CA1072969A - Hypolipidemic p-aminobenzoic acids - Google Patents
Hypolipidemic p-aminobenzoic acidsInfo
- Publication number
- CA1072969A CA1072969A CA269,483A CA269483A CA1072969A CA 1072969 A CA1072969 A CA 1072969A CA 269483 A CA269483 A CA 269483A CA 1072969 A CA1072969 A CA 1072969A
- Authority
- CA
- Canada
- Prior art keywords
- compound
- benzodioxol
- benzoic acid
- hypolipidemic
- ester
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
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
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
- A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
- A61K31/245—Amino benzoic acid types, e.g. procaine, novocaine
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
- C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
- C07D317/58—Radicals substituted by nitrogen atoms
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
ABSTRACT
A hypolipidemic composition characterized in that it contains a compound corresponding to the formula
A hypolipidemic composition characterized in that it contains a compound corresponding to the formula
Description
10~296g This invention relates to preparing a novel sub-stituted p-aminobenzoic acid that is useful for treatment of hypolipidemia.
It is recognized that cholesterol and trigly-cerides play a major role in the formation of arthero-sclerotic plaques by accelerating the deposition of blood lipids in the arterial wall.
The present invention concerns the novel compound 4-(1,3-benzodioxol-5-ylmethylamino)benzoic acid, which is useful for reducing plasma lipid level in animals.
More particularly, this invention provides a process for producing 4-(1,3-benzodioxol-5-ylmethylamino)-benzoic acid which comprises selecting a process from the group consisting of (A) reacting piperonal with p-amino-benzoic acid followed by reduction of the Schiff base thus formed and (B) saponification of an ester of said acid followed by acidification. A convenient method of carrying out the Schiff base procedure involves mixing the Schiff base with an excess of ethanol and water. Dilute aqueous sodium hydroxide, for example about l molar equivalent of the Schiff base, optionally can be added to the mixture.
Sodium borohydride, NaBH4, (1 molar equivalent) is added at room temperature and stirred until it dissolves. The mixture is then heated to reflux for l to 2 hours. The mixture is poured onto ice and acidified~ The product may be filtered off as a precipitate and further purified by known procedures.
The compound of the invention also can be pre-pared by saponification of an ester, preferably a lower alkyl ester, of 4-(1,3-benzodioxol-5-ylmethylamino)benzoic acid followed by acidification according to known procedures.
17,869-F -l-The compound of the present invention is a crystal-line solid w~ich is soluble in many common organic solvents such as, for example, acetone, benzene, alcohols, or liquid alkanes.
The compound has shown hypolipidemic 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 tri-glyceride content of the serum. The compound of the present invention is therefore suitable for use in treating serum hyperlipidemia in mammals and in particular is useful for the treatment of hypercholesterolemia and hypertriglyceridemia, that is, abnormally high levels of lipids, cholesterol, or triglycerides, respectively, in the serum. The compound can be administered orally or parenterally by subcutaneous, intravenous, or intraperitoneal injection or by implantation, oral administration being preferred.
~he hypolipidemic amount of the p-aminobenzoic acid compound 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 desired lipid level to be obtained, whether or not the animal is hyperlipidemic, the period of administration and the method of administration. In general, an effective daily dosage range is from 1 to 400 mg/kg of body weight, with a daily dosage range of from about 5 to 30 mg/kg of body weight being preferred.
For oral administration, pharmaceutical prepara-tions of the compound can be made by conventional techniques.
These techniques involve granulating and compressing when 17,869-F -2-- : .. : .. . .
96g necessary or variously mixing and dissolving or suspending the ingredients as appropriate to the desired end product.
Numerous pharmaceutical forms to carry the compound can be used. For example, the pure compound can be used or it can be mixed with a solid carrier. Generally, inorganic pharma-ceutical carriers are preferable and particularly solid inorganic carriers. One reason for this is the large number of inorganic materials which are known to be pharmaceuti-cally safe and acceptable, as well as very convenient in preparing formulations. The compositions may ta~e the form of tablets, linguets, powders, capsules, slurries, troches, or lozenges, and such compositions can be prepared by stan~ard 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, disintegrating agents such as maize starch or alginic acid, and lubricating agents such as magnesium stearate may be used.
If 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 the compound of this invention is high enough to allow the use of pharmaceutically--acceptable oils as carriers. For example, vegetable or animal oils such as sunflower oil, safflower oil, maize oil or cod liver oil can be used. Glycerine can 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 solu-bility of the compound in the oil is low, the preparations can be administèred in the form of a slurry.
17,869-F -3-.
.
~7Z9~9 Emulsion compositions may be formulated using emulsifying agents such as sorbitan trioleate, polyoxyethylene sorbitan monooleate, lecithin, gum acacia or gum tragacanth.
Aqueous based suspensions may be prepared with the aid of wetting agents such as polyethylene oxide condensation 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 sweeting agents, flowing agents, coloring materials, or preservatives.
The compound of the invention can also be incorpor-ated 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 compositions preferably contain from 0.02 to 2.0 percent by weight of the active ingredient when administered as the total diet. The compositions can contain higher concen-trations of the active ingredient when administered as a supplement.
For parenteral use, the compound can be formulated with sterile ingredients, compounded and packaged ascepti-cally and may be administered intravenously or intramuscu-larly. Useful solvents for formulation in such use are the polyhydric aliphatic alcohols and mixtures thereof. Es-pecially satisfactory are the pharmaceutically acceptable 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 17,869-F -4-. . .
c 9~9 desired. An 80 percent aqueous propylene glycol solution is a particularly convenient solvent system. A pH, about 7.4, and isotonicity compatible with body isotonicity, is 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 such as 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 invention is illustrated by the following examples.
A mixture of 2 moles piperonal, 2 moles p-amino-benzoic acid, and 2 liters toluene was heated at reflux for
It is recognized that cholesterol and trigly-cerides play a major role in the formation of arthero-sclerotic plaques by accelerating the deposition of blood lipids in the arterial wall.
The present invention concerns the novel compound 4-(1,3-benzodioxol-5-ylmethylamino)benzoic acid, which is useful for reducing plasma lipid level in animals.
More particularly, this invention provides a process for producing 4-(1,3-benzodioxol-5-ylmethylamino)-benzoic acid which comprises selecting a process from the group consisting of (A) reacting piperonal with p-amino-benzoic acid followed by reduction of the Schiff base thus formed and (B) saponification of an ester of said acid followed by acidification. A convenient method of carrying out the Schiff base procedure involves mixing the Schiff base with an excess of ethanol and water. Dilute aqueous sodium hydroxide, for example about l molar equivalent of the Schiff base, optionally can be added to the mixture.
Sodium borohydride, NaBH4, (1 molar equivalent) is added at room temperature and stirred until it dissolves. The mixture is then heated to reflux for l to 2 hours. The mixture is poured onto ice and acidified~ The product may be filtered off as a precipitate and further purified by known procedures.
The compound of the invention also can be pre-pared by saponification of an ester, preferably a lower alkyl ester, of 4-(1,3-benzodioxol-5-ylmethylamino)benzoic acid followed by acidification according to known procedures.
17,869-F -l-The compound of the present invention is a crystal-line solid w~ich is soluble in many common organic solvents such as, for example, acetone, benzene, alcohols, or liquid alkanes.
The compound has shown hypolipidemic 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 tri-glyceride content of the serum. The compound of the present invention is therefore suitable for use in treating serum hyperlipidemia in mammals and in particular is useful for the treatment of hypercholesterolemia and hypertriglyceridemia, that is, abnormally high levels of lipids, cholesterol, or triglycerides, respectively, in the serum. The compound can be administered orally or parenterally by subcutaneous, intravenous, or intraperitoneal injection or by implantation, oral administration being preferred.
~he hypolipidemic amount of the p-aminobenzoic acid compound 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 desired lipid level to be obtained, whether or not the animal is hyperlipidemic, the period of administration and the method of administration. In general, an effective daily dosage range is from 1 to 400 mg/kg of body weight, with a daily dosage range of from about 5 to 30 mg/kg of body weight being preferred.
For oral administration, pharmaceutical prepara-tions of the compound can be made by conventional techniques.
These techniques involve granulating and compressing when 17,869-F -2-- : .. : .. . .
96g necessary or variously mixing and dissolving or suspending the ingredients as appropriate to the desired end product.
Numerous pharmaceutical forms to carry the compound can be used. For example, the pure compound can be used or it can be mixed with a solid carrier. Generally, inorganic pharma-ceutical carriers are preferable and particularly solid inorganic carriers. One reason for this is the large number of inorganic materials which are known to be pharmaceuti-cally safe and acceptable, as well as very convenient in preparing formulations. The compositions may ta~e the form of tablets, linguets, powders, capsules, slurries, troches, or lozenges, and such compositions can be prepared by stan~ard 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, disintegrating agents such as maize starch or alginic acid, and lubricating agents such as magnesium stearate may be used.
If 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 the compound of this invention is high enough to allow the use of pharmaceutically--acceptable oils as carriers. For example, vegetable or animal oils such as sunflower oil, safflower oil, maize oil or cod liver oil can be used. Glycerine can 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 solu-bility of the compound in the oil is low, the preparations can be administèred in the form of a slurry.
17,869-F -3-.
.
~7Z9~9 Emulsion compositions may be formulated using emulsifying agents such as sorbitan trioleate, polyoxyethylene sorbitan monooleate, lecithin, gum acacia or gum tragacanth.
Aqueous based suspensions may be prepared with the aid of wetting agents such as polyethylene oxide condensation 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 sweeting agents, flowing agents, coloring materials, or preservatives.
The compound of the invention can also be incorpor-ated 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 compositions preferably contain from 0.02 to 2.0 percent by weight of the active ingredient when administered as the total diet. The compositions can contain higher concen-trations of the active ingredient when administered as a supplement.
For parenteral use, the compound can be formulated with sterile ingredients, compounded and packaged ascepti-cally and may be administered intravenously or intramuscu-larly. Useful solvents for formulation in such use are the polyhydric aliphatic alcohols and mixtures thereof. Es-pecially satisfactory are the pharmaceutically acceptable 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 17,869-F -4-. . .
c 9~9 desired. An 80 percent aqueous propylene glycol solution is a particularly convenient solvent system. A pH, about 7.4, and isotonicity compatible with body isotonicity, is 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 such as 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 invention is illustrated by the following examples.
A mixture of 2 moles piperonal, 2 moles p-amino-benzoic acid, and 2 liters toluene was heated at reflux for
2 hours. The reaction mixture was cooled and filtered, giving 520 g. t96.6% yield) of Schiff base having a melting point of 235-238C.
Analysis:
C _H N
Calculated 66.91 4.12 5.20 Found 66.7 4.26 5.51 : ! .
;
17,869~F -5-l~Z969 The above Schiff base (1.89 moles) was reduced with sodium borohydride in 1 1. ethanol and 2 1. IN NaOH.
Recrystallization of the crude product (322.8 g.) from iso-propyl alcohol and then from ethanol gave 221.2 g. 4-(1,3-benzodioxol-5-ylmethvlamino)benzoic acid, m.p. 196-198C.
Analysis: -C H N
Calculated 66.42 4.83 5.16 Found 66.5 4.83 5.23 A mixture of 22.5 grams (0.15 mol) piperonal and 24.8 grams (0.15 mol) ethyl p-aminobenzoate in 500 ml of benzene was refluxed until 0.15 mol. of water had been collected in a trap. The reaction was cooled and yellow crystals formed. The mixture was filtered and the crystal-line product was washed with benzene and vacuum dried. This Schiff base weighed 31.97 grams (0.107 mol.).
The Schiff base was dissolved in 500 ml of anhy-drous ethanol and warmed to 40C. Sodium borohydride (4.5 grams) was added, and the resulting slurry was refluxed for 45 minutes. The reaction mass was cooled, poured over 800 ml. of ice water, and the crude 4-(1,3-benzodioxol-5-ylmethyl-amino)benzoic acid ethyl ester precipitated out. The pre-cipitate was collected and washed with water. After vacuum dxying, 30.4 grams of the white crystalline ester was ob-tained.
The ester had a melting point of 120-122C. Ele-mental analysis:
- C H N
Calculated 68.21 5.72 4.68 Found 68.1 5.82 4.74 17,869-F -6--.. . . . . . .:
~ 2969 4-(1,3-Benzodioxol-5-ylmethylamino)benzoic acid was prepared from the above ester as follows. 15 Grams of the ester was mixed with 150 ml. of 20~ sodium hydroxide and 150 ml of ethyl alcohol. The resulting slurry was refluxed for 4 hours and then cooled. The clear solution that result-ed was poured onto 800 grams of ice. The reaction mass was acidified with concentrated HCl. Crystalline 4-(1,3-benzodioxol-5-ylmethylamino)benzoic acid formed and was filtered off, washed with water, and dried. The product was recrystallized from acetonitrile. The compound had a melting point of 193-196C. Elemental analysis:
C H N
Calculated 66.42 4.83 5.16 Found 66.7 4.90 5.50 The hypolipidemic effect of the active compound of the invention is illustratively demonstrated in rats. In this procedure, the compound is dissolved in acetone, taken up on a silica gel, and mixed with ground feed to yield concentrations of 0.125 weight 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 blood samples were collected. The liver was removed, weighed, and frozen for future analysis. The relative levels of serum cholesterol in the blood samples was determined by the Henly method; A. A. Henly, Analyst, 82, 286 (1957). Liver choles-terol was measured by the Sperry-Webb method; Journal of Biological Chemistry 187, 97 (1950). The relative levels of i triglycerides in the blood and liver samples were determined ~`1, ' ~.
.
17,869-F ! _7_ ' : ' : : -.
~ X9~,9 by the Van Handel and Zilversmit method; J. Lab. Clin. Med.
50, 152 (1957j and Clin. Chem. 7, 249 (1961). Taking the average levels of the control rats as standard, the mean results obtained in the treated groups is thereby ascertained.
The data below represent relative change in values for the treated animals compared to the control group.
Serum cholesterol -32 Serum triglycerides -77 Liver cholesterol +15 Liver triglycerides -21 Liver weight + 5 17,869-F -8-
Analysis:
C _H N
Calculated 66.91 4.12 5.20 Found 66.7 4.26 5.51 : ! .
;
17,869~F -5-l~Z969 The above Schiff base (1.89 moles) was reduced with sodium borohydride in 1 1. ethanol and 2 1. IN NaOH.
Recrystallization of the crude product (322.8 g.) from iso-propyl alcohol and then from ethanol gave 221.2 g. 4-(1,3-benzodioxol-5-ylmethvlamino)benzoic acid, m.p. 196-198C.
Analysis: -C H N
Calculated 66.42 4.83 5.16 Found 66.5 4.83 5.23 A mixture of 22.5 grams (0.15 mol) piperonal and 24.8 grams (0.15 mol) ethyl p-aminobenzoate in 500 ml of benzene was refluxed until 0.15 mol. of water had been collected in a trap. The reaction was cooled and yellow crystals formed. The mixture was filtered and the crystal-line product was washed with benzene and vacuum dried. This Schiff base weighed 31.97 grams (0.107 mol.).
The Schiff base was dissolved in 500 ml of anhy-drous ethanol and warmed to 40C. Sodium borohydride (4.5 grams) was added, and the resulting slurry was refluxed for 45 minutes. The reaction mass was cooled, poured over 800 ml. of ice water, and the crude 4-(1,3-benzodioxol-5-ylmethyl-amino)benzoic acid ethyl ester precipitated out. The pre-cipitate was collected and washed with water. After vacuum dxying, 30.4 grams of the white crystalline ester was ob-tained.
The ester had a melting point of 120-122C. Ele-mental analysis:
- C H N
Calculated 68.21 5.72 4.68 Found 68.1 5.82 4.74 17,869-F -6--.. . . . . . .:
~ 2969 4-(1,3-Benzodioxol-5-ylmethylamino)benzoic acid was prepared from the above ester as follows. 15 Grams of the ester was mixed with 150 ml. of 20~ sodium hydroxide and 150 ml of ethyl alcohol. The resulting slurry was refluxed for 4 hours and then cooled. The clear solution that result-ed was poured onto 800 grams of ice. The reaction mass was acidified with concentrated HCl. Crystalline 4-(1,3-benzodioxol-5-ylmethylamino)benzoic acid formed and was filtered off, washed with water, and dried. The product was recrystallized from acetonitrile. The compound had a melting point of 193-196C. Elemental analysis:
C H N
Calculated 66.42 4.83 5.16 Found 66.7 4.90 5.50 The hypolipidemic effect of the active compound of the invention is illustratively demonstrated in rats. In this procedure, the compound is dissolved in acetone, taken up on a silica gel, and mixed with ground feed to yield concentrations of 0.125 weight 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 blood samples were collected. The liver was removed, weighed, and frozen for future analysis. The relative levels of serum cholesterol in the blood samples was determined by the Henly method; A. A. Henly, Analyst, 82, 286 (1957). Liver choles-terol was measured by the Sperry-Webb method; Journal of Biological Chemistry 187, 97 (1950). The relative levels of i triglycerides in the blood and liver samples were determined ~`1, ' ~.
.
17,869-F ! _7_ ' : ' : : -.
~ X9~,9 by the Van Handel and Zilversmit method; J. Lab. Clin. Med.
50, 152 (1957j and Clin. Chem. 7, 249 (1961). Taking the average levels of the control rats as standard, the mean results obtained in the treated groups is thereby ascertained.
The data below represent relative change in values for the treated animals compared to the control group.
Serum cholesterol -32 Serum triglycerides -77 Liver cholesterol +15 Liver triglycerides -21 Liver weight + 5 17,869-F -8-
Claims (3)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for producing 4-(1,3-benzodioxol--5-ylmethylamino)benzoic acid which comprises selecting a process from the group consisting of (A) reacting piperonal with p-aminobenzoic acid followed by reduction of the Schiff base thus formed and (B) saponification of an ester of said acid followed by acidification.
2. A process for producing 4-(1,3-benzodioxol--5-ylmethylamino)benzoic acid which comprises reacting piperonal with p-aminobenzoic acid followed by reduction of the Schiff base thus formed.
3. A process for producing 4-(1,3-benzodioxol--5-ylmethylamino)benzoic acid which comprises saponifi-cation of an ester of said acid followed by acidification.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US65009076A | 1976-01-19 | 1976-01-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1072969A true CA1072969A (en) | 1980-03-04 |
Family
ID=24607411
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA269,483A Expired CA1072969A (en) | 1976-01-19 | 1977-01-11 | Hypolipidemic p-aminobenzoic acids |
Country Status (14)
| Country | Link |
|---|---|
| JP (1) | JPS5289660A (en) |
| AT (1) | AT347923B (en) |
| AU (1) | AU500881B2 (en) |
| BE (1) | BE850516A (en) |
| CA (1) | CA1072969A (en) |
| CH (1) | CH628340A5 (en) |
| DE (1) | DE2702058C2 (en) |
| DK (1) | DK153471C (en) |
| FR (1) | FR2338040A1 (en) |
| GB (2) | GB1521458A (en) |
| IE (1) | IE44858B1 (en) |
| NL (1) | NL7700480A (en) |
| NO (1) | NO145839C (en) |
| SE (1) | SE435175B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0424904Y2 (en) * | 1987-09-18 | 1992-06-12 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE716668C (en) * | 1938-02-15 | 1942-01-27 | Dr Aladar Skita | Process for the preparation of derivatives of substituted aminobenzoic acids |
| FR2080069A5 (en) * | 1970-02-23 | 1971-11-12 | Commissariat Energie Atomique | |
| US3868416A (en) * | 1973-10-01 | 1975-02-25 | American Cyanamid Co | Hypolipidemic 4-(monoalkylamino)benzoic acid derivatives |
-
1977
- 1977-01-07 AU AU21140/77A patent/AU500881B2/en not_active Expired
- 1977-01-10 DK DK008177A patent/DK153471C/en not_active IP Right Cessation
- 1977-01-11 CA CA269,483A patent/CA1072969A/en not_active Expired
- 1977-01-17 GB GB1803/77A patent/GB1521458A/en not_active Expired
- 1977-01-17 JP JP384477A patent/JPS5289660A/en active Granted
- 1977-01-17 GB GB52242/77A patent/GB1521459A/en not_active Expired
- 1977-01-18 NL NL7700480A patent/NL7700480A/en active Search and Examination
- 1977-01-18 FR FR7701296A patent/FR2338040A1/en active Granted
- 1977-01-18 SE SE7700490A patent/SE435175B/en not_active IP Right Cessation
- 1977-01-18 NO NO770151A patent/NO145839C/en unknown
- 1977-01-19 BE BE174188A patent/BE850516A/en not_active IP Right Cessation
- 1977-01-19 CH CH65877A patent/CH628340A5/en not_active IP Right Cessation
- 1977-01-19 AT AT31277A patent/AT347923B/en not_active IP Right Cessation
- 1977-01-19 DE DE2702058A patent/DE2702058C2/en not_active Expired
- 1977-01-19 IE IE104/77A patent/IE44858B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| DK153471C (en) | 1988-11-21 |
| DE2702058A1 (en) | 1977-07-28 |
| NO145839C (en) | 1982-06-09 |
| DE2702058C2 (en) | 1985-09-19 |
| CH628340A5 (en) | 1982-02-26 |
| AT347923B (en) | 1979-01-25 |
| NL7700480A (en) | 1977-07-21 |
| NO145839B (en) | 1982-03-01 |
| SE7700490L (en) | 1977-07-20 |
| BE850516A (en) | 1977-07-19 |
| DK153471B (en) | 1988-07-18 |
| GB1521458A (en) | 1978-08-16 |
| FR2338040A1 (en) | 1977-08-12 |
| NO770151L (en) | 1977-07-20 |
| DK8177A (en) | 1977-07-20 |
| IE44858L (en) | 1977-07-19 |
| ATA31277A (en) | 1978-06-15 |
| SE435175B (en) | 1984-09-10 |
| GB1521459A (en) | 1978-08-16 |
| FR2338040B1 (en) | 1980-04-30 |
| JPS6233230B2 (en) | 1987-07-20 |
| AU500881B2 (en) | 1979-06-07 |
| AU2114077A (en) | 1978-07-13 |
| JPS5289660A (en) | 1977-07-27 |
| IE44858B1 (en) | 1982-04-21 |
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Legal Events
| Date | Code | Title | Description |
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| MKEX | Expiry |