic acid which comprises reacting 4-amino-benzoic acid with 5-chloro-2-thiophenecarboxaldehyde followed by reduction of the Schiff base thus formed.
4. A process for preparing 4-(4,5-dichloro-2--thienylmethylamino)benzoic acid which comprises reacting 18,307-F
4-aminobenzoic acid with 4,5-dichloro-2-thiophenecarboxalde-hyde followed by reduction of the Schiff base thus formed.
4-aminobenzoic acid with 4,5-dichloro-2-thiophenecarboxalde-hyde followed by reduction of the Schiff base thus formed.
5. A process for preparing 4-(5-bromo-2-thienyl-methylamino)benzoic acid which comprises reacting 4-amino-benzoic acid with 5-bromo-2-thiophenecarboxaldehyde followed by reduction of the Schiff base thus formed.
6. A process for preparing 4-(4-chloro-2-thienyl-methylamino)benzoic acid which comprises reacting 4-amino-benzoic acid with 4-chloro-2-thiophenecarboxaldehyde followed by reduction of the Schiff base thus formed.
7. A process for preparing ethyl 4-(5-chloro-2--thienylmethylamino)benzoate which comprises reacting ethyl 4-aminobenzoate with 5-chloro-2-thiophenecarboxaldehyde followed by reduction of the Schiff base thus formed.
18,307-F
18,307-F
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US78546777A | 1977-04-07 | 1977-04-07 | |
| US785,467 | 1977-04-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1108159A true CA1108159A (en) | 1981-09-01 |
Family
ID=25135597
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA300,577A Expired CA1108159A (en) | 1977-04-07 | 1978-04-06 | Substituted 4-(((2-thienyl)methyl)amino) benzoic acids and a method for treating hypolipidemia |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS53149968A (en) |
| BE (1) | BE865809A (en) |
| CA (1) | CA1108159A (en) |
| CH (1) | CH629796A5 (en) |
| DE (1) | DE2814798A1 (en) |
| DK (1) | DK153403C (en) |
| FR (1) | FR2386542A1 (en) |
| GB (1) | GB1565936A (en) |
| IE (1) | IE46713B1 (en) |
| IT (1) | IT1094318B (en) |
| NL (1) | NL7803669A (en) |
| NO (1) | NO149241C (en) |
| NZ (1) | NZ186886A (en) |
| SE (1) | SE446734B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4143151A (en) * | 1978-07-03 | 1979-03-06 | The Dow Chemical Company | Method for treating hyperglycemia in mammals using arylamino benzoic acids |
| JPS6421196A (en) * | 1987-07-15 | 1989-01-24 | Nippon Concrete Ind Co Ltd | Auger screw |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2983729A (en) * | 1958-04-30 | 1961-05-09 | Monsanto Chemicals | Preparation of 5-halothienyl amines |
| ZA726590B (en) * | 1971-10-08 | 1973-06-27 | Ici Australia Ltd | Pesticidal compositions compounds contained therein and their preparation and use |
| US4185115A (en) * | 1975-03-12 | 1980-01-22 | American Cyanamid Company | Antilipidemic para-[aryl(alkyl or alkenyl)amino]-benzoic acid derivatives |
-
1978
- 1978-04-03 CH CH355178A patent/CH629796A5/en not_active IP Right Cessation
- 1978-04-04 IT IT21941/78A patent/IT1094318B/en active
- 1978-04-05 NZ NZ186886A patent/NZ186886A/en unknown
- 1978-04-05 IE IE678/78A patent/IE46713B1/en not_active IP Right Cessation
- 1978-04-05 FR FR7810111A patent/FR2386542A1/en active Granted
- 1978-04-05 DE DE19782814798 patent/DE2814798A1/en active Granted
- 1978-04-06 SE SE7803910A patent/SE446734B/en not_active IP Right Cessation
- 1978-04-06 NL NL7803669A patent/NL7803669A/en not_active Application Discontinuation
- 1978-04-06 CA CA300,577A patent/CA1108159A/en not_active Expired
- 1978-04-06 GB GB13449/78A patent/GB1565936A/en not_active Expired
- 1978-04-06 NO NO781214A patent/NO149241C/en unknown
- 1978-04-06 DK DK153178A patent/DK153403C/en not_active IP Right Cessation
- 1978-04-06 JP JP4075978A patent/JPS53149968A/en active Granted
- 1978-04-07 BE BE186657A patent/BE865809A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| BE865809A (en) | 1978-10-09 |
| NO781214L (en) | 1978-10-10 |
| DE2814798C2 (en) | 1988-05-26 |
| JPS6126790B2 (en) | 1986-06-21 |
| DK153403B (en) | 1988-07-11 |
| IE46713B1 (en) | 1983-09-07 |
| GB1565936A (en) | 1980-04-23 |
| DK153403C (en) | 1988-11-28 |
| SE446734B (en) | 1986-10-06 |
| NO149241B (en) | 1983-12-05 |
| SE7803910L (en) | 1978-10-08 |
| CH629796A5 (en) | 1982-05-14 |
| FR2386542B1 (en) | 1981-07-10 |
| FR2386542A1 (en) | 1978-11-03 |
| IT7821941A0 (en) | 1978-04-04 |
| DE2814798A1 (en) | 1978-10-19 |
| IE780678L (en) | 1978-10-07 |
| JPS53149968A (en) | 1978-12-27 |
| NL7803669A (en) | 1978-10-10 |
| DK153178A (en) | 1978-10-08 |
| NZ186886A (en) | 1980-02-21 |
| IT1094318B (en) | 1985-07-26 |
| NO149241C (en) | 1984-03-14 |
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