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GB2107584A - Treatment of gastro-intestinal diseases - Google Patents

Treatment of gastro-intestinal diseases Download PDF

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GB2107584A
GB2107584A GB08131856A GB8131856A GB2107584A GB 2107584 A GB2107584 A GB 2107584A GB 08131856 A GB08131856 A GB 08131856A GB 8131856 A GB8131856 A GB 8131856A GB 2107584 A GB2107584 A GB 2107584A
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alkyl
amine
salt
amino
acid
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GB08131856A
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Hiroshi Wada
Masatoshi Kawamori
Hajime Tamaki
Yuichi Onoda
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Mitsubishi Tanabe Pharma Corp
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Tanabe Seiyaku Co Ltd
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Priority to GB08131856A priority Critical patent/GB2107584A/en
Priority to EP82305594A priority patent/EP0078152B1/en
Priority to DE8282305594T priority patent/DE3271037D1/en
Priority to IT49332/82A priority patent/IT1196554B/en
Priority to DK198204675A priority patent/DK172690B1/en
Priority to JP57185883A priority patent/JPS5877814A/en
Priority to GB08230027A priority patent/GB2114975B/en
Priority to DE19823239172 priority patent/DE3239172A1/en
Priority to FR8217722A priority patent/FR2515039A1/en
Publication of GB2107584A publication Critical patent/GB2107584A/en
Priority to US06/621,124 priority patent/US4529602A/en
Priority to JP62282659A priority patent/JPS63165361A/en
Priority to SG107/88A priority patent/SG10788G/en
Priority to HK415/88A priority patent/HK41588A/en
Priority to JP1273358A priority patent/JPH02167258A/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C301/00—Esters of sulfurous acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/28—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/57—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton
    • C07C309/58—Carboxylic acid groups or esters thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C323/58—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups with amino groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/22—Ortho- or ortho- and peri-condensed systems containing three rings containing only six-membered rings
    • C07C2603/26—Phenanthrenes; Hydrogenated phenanthrenes

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Abstract

A sulfodehydroabietic acid of the formula: <IMAGE> and a pharmaceutically acceptable salt thereof for use in the therapeutic treatment and/or prophylaxis of gastro-intestinal diseases are disclosed.

Description

SPECIFICATION Treatment of gastro-intestinal diseases This invention relates to sulfodehydroabietic acid of the formula:
or a pharmaceutically acceptable salt thereof for use in the therapeutic treatment and/or prophylaxis of gastro-intestinal diseases.
It is known that sulfodehydroabietic acid (I) (chemical name: 1 ,4a-dimethyl-1 -carboxy-6-sulfo- 7-isopropyl-1 ,2,3,4, 4a, 9, 10, 1 Oa-octahydrophenanthrene)is prepared by sulfonation of pseudopimaric acid, pyroabietic acid or dehydroabietic acid (U.S. Patent No. 2,121,032, J. Am Chem. Soc., Vol. 60, pp. 2340-2341(1938), ibid., Vol. 60, pp. 2631-2636 (1938) and ibid., Vol. 63, pp. 1838-1843 (1941)). It is also known that sodium and p-toluidine salts of sulfodehydroabietic acid are obtained by conventional neutralization of said abietic acid.
Moreover, U.S. Patent No. 2,121,032 discloses that sulfodehydroabietic acid (I) is useful as a detergent and wetting agent. However, no pharmacological activity of sulfodehydroabietic acid or its salts has been known up to now.
We have now found that sulfodehydroabietic acid (I) and its salts shows useful therapeutic effects on gastrointestinal diseases. That is, they have a potent anti-peptic ulcer activity and are useful for the therapeutic treatment and/or prophylaxis of peptic ulcer diseases or gastritis. For example, sulfodehydroabietic acid (I) and its salts show preventive effects against pepsin secretion, gastric acid secretion, pylorus-ligated ulcers, drug-induced ulcers and stress-induced ulcers. Therefore, the compounds of the present invention can be used for the treatment and/or prophylaxis of a wide variety of gastro-intestinal diseases including gastritis and acute or chronic peptic ulcer diseases (e.g., gastric ulcer and duodenal ulcer).Moreover, the compounds of the present invention show no substantial mineralo-corticoid- or aldosterone-like effect and can be used without unfavorable side effects such as hypokalaemia. For example, when a test compound was administered orally to rats, sulfodehydroabietic acid calcium salt at a dose of 50 or 500 mg/kg showed no substantial change in both the urine volume and urinary sodiumpotassium ratio. Further, the toxicity of the compounds of the present invention is remarkably low. For example, the 50% lethal dose (LD50) of sulfodehydroabietic acid calcium salt estimated by oral administration thereof to mice was more than 2,000 mg/kg.
Salts of sulfodehydroabietic acid (I) which can be used for therapeutic treatment or prophylaxis of the above-mentioned gastro-intestinal diseases include the salts thereof with any pharmaceutically acceptable cation-forming substance. Such salts include, for example, those of sulfodehydroabietic acid (I) with metals, metal hydroxides or amines, and said amines may be either primary, secondary, tertiary or quartenary amines such as alkylamines, dialkylamines, trialkylamines, alkylenediamines, cycloalkylamines, arylamines, aralkylamines, heterocyclic amines, a-amino acids, amino acids, peptides or quartenary amines derived therefrom.In addition, these alkylamines, alkylenediamines, cycloalkylamines, aryl or aralkylamines, heterocyclic amines, amino acids and so forth may be optionally substituted with a group or groups selected from hydroxy, alkoxy, carboxy, acyl, acyloxy, aminoalkyl, alkylamino, alkyl, guanidino, carbamoyl, methylthio, mercapto, dialkyl-sulfonium and halogen groups; and further the amino acids or peptides may be, if required, in the form or the corresponding acid am ides or esters.
More specifically, for example, the salts of sulfodehydroabietic acid with metals or metal hydroxides includes the salts thereof with alkali metals such as sodium, lithium or potassium; alkali earth metals such as magnesium, calcium or barium; aluminum or aluminum hydroxides such as aluminum monohydroxide ar aluminum dihydroxide; and the like.Suitable examples of the salts of sulfodehydroabietic acid with mono-, di-, or trialkylamines include the salts thereof with alkylamines such as methylamine, ethylamine, propylamine or isopropylamine; dialkylamines such as dimethylamine, diethylamine or di-n-propylamine; trialkylamines such as trimethylamine or triethylamine; dialkylamino-alkylamines such as 2-dimethylaminoethylamine or 2diethylaminopropylamine; alkoxy-alkylamines such as 2-methoxyethylamine or 3-ethoxy-n-propylamine; hydroxy-alkylamines such as ethanolamine, 3-hydroxy-n-propylamine and the like. The salts of sulfodehydroabietic acid with the alkylenediamines include, for example, the salts thereof with ethylenediamine, trimethylenediamine, tetramethylenediamine, pentamethylenedi amine, hexamethylenediamine and the like.The salts of sulfodehydroabietic acid with the cycloalkylamines include, for example, the salts thereof with cyclopropylamine, cyclobutylamine, cyclopentylamine, cyclohexylamine and the like. The salts of sulfodehydroabietic acid with the aralkyl amines include, for example, the salts thereof with benzylamine, phenethylamine, 4methoxyphenethylamine and the like. The salts of sulfodehydroabietic acid with the arylamines include, for example, the salts thereof with alkyl N-acyl-p-aminobenzoates such as ethyl Npiperidinoacetyl-p-aminobenzoate, ethyl N-prolyl-p-aminobenzoate, ethyl N-pipecolyl-p-aminobenzoate and the like.The salts of sulfodehydroabietic acid with the heterocyclic amines include, for example, the salts thereof with morpholine, piperazine, 3-(3,4-dihydroxy-phenyl)-8,8-dimethyl 1 ,8-diazoniaspiro[4. 5]decane, 1 -(2-d i methyl-aminoethyl)-4-phenyl-2-pyrrol idone, homocysteine thiolactone, 1-ethyl-2-aminomethyl-pyrrolidine.Moreover, representative examples of the a- or amino acids which can be used to form the salts with sulfodehydroabietic acid are shown by the formulae:
or NH2-B-CH2COR3 (II) wherein R' is hydrogen, amino, guanidino, carbamoyl, dimethylthionia, 4-imidazolyl, mercapto or methylthio, R2 is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkylamino or palkoxyanilino, R3 is hydroxy or alkoxy, A is single bond or straight or branched alkylene, and B is straight alkylene (said alkylene being optionally substituted with aryl).For example, said a- or amino acids to be used in the present invention include lysine, ornithine, arginine, asparagine, glutamine, methionine, histidine, ethyl cysteinate, ethyl asparaginate, ethyl glutaminate, asparagine amide, glutamine amide, asparagine methylamide, glutamine methylamide, asparagine isopropylamide, glutamine isopropylamide, asparagine octylamide, glutamine octylamide, glutamine di-n-propylamide, asparagine cyclohexylamide, glutamine cyclohexylamide, asparagine pmethoxyanilide, glutamine p-methoxyanilide, S-methylmethionine (i.e., 3-(S,S-dimethylthionia)-a- aminobutyric acid), 6-aminocaproic acid, methyl 4-amino-3-phenylbutylate, and the like.Furthermore, suitable examples of the peptides which can be used to form the salts of the invention include dipeptides such as carnosine, homocarnosine (i.e., N-y-aminobutyryl-histidine),anserin (i.e., N-P-alanyl-l-methylhistidine), balenin (i.e., n-P-alanyl-2-methylhistidine) and the like.
Of the above-mentioned various salts, all sulfodehydroabietic acid salts except the sodium and p-toluidine salts thereof are novel compounds. In addition, among such a wide variety of novel sulfodehydroabietic acid salts, preferred groups of compounds are the salts of sulfodehydroabietic acid with a metal selected from the group consisting of lithium, potassium, magnesium, calcium and aluminum; a metal hydroxide, selected from the group consisting of aluminum monohydroxide and aluminum dihydroxide; or an amine selected from the group consisting of alkyl (C, 5)amine, di-alkyl(C, 5)amine, tri-alkyl(Cl 5)amine, cycloalkyl(C3 6)amine, di-aikyl(C1 5)-am- ino-alkyl(C, 5)amine, alkoxy(C15)-alkyl(Cl 5)amine, hydroxy-alkyl (C1 5)amine, alkylene(C26)diam- ine, aralkyl(C78)amine, alkyl(C1 5) N-piperidinoacetyl-p-aminobenzoate, aIkyl(C1 5) N-prolyl-p-aminobenzoate, alkyl(C, 5) N-pipecolyl-p-aminobenzoate, morpholine, piperazine, 3-(3,4-dihydroxy phenyl)-8, 8-dimethyl- 1 , 8-diazoniaspiro [4.5] decane, 1 -(2-dimethyíaminoethyl)-4-phenyl-2-pyrro- lidone and homocysteine thiolactone. Other preferred amine salts include the salts of sulfodehydroabietic acid with an a-amino acid of the formula (II) in which R' is amino, guanidino, carbamoyl, dimethylthionia, 4-imidazolyl, mercapto or methylthio, R2 is hydroxy, alkoxy(1 5), amino, alkyl(C, 8)amino, di-aikyl(C, 5)amino, cycloalkyl(C36)-amino or p-alkoxy(C, 5)anilino and A is straight alkylene(C, 5);; a amino acid of the formula (III) in which R3 is hydroxy or alkoxy(C, 5) and B is straight alkylene(C1 5) (said alkylene being optionally substituted with phenyl); and carnosine.
Pharmaceutically acceptable salts of sulfodehydroabietic acid (I) can be readily obtained. For example, the metal salt of sulfodehydroabietic acid (I) may be prepared be neutralizing the compound (I) or its monohydrate with a metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, aluminum hydroxide), a metal carbonate (e.g., sodium carbonate, potassium carbonate, lithium carbonate) or a metal bicarbonate (e.g, sodium bicarbonate, potassium bicarbonate) in a solvent. Water, methanol, ethanol, tetrahydrofuran, dimethylsulfoxide, dimethylformamide or a mixture thereof are suitable as the solvent. It is preferred to carry out the neutralization reaction at a temperature of O to 50"C. The metal salt of sulfodehydroabietic acid (I) other than the sodium salt may be prepared by reacting sulfodehydroabietic acid sodium salt with a metal halide (e.g., calcium chloride, aluminum chloride), a metal sulfate (e.g., magnesium sulfate) or a metal nitrate (e.g., barium nitrate) in an aqueous solvent (e.g., water). Said reaction may be preferably carried out at a temperature of O to 50,C.
Alternatively, the metal salts such as calcium and magnesium salts may be prepared by reacting sulfodehydroabietic acid silver salt with a metal halide (e.g., calcium chloride, magnesium chloride) in an aqueous solvent (e.g., water). It is preferred to carry out the reaction at a temperature of 0 to 50"C.
On the other hand, the aluminum hydroxide salt of sulfodehydroabietic acid (I) may be prepared by reacting the compound (I) or its monohydrate with aluminum alkoxide (e.g., aluminum methoxide, aluminum ethoxide, aluminum isopropoxide) in the presence of water in a solvent. Methanol, ethanol, isopropanol and dimethylsulfoxide are suitable as the solvent. This reaction may be preferably carried out at a temperature of 0 to 60"C.
Further, the salts of sulfodehydroabietic acid (I) with the amine may also be prepared in the same manner as described above, i.e. by neutralizing the compound (I) or its monohydrate with the amine in a solvent, or by reacting sulfodehydroabietic acid silver salt with a hydrohalide (e.g., hydrochloride) or quartenary salt of the amine in a solvent. Water, methanol, ethanol and the like are suitable as the solvent for the neutralization reaction. It is preferred to carry out the neutralization reaction at a temperature of 0 to 50"C. On the other hand, water is suitable as the solvent for the reaction of sulfodehydroabietic acid with the hydrohalide or quartenary salt of the amine, and said reaction may be preferably carried out at a temperature of 0 to 50"C.
Sulfodehydroabietic acid and a salt thereof can preferably be administered orally in a solid dosage form such as tablets, capsules, powders or granules, or in a liquid dosage form such as solutions or suspensions. In order to prepare pharmaceutical preparations suitable for oral administration, the active ingredient is worked up with pharmaceutical adjuvants or excipients.
Suitable adjuvants for the solid dosage form such as tablets or capsules include, for example, binders (e.g., acacia, gelatin, dextrin, hydroxypropyl cellulose, methyl cellulose, polyvinylpyrrolidone), diluents (e.g., lactose, sucrose, mannitol, corn starch, potato starch, calcium phosphate, calcium citrate, crystalline cellulose), lubricants (e.g., magnesium stearate, calcium-stearate, stearic acid, talc, anhydrous silicic acid), disintegrants (e.g., corn starch, potato starch, carboxymethyl cellulose and its calcium salt, alginic acid), wetting agents (e.g., sodium lauryl sulfate) and so forth.On the other hand, suitable adjuvants for the liquid dosage form such as solutions or suspensions include, for example, liquid vehicles (e.g., water), suspending agents (e.g., acacia, gelatin, methyl cellulose, sodium carboxymethyl cellulose, hydrorymethyl cellulose, aluminum stearate gel), surfactants (e.g., lecithin, sorbitan monooleate, glycerin monostearate), nonaqueous vehicles (e.g., glycerin, propylene glycol, vegitable oil) and so forth. The liquid dosage form may further contain preservatives (e.g., methyl p-hydroxybenzoate, propyl phydroxy benzoate), flavoring agents and/or coloring agents.
The therapeutic dose of sulfodehydroabietic acid (I) or its salt will of course vary with the conditions of diseases to be treated and its severity. In general, however, it may be used as a dose of about 20 to about 300mg/kg, more especially about 40 to about 120mg, per kilogram of body weight per day.
As mentioned hereinbefore, sulfodehydroabietic acid (I) or its salt shows potent anti-ulcer activity without aldosterone-like side effect and is useful for the treatment or prophylaxis of gastro-intestinal diseases such as peptic ulcer diseases and gastritis. The term "peptic ulcer disease" has historically been used to describe the diseases characterized by ulceration of the upper gastro-intestinal tract and include the disease characterized by ulceration of the body of the stomach, commonly called gastric ulcers as well as the diseases characterized by ulceration of the duodenum, commonly called duodenal ulcers. Accordingly, the term "peptic ulcer disease" used throughout the specification and claims should be interpreted to include both of the above-mentioned gastric ulcers and duodenal ulcers.
The following Experiments and Examples are merely for illustrative purposes and are not to be construed as limitation of the present invention.
Experiment 1 [Preventive effect on acid and pepsin secretions] (Method) Male SD-strain rats (6 to 7 weeks old) were starved for 48 hours, and then the pylori were ligated. Immediately after ligation, the solution of a test compound in distilled water was administered orally into the stomachs in an amount of 0.2ml per 1009 of body weight (Dose: 100mg/kg). Five hours after said administration of the test compound, the rats were sacrificed and the stomachs were removed. The gastric contents were centrifuged at 2,500 rpm for 10 minutes and the gastric juice was collected as the supernatant. The concentration of pepsin in the gastric juice was determined by Anson's method (c.f., J. Gen.Physiol., 22, pp. 77-89 (1938)) using hemoglobin as the substrate, and the preventive effect of the test compound on the pepsin secretion was estimated in terms of "decrease in pepsin output" according to the following formula:
Average value of pepsin concentration in gastric juice of medicated rats Decrease (%) = 1 x X 100 in pepsin Average value of pepsin concentration concentration in gastric juice of non-medicated rats On the other hand, the concentration of free acid in the gastric juice was determined by titrating said gastric juice with 0.1 N NaOH using Methyl Yellow as the indicator, and the preventive effect of the test compound on the gastric acid secretion was estimated in terms of "the decrease in acidity of gastric juice" according to the following formula:
Free acid concentration in gastric juice of medicated Decrease (%) rats in acidity of = 1 x ~~~~~~~~~~~~~~~~~~~ X 100 gastric juice Free acid concentration in gastric juice of non medicated rats (Results) The results are shown in the following Tables 1 s 2.
Table 1 Salts of sulfodehydro- Decrease (%) in pepsin Nos. abietic acid used concentration 1. Sodium salt 92 2. Calcium salt 99 3. 2/3 Aluminum salt 95 4. 2 Aluminum dihydroxide salt 69 5. Aluminum monohydroxide salt 91 6. 2 (2-Dimethylaminoethyl)amine salt 92 7. 2 Cyclohexylamine salt 71 8. 2 Isopropylamine salt 95 9. 2 Morpholine salt 92 10. 2 (2-Methoxyethyl)amine salt 98 11. Tetramethylenediamine salt 84 12. Ethylenediamine salt 94 13. Hexamethylenediamine salt 94 14. Arginine salt 77 1 5. Glutamine salt 90 16. Asparaginesalt 90 17. Lysine salt 94 18. Carnosine salt 72 19. S-Methylmethionine salt 84 Table 2 Salts of sulfodehydro- Decrease (%) in Nos. abietic acid used acidity of gastric juice 1. 2 Sodium salt 54 2. Calcium salt 30 3. 2 (2-Dimethylaminoethyl)amine salt 31 4. 2 Isopropylamine salt 40 5. Tetramethylenediamine salt 36 6.Hexamethylenediamine salt 32 7. Glutamine salt 39 8. Asparagine salt 38 Experiment 2 [Effect on Shay rat ulcers] (Method) Male SD-strain rats (6 to 7 weeks old) were starved for 48 hours and then the pylori were ligated. Immediately after ligation, the solution of a test compound in distilled water was administered orally into the stomachs in an amount of 0.5ml per 1009 of body weight (Dose: 300mg/kg). Seventeen hours after the administration of the test compound, the degree of ulceration in forestomach was examined according to the method of Takagi et al (Chem. Pharm.
Bull., 11(10), pp. 1282-1290 (1963)) with a modified scoring system. Depending on the diameter of each lesions, the ulcers were classified into the following 4 grades.
Ulcer score Ulcer with diameter less than 1 mum 1 point Ulcer with diameter of 1 -3mm 3 points Ulcer with diameter of 3-5 mm 5 points Ulcer with diameter over 5mm or perforation : 10 points Ulcer index was calculated by the sum of the number of ulcers in each degree multiplied by respective ulcer score.
Further, based on the ulcer index determined above, the preventive effect of the test compound on Shay rat ulcer was calculated by the following formula:
The average value of ulcer Preventive indexes in medicated rates effect on = 1 The ~~~~~~~~~~~~~~~~~~~ X 100 Shay rat The average value of ulcer ulcers (%) indexes in non-medicated rats (Results) The results are shown in the following Table 3.
Table 3 Preventive effect on Test compounds Shay rat ulcers (%) (The compound of the present invention) Sulfodehydroabietic acid calcium salt 100 (Positive control) Carbenoxolone disodium salt 40 Experiment 3 [Effect on stress-induced ulcers] (Method) Male ddY-strain mice (4 weeks old) weighing about 20g were starved for about 7 hours. A solution of a test compound in distilled water was administered orally to the mice in an amount of 0.1 ml per 1 0g of body weight (Dose: 100mg/kg). Immediately after administration of the test compound, the mice were placed in a stress cage and immersed to the level of the cervix in a water bath (24 + 0.5"C) for 16 hours.Then, the stomach was removed and slightly inflated by injecting 1.2ml of a 1% formalin solution to fix the inner layers of the gastric walls. The stomach was then incised along the greater carvature, and the number of ulceration was examined.
(Results) Sulfodehydroabietic acid disodium salt showed 22% decrease in the number of stress-induced ulcers.
Experiment 4 [Effect on aspirin-induced ulcers] (Method) Male Donryu-strain rats (8 to 9 weeks old) were starved overnight, and a solution or suspension of a test compound in distilled water was administered orally into the stomachs in an amount of one ml per 1009 of body weight. Half an hour later, a suspension of aspirin in 0.25% CMC solution was administered orally to the rats in an amount of 0.5ml per 1009 of body weight (Dose: 200mg/kg). Four hours after the administration of aspirin, the rats were sacrificed and the stomachs were removed and inflated by injecting 1 0ml of 1 % formalin solution to fix the inner layers of the gastric walls. The stomach was then incised along the greater curvature and the lengths of the lesions were measured and summated to give ulcer index (in mm) for each animal.The preventive effect of the test compound on aspirin-induced ulcers were calculated by the following formula:
The average value of ulcer indexes in medicated rats Preventive effect = 1 - X 100 on aspirin-induced The average value ulcers (%) Onfonulcm%cInicda?exSri9s (Results) The results are shown in the following Table 4.
Table 4 Preventive effect on aspirin-induced Test compounds Dose (p.o.) ulcers (%) Sulfodehydroabietic acid 2m mol./kg 33 carnosine salt (1,248mg/kg) Sulfodehydroabietic acid 2m mol./kg 85 S-methylmethionine salt (1 (1,086mg/kg) Sulfodehydroabietic acid 2m mol./kg 82 disodium salt ( 847mg/kg) Experiment 5 Effect on urine volume and urinary electrolytes (Method) Male SD-strain rats (6 to 7 weeks old) were starved overnight, and a physiological saline solution (3ml/1 00g of body weight) was orally administered to the rats. One hour later, a solution or suspension of a test compound in a 0.25 % CMC-physiological saline solution was administered orally to the rats in an amount of 3ml per 1009 of body weight (Dose: 50 and 500mg/kg).Immediately after administration of the test compound, the rats were placed into metabolie cage (2 rats per cage) and deprived of water and food for 5 hours. The urine samples which were excreted during a 5 hour period were collected. Sodium and potassium in the urine was estimated by a flame photometer (Hitachi Model-205).
(Results) The results are shown in the following Table 5.
Table 5 Dose Urine volume Test compounds (mg/kg) (ml) Na/K (The test compound of the present invention) Sulfodehydroabietic acid 50 11.5 5.2 calcium salt 500 11.3 6.8 Carbenoxolone disodium salt 50 9.3 3.2 Control - 12.3 5.8 Carbenoxolone (chemical name: 3-fl-hydroxy-1 1-oxoolean-1 2-en-30-oic acid hydrogen succinate) disodium salt is known to protect animals from experimentally-induced gastric ulceration and in human gastric ulcer patients has been shown in numerous clinical trials to be an effective gastric anti-ulcer agent. However, carbenoxolone disodium salt has a side effect such as an aldosternone-like effect. As can be seen from Table 5, the compound of the present invention is quite free from such side effect.
Experiment 6 [Effect on urinary electrolytes] (Method) Male SD-strain rats (6 to 7 weeks old, one group: 5-8 rats) were starved overnight, and a physiological saline solution (3ml/100g of body weight) was orally administered to the rats.
One hour later, a solution or suspension of a test compound in a 0.25 % CMC-physiological saline solution was administered orally to the rats in an amount of 3ml per 1009 of body weight (Dose: 50, 500 or 1,000mg/kg). Immediately after administration of the test compound, the rats were placed into metabolic cage (one rat per cage) and deprived of water and food for 4 hours. The urine samples which were excreted during a 4 hour period were collected. Sodium and potassium in the urine was estimated by a flame photometer (Hitachi Model-205).
(Results) The results are shown in the following Table 6.
Table 6 Dose Urine volume Na/k Test compound mg/kg p.o. (ml) ratio Sulfodehydroabietic 500 4.8 + 0.4 7.4 i 1.0 acid disodium salt 1000 4.3 + 0.3 5.9 + 0.4 Carbenoxolone disodium salt 50 5.2 + 0.3 3.7 + 0.3" Control 5.7*0.6 6.1*0.3 ""= significant difference from control (p < 0.01) Experiment 7 After male ddY-strain mice (4 weeks old) were starved for 4 hours, a solution or suspension of a test compound in distilled water containing a small amount of Tween 80 was administered orally to the mice in an amount of 0.1 ml per 1 0g of body weight. After administration of the test compound, the mice were allowed free access to water and food. The mortality of the mice was observed for 7 days and the 50% lethal dose (LDso) was calculated therefrom. As a result, the LD50 of sulfodehydroabietic acid calcium salt was more than 2,000 mg/kg.
Example 1 1.369 of sulfodehydroabietic acid monohydrate (chemical name: 1 ,4a-dimethyl-1 -carboxy-6- sulfo-7-isopropyl-1 ,2,3,4,4a,9, 10,1 Oa-octahydro-phenanthrene monohydrorate) are dissolved in 1 Oml of ethanol, and a solution of 288mg of lithium hydroxide monohydrate in 3ml of water is added thereto under cooling. 100ml of acetone are added to the mixture, and the precipitates are collected therefrom. 1.49 of sulfodehydroabietic acid dilithium salt (i.e., 1 ,4a-dimethyl-1 - carboxy-6-sulfo-7-isopropyl- 1 ,2,3, 4,4a, 9,1 0,1 Oa-octahydro-phenanthrene dilithium salt) monohydrate are obtained.
M.p. > 300"C (decomp.) IR # max nujol (cm-): 3430, 1540, 1400, 1160 Example 2 1.369 of sulfodehydroabietic acid monohydrate and 0.3839 of potassium hydroxide are treated in the same manner as described in Example 1, whereby 1.39 of sulfodehydroabietic acid dipotassium salt monohydrate are obtained.
M.p. > 300"C IR # max nujol (cam-): 3500-3200 (broad), 1530, 1190 Example 3 639 of sulfodehydroabietic acid monohydrate and 12.69 of sodium hydroxide are treated in the same manner as described in Example 1, whereby 52.79 of sulfodehydroabietic acid disodium salt monohydrate are obtained M.p. > 300 C (decomp.) IR muajol (cm-'): 3450, 1550, 1400, 1210, 1160, 1095, 1030 Example 4 1.369 of sulfodehydroabietic acid disodium salt are dissolved in 6ml of water, and a 50% aqueous calcium chloride solution are dropwised thereto untill precipitation occures. 2ml of ethanol are added to the mixture, and the precipitates are collected therefrom.The precipitates are washed with water and with ethanol, and then dried. 1.59 of sulfodehydroabietic acid calcium salt 3/2 hydrate are obtained.
M.p. > 300"C (decomp.) IR nmuaixo.I(cmi): 3550,3350, 1640, 1400, 1230, 1180 Example 5 1.369 of sulfodehydroabietic acid disodium salt and a 50% aqueous magnesium sulfate solution are treated in the same manner as described in Example 4, whereby 1.39 of sulfodehydroabietic acid magnesium salt monohydrate are obtained.
M.p. > 300 C (decomp.) IR # max nujol (cm-): 3430, 1510, 1390, 1160 Example 6 1.329 of sulfodehydroabietic acid disodium salt and 0.2ml of 50% aqueous aluminum chloride solution are treated in the same manner as described in Example 4, whereby 1.09 of sulfodehydroabietic acid 2/3 aluminum salt 7/3 hydrate is obtained.
M.p. > 300 C IR ( nuajol (cm-'): 3500-3100 (br), 1600, 1440, 1200, 1150, 1030 Example 7 A solution of 1 .62g of aluminum isopropoxide in 12ml of ethanol and 0.2889 of water are added to 10ml of an ethanol solution containing 1.529 of sulfodehydroabietic acid monohydrate, and the mixture is concentrated under reduced pressure to dryness. 1.719 of sulfodehydroabietic acid di(aluminum dihydroxide) salt dihydrate are obtained as colorless crystalline powder.
M.p. > 300 C (decomp.) IR # max nujol (cm-): 3400 (br), 1570, 1440, 1200, 1160, 1100, 1050, 1030 Example 8 1 .36g of sulfodehydroabietic acid monohydrate are dissolved in 1 0ml of methanol, and 404mg of isopropylamine are added thereto. The mixture is evaporated under reduced pressure to remove the solvent. The residue is recrystallized from methanol, whereby 1.49 of sulfodehydroabietic acid with di(isopropylamine) salt are obtained as needles.
M.p. > 300 C (decomp.) IR # max nujol(cm-): 2750-2500, 1610, 1520, 1380, 1190, 1160, 1020 Example 9 1 .3g of sulfodehydroabietic acid monohydrate and 0.29 of cyclohexylamine are treated in the same manner as described in Example 8, whereby O.9g of sulfodehydroabietic acid di(cyclohexylamine) salt is obtained as needles.
M.p. > 300 C (recrystallized from methanol) IR # max. nujol (cm-): 2800-2400, 1625, 1510, 1370 1210, 1135, 1020 Example 10 1 .3g of sulfodehydroabietic acid monohydrate and 0.369 of 2-dimethylaminoethylamine are treated in the same manner as described in Example 8, whereby 0.8g of sulfodehydroabietic acid di(2-dimethylaminoethylamine)salt monohydrate is obtained as needles.
M.p. 240-242 'C (decomp.) (recrystallized from ethanol-tetrahydrofuran) IR mflU,xOI (cm-'): 3500-3050, 2780-2300, 1620, 1520, 1190, 1180, 1150, 1020 Example ii 1 .3g of sulfodehydroabietic acid monohydrate and 0.29 of morpholine are treated in the same manner as described in Example 8, whereby 1 .24g of sulfodehydroabietic acid dimorpholine salt hemihydrate are obtained as needles.
M.p. 288-290'C (decomp.) (recrystallized from methanol-acetone) |R # max. nujol (cm-1): 3600-3300, 2750-2500, 1630, 1360, 1180, 1140, 1100, 1030 Example 12 1.39 of sulfodehydroabietic acid monohydrate and 0.3539 of piperazine are treated in the same manner as described in Example 8, whereby 0.829 of sulfodehydroabietic acid piperazine salt hemihydrate is obtained as needles.
M.p. > 300"C (decomp.) IR # max nujol(cm-): 3450,2750-2500, 1630, 1180, 1095, 1035 Example 13 1.39 of sulfodehydroabietic acid monohydrate and 0.6169 of 2-methoxyethylamine are treated in the same manner as described in Example 8, whereby 0.98g of sulfodehydroabietic acid di(2-methoxyethylamine) salt is obtained as needles.
M.p. 275--277 C (recrystallized from methanol-ethyl acetate) IR &gamma; max nujol (cm-): 3400-3050,2750-2150, Y 1630, 1520, 1160, 1115, 1030 Example 14 1.39 of sulfodehydroabietic acid monohydrate and 0.9949 of phenethylamine are treated in the same manner as described in Example 8, whereby 1.429 of sulfodehydroabietic acid di(phenethylamine) salt are obtained as needles.
M.p. 281-284'C (decomp.) (recrystallized from methanol) IR t malx ' (cm-1): 3400-3000, 2300-2100, 1630, 1480, 1360, 1190, 1170, 1030 Example 16 1.39 of sulfodehydroabietic acid monohydrate and 0.2989 of tetramethylenediamine are treated in the same manner as described in Example 8, whereby 1.069 of sulfodehydroabietic acid tetramethylenediamine salt hemihydrate are obtained.
M.p. 284-287 'C (decomp.) (recrystallized from methanol-aqueous tetrahydrofuran) IR # max. nujol (cm-): 3550-3400, 2800-2100, 1610, 1500, 1360, 1160, 1025 Example 17 1.39 sulfodehydroabietic acid monohydrate and 0.49 of hexamethylenediamine are treated in the same manner as described in Example 8, whereby 0.779 of sulfodehydroabietic acid hexamethylenediamine salt hemihydrate is obtained.
M.p. 290 C (decomp.) (recrystallized from water-acetone) IR ( 3 ' (cm-'): 3530, 3490, 2750-2300, 1615, 1510, 1375, 1190, 1160, 1020 Example 18 2.69 of sulfodehydroabietic acid monohydrate are dissolved in 20ml of methanol, and a solution of 0.949 of L-lysine in 1 0ml of water is added thereto. The mixture is concentrated under reduced pressure to dryness. The residue is recrystallized from a mixture of methanol and water, whereby 39 of sulfodehydroabietic acid L-lysine salt monohydrate are obtained as crystalline solid.
M.p. 236 C (decomp.) lRmnujxo(cml): 3400, 1680, 1590, 1165 Example 19 1.39 of sulfodehydroabietic acid monohydrate and 0.459 of L-ornithine are treated in the same manner as described in Example 18, whereby 1.49 of sulfodehydroabietic acid L-ornithine salt monohydrate are obtained crystalline solid.
M.p. 213-215'C (recrystallized from methanol IR # max nujol (cm-'): 3400, 3160-3100, 2750-2200, 1700, 1650, 1190, 1150 Example 20 2.859 of sulfodehydroabietic acid monohydrate and 1.759 of L-arginine acetate are treated in the same manner as described in Example 18, whereby 2.99 of sulfodehydroabietic acid Larginine salt hemihydrate are obtained as colorless prisms.
M.p. 230 C (recrystallized from methanol-water) IR # max. nujol(cm-): 3350, 3200, 3100, 1680-1630 (br), 1180 Example 21 1.39 of sulfodehydroabietic acid monohydrate and 0.5139 of L-asparagine are treated in the same manner as described in Example 18, whereby 1.59 of sulfodehydroabietic acid Lasparagine salt monohydrate are obtained as crystalline solid.
M.p. > 300 C (decomp.) (recrystallized from water) IR # max nujol (cm-1): 3400-3200, 2750-2300, 1740, 1680, 1270, 1170 Example 22 1.39 of sulfodehydroabietic acid monohydrate and 0.59 of L-glutamine are treated in the same manner as described in Example 18, whereby 1.19 of sulfodehydroabietic acid Lglutamine salt hemihydrate are obtained as crystallin solid.
M.p. > 240 C (recrystallized from methanol-acetone) IR # max nujol (cm-): 3400-3100, 2750-2300, 1750, 1690, 1670, 1590, 1240, 1200, 1170, 1140 Example 23 1.39 of sulfodehydroabietic acid monohydrate and 0.519 of L-methionine are treated in the same manner as described in Example 18, whereby 1.49 of sulfodehydroabietic acid Lmethionine salt are obtained as crystalline solid.
M.p. 250-252 C (decomp.) (recrystallized from methanol-ethyl acetate) IR , nUaix' (cm-'): 3450-3050, 2800-2300, 1750, 1690, 1280, 1200, 1190, 1160 Example 24 1.39 of sulfodehydroabietic acid monohydrate and 0.649 of L-histidine are treated in the same manner as described in Example 18, whereby 1.09 of sulfodehydroabietic said L-histidine salt monohydrate is obtained as crystalline solid.
M.p. 225 C (decomp.) (recrystallized from methanol-water) IR i muaiol (cm-1): 3400-3100, 2750-2300, 1690, 1610, 1160 Example 25 1.39 of sulfodehydroabietic acid are dissolved in 15ml of ethanol, and 0.472mg of silver carbonate and 20ml of water are added thereto. 0.6359 of ethyl L-cysteinate hydrochloride are added to the mixture, and said mixture is stirred at room temperature. The precipitates are filtered off, and the filtrate is concentrated to dryness under reduced pressure. The residue is recrystallized from a mixture of methanol and ethyl acetate, whereby 1.59 of sulfodehydroabietic acid ethyl L-cysteinate salt hemihydrate are obtained.
M.p. 239-241 C (decomp.) IR # max nujol (cm-): 3400-3100, 2750-2400, 1750, 1690, 1210, 1150, 1030 Example 26 1.39 of sulfdoehydroabietic acid, 0.4729 of silver carbonate and 0.6729 of ethyl Lasparaginate hydrochloride are treated in the same manner as described in Example 25, whereby O.9g of salt of sulfodehydroabietic acid ethyl L-asparaginate salt is obtained.
M.p. > 260 C (decomp.) (recrystallized from ethanol-ethyl acetate) IR mflUaxO (cm-'): 3450, 3300, 3200, 2800-2400, 1760, 1710, 8690, 1610, 1250, 1190, 1160 Example 27 1.319 of sulfodehydroabietic acid, 0.4729 of silver carbonate and 0.939 of ethyl Lglutaminate hydrochloride are treated in the same manner as described in Example 25, whereby 0.89 of sulfodehydroabietic acid ethyl L-glutaminate salt monohydrate is obtained.
M.p. > 254 C (decomp.) (recrystallized from water-ethanol) IR t mux (cm-'): 3500-3050, 2750-2300, 1740, 1690-1640, 1200, 1180, 1160, 1140 Example 28 1.39 of sulfodehydroabietic acid, 0.4729 of silver carbonate and 0.5269 of L-homocysteine thiolactone hydrochloride are treated in the same manner as described in Example 25, whereby 1.49 of sulfodehydroabietic acid L-homocysteine thiolactone salt are obtained.
M.p. 289-291 C (decomp.) (recrystallized from methanol-ethyl acetate) IR # max nujol(cm-): 3400, 3150, 2750-2400, 1710, 1505, 1185, 1150, 1030 Example 29 1.39 of sulfodehydroabietic acid, 0.59 of silver carbonate and 0.5739 of L-asparagine amide hydrochloride are treated in the same manner as described in Example 25, whereby 0.99 of sulfodehydroabietic acid L-asparagine amide salt is obtained.
M.p. > 300 C (decomp.) (recrystallized from ethanol) IR mnuaixoI(cml): 3400-3200,2750-2300, 1690 1650, 1605, 1195, 1155 Example 30 1.39 of sulfodehydroabietic acid, 0.59 of silver carbonate and 0.6219 of L-glutamine amide hydrochloride are treated in the same manner as described in Example 25, whereby 1.149 of sulfodehydroabietic acid L-glutamine amide salt hemihydrate are obtained.
M.p. > 300 'C (decomp.) (recrystallized from methanol-ethyl acetate) IR t muaix ' (cm-'): 3370, 3200, 2800-2300, 1690, 1650, 1530, 1200, 1165, 1100 Example 31 1.529 of sulfodehydroabietic acid monohydrate are dissolved in 5ml of methanol, and a solution of 0.9079 of L-glutamine cyclohexylamide in 20ml of methanol is added thereto. The mixture is concentrated under reduced pressure to remove solvent until the volume of said mixture is 5ml. Ether is added to the residue and the precipitates (white crystalline) are collected therefrom. 1.359 of sulfodehydroabietic acid L-glutamine cyclohexylamide salt are thereby obtained.
M.p. > 190 C (decomp.) IR muaix ' (cm-'): 3400, 3210, 3070, 2750-2300, 1695, 1670, 1650, 1570, 1255 1180, 1160 Example 32 1.149 of sulfodehydroabietic acid monohydrate and 0.4359 of L-asparagine methylamide are treated in the same manner as described in Example 31, whereby 1.39 of sulfodehydroabietic acid L-asparagine methylamide salt are obtained.
M.p. 240"C (decomp.) (recrystallized from ethanol-ether) IR mfluaxoi (cm - '): 3430-3050, 2750-2300, 1710, 1680, 1655, 1560, 1180, 1170, 1140 Example 33 1.149 of sulfodehydroabietic acid monohydrate and 0.739 of L-asparagine n-octylamide are treated in the same manner as described in Example 31, whereby 1.29 of sulfodehydroabietic acid L-asparagine n-octylamide salt hemihydrate are obtained as crystalline powder.
M.p. 87"C (decomp.) IR muajxol (cm-'): 3400-3100, 2750-2300, 1700, 1680, 1655, 1620, 1560, 1180, 1160, 1140 Example 34 1.149 of sulfodehydroabietic acid monohydrate and 0.5259 of L-asparagine isopropylamide are treated in the same manner as described in Example 31, whereby 1.429 of sulfodehydroabietic acid L-asparagine isopropylamide salt are obtained.
M.p. 141 "C (decomp.) (recrystallized from ethanol-acetone) Example 35 1.1419 of sulfodehydroabietic acid monohydrate and 0.6399 of L-asparagine cyclohexylamide are treated in the same manner as described in Example 31, whereby 1.49 of sulfodehydroabietic acid L-asparagine cyclohexylamide salt monohydrate are obtained.
M.p. 228 "C (decomp.) (recrystallized from ethanol-acetone) IRd I (cm-'): 3430-3100, 2800-2300, 1690, 1680, 1660, 1620, 1560, 1215, 1160, 1140 Example 36 1.129 sulfodehydroabietic acid monohydrate and 0.79 of L-asparagine p-methoxyanilide are treated in the same manner as described in Example 31, whereby 1.49 of sulfodehydroabietic acid L-asparagine p-methoxyanilide salt hemihydrate are obtained as powder.
M.p. > 170"C (decomp.) IR d mflUaJOI (cm-'): 3450-3050, 2750-2300, 1690, 1655, 1620, 1610, 1550, 1510, 1240, 1170, Example 37 1.149 of sulfodehydroabietic acid monohydrate and 0.7719 of L-glutamine n-octylamide are treated in the same manner as described in Example 31, whereby 1.429 of sulfodehydroabietic acid L-glutamine n-octylamide salt monohydrate are obtained.
M.p. 141 "C IR mnuLo.I(cml): 3450-3100, 2750-2250, 1690, 1660, 1570, 1510, 1200, 1180, 1130 Example 38 1.149 of sulfodehydroabietic acid monohydrate and 0.5679 of L-glutamine isopropylamide are treated in the same manner as described in Example 31, whereby 1.629 of sulfodehydroabietic acid L-glutamine isopropylamide salt hemihydrate are obtained.
M.p. > 190"C (decomp.) (recrystallized from ethanol-acetone) IR # max. nujol (cm-): 3500-3050, 2750-2300, 1700, 1670, 1610, 1550, 1520, 1255, 1210, 1160, 1140, 1100 Example 39 1.049 of sulfodehydroabietic acid monohydrate and 0.639 of L-glutamine di-n-propylamide are treated in the same manner as described in Example 31, whereby 0.69 of sulfodehydroabietic acid L-glutamine di-n-propylamide salt monohydrate is obtained.
M.p. > 139"C (decomp.) (recrystallized from methanol-ether) IRfi nnUa (cm-'): 3400-3100, 2750-2300, 1700, 1660. 1240, 1200, 1160 Example 40 11.69 of S-methyl-L-methionine iodide are dissolved in 50ml of water, and the solution is passed through a column packed with 100ml of a weekly basic ion exchange resin (manufactured by Rohm 8 Hass Co. under the trade name "Amberlite IR 45"). Then, the column is washed with about 200ml of water. The effluent and washings are combined, and a solution of 15.29 of sulfodehydroabietic acid monohydrate in 150ml of methanol is added to the combined solution. The mixture is concentrated to dryness at a temperature below 50"C under reduced pressure.The residue in dissolved in 200ml of a 50 % aqueous ethanol solution, and 800ml of acetone are added thereto. The mixture is allowed to stand at room temperature. The precipitates are collected, whereby 189 of sulfodehydroabietic acid S-methyl-L-methionine salt dihydrate are obtained as crystals.
M.p. 268 C (decomp.) IR # max (cm-): 3460, 3340, 1695, 1680, 1630, 1520, 1230, 1210, 1170, 1140, 1035 Example 41 1.539 of sulfodehydroabietic acid monohydrate are suspended in 17.6ml of water, and a solution of 0.859 of carnosine in 3.3ml of water is added thereto under stirring. The mixture is heated to make a solution, and the hot solution is filtered with charcol. The filtrate is allowed to stand at room temperature, whereby 2.29 of sulfodehydroabietic acid carnosine salt monohydrate are obtained as needles.
M.p. 190-224 C (decomp.) IRa nlUa ' (cm-'): 3600-3100, 2800-2300, 1700, 1660, 1630, 1230, 1200, 1170 Example 42 1.39 of sulfodehydroabietic acid monohydrate and 0.4489 of 6-aminocaproic acid are treated in the same manner as described in Example 18, whereby 1.19 of sulfodehydroabietic acid 6aminocaproic acid salt are obtained.
M.p. 220-222 "C (decomp.) (recrystallized from methanol-water) IR ( nquaxOl (cm-'): 3300, 3070, 2750-2300, 1710, 1670, 1210, 1160 Example 43 1.149 of sulfodehydroabietic acid monohydrate and 0.879 of ethyl N-piperidinoacetyl-paminobenzoate are treated in the same manner as described in Example 8, whereby 1.49 of the salt(monohydrate) of sulfodehydroabietic acid with ethyl N-piperidinoacetyl-p-aminobenzoate are obtained.
M.p. 171 "C (recrystallized from ethanol-water) IR # max nujol (cm-1): 3500-3080, 2750-2300, 1700, 1680, 1605, 1550, 1280, 1210, 1150, 1115 Example 44 1.39 of sulfodehydroabietic acid monohydrate and 0.8629 of ethyl N-L-prolyl-p-aminobenzoate are treated in the same manner as described in Example 8, whereby 1.19 of the salt of sulfodehydroabietic acid with ethyl N-L-prolyl-p-aminobenzoate are obtained.
M.p. 273-275 C (recrystallized from methanol) IR # nujol (cm-) 3430, 3300-3100, 1715-1705, 1605, 1550, 1280, 1210, 1180, 1150 Example 45 1.29 of sulfodehydroabietic acid monohydrate and 0.839 of ethyl N-pipecolyl-p-aminobenzoate are treated in the same manner as described in Example 8, whereby 0.89 of the salt (monohydrate) of sulfodehydroabietic acid with ethyl N-pipecolyl-p-aminobenzoate is obtained.
M.p. 230 C (decomp.) (recrystallized from ethanol-ether) IR mflUaxOI (cm-'): 3430-3050, 2750-2300, 1700, 1675, 1600, 1545, 1270, 1200, 1180, 1150, 1100 Example 46 1.149 of sulfodehydroabietic acid monohydrate, 0.49 of silver carbonate and 0.669 of 3-(3,5dihydroxyphenyl)-8,8-dimethyl-1,8-diazaspiro [4,5] decane dibromide are treated in the same manner as described in Example 25, whereby 0.89 of the salt of sulfodehydroabietic acid with 1/2 3-(3,4-dihydroxyphenyl)-8,8-dimethyl-1 ,8-diazaspiro [4,5] decane is obtained as crystalline powder.
M.p. 265 C (recrystallized from methonol-ethyl acetate) IR mUaOI (cm-1): 3500-3200, 1700, 1600, 1520, 1250, 1200, 1150, 1130, 1030, Example 47 1.149 of sulfodehydroabietic acid monohydrate, 0.79 of 1-(2-dimethylaminoethyl)-4-phenyl-2pyrrolidone are treated in the same manner as described in Example 8, whereby 1.309 of the salt of sulfodehydroabietic acid with 1-(2-dimethylaminoethyl)-4-phenyl-2-pyrrolidone are obtained.
M.p. 216-21 8"C (decomp.) (recrystallized from ethanol-ether) 185 flmUJ)O (cm-): 3400, 2750-2400, 1720, 1690, 1600, 1260, 1200, 1130, 1030 Example 48 1.149 of sulfodehydroabietic acid monohydrate, 0.589 of methyl 4-amino-3-phenylbutylate are treated in the same manner as described in Example 8, whereby 0.79 of the salt of sulfodehydroabietic acid with methyl 4-amino-3-phenylbutylate is obtained.
M.p. 242 C (decomp.) (recrystalized from a mixture of methanol and ether) IR # max. nujol (cm-): 3300-3050, 1720, 1700, 1630 1520, 1240, 1180, 1160, 1030 Example 49 (Tablets) Sulfodehydroabietic acid calcium salt 2509 Corn starch 25g The mixture of these ingredients was granulated with the aid of 10g of hydroxypropyl cellulose (a binding agent).
Twelve g of crystalline cellulose and 3g of magnesium stearate were added to the resultant granules, and the mixture was then compressed into tablets of suitable concaved form (1Omm in diameter, weight 300mg).
Example 50 (Granules) Sulfodehydroabietic acid calcium salt 1 00g Corn starch 5g The mixture of these ingredients was granulated with the aid of 5g of polyvinylpyrrolidone (a binding agent), and the resultant granules was passed through a standard sieve (840 ju aperture) to give granules containing 1000mg of said calcium salt per 1100mg of granules.
Example 51 (Capsules) Sulfodehydroabietic acid calcium salt 5009 Corn starch 509 Crystalline cellulose 479 Magnesium stearate 39 The above-mentioned ingredients were thoroughly mixed and mixture was encapsulated to give capsules containing 600mg of said mixture per each capsules.

Claims (9)

1. Sulfodehydroabietic acid of the formula:
or a pharmaceutically acceptable salt thereof solely for use in therapeutic treatment or prophylaxis of a gastro-intestinal disease.
2. Sulfodehydroabietic acid or as a salt thereof as claimed in claim 1 for use in therapeutic treatment or prophylaxis of a peptic ulcer disease or gastritis.
3. A salt of sulfodehydroabietic acid as claimed in claim 1, which is a salt of sulfodehydroabietic acid with a metal selected from lithium, potassium, sodium, magnesium calcium and aluminium; a metal hydroxide selected from aluminium monohydroxide and aluminium dihydroxide; or an amine selected from alkyl(C1 5)amine, di-alkyl(C15)amine, tri-alkyl(C15)amine, cycloalkyl(C36)amine, di-alkyl-(C1-5)amino-alkyl(C1-5)amine, alkoxy(C1,5)-alkyl(C1-5)alkyl(C, 5)am- ine, hydrnxy-alkyl(C15)amine, alkylene(C26)diamine, aralkyl-(C78)amine, alkyl(C ,~5) N-piperidinoacetyl-p-aminobenzoate, alkyl(C, 5) N-prolyl-p-aminobenzoate, alkyl (C, 5) N-pipecolyl-p-aminobenzoate, morpholine, piperazine, 3-(3,4-dihydroxyphenyl)-8,8-dimethyl-1,8-diazoniaspiro[4.5]de- cane, 1 (2-dimethyl-aminoethyl)-4-phenyl-2-pyrrolidone, homocysteine thiolactone, an a-amino acid of the formula: R' -A-CH-COR2 NH2 wherein R' is amino, guanidino, carbamoyl, dimethylthionia, 4-imidazolyl, mercapto or methylthio, R2 is hydroxy, alkoxy(C,5), amino, alkyl (C,8)amino, di-alkyl(C,5)amino, cycloalkyl(C36)- amino or p-alkoxy(C, s) anilino, and A is straight alkylene (Cr 5) a amino acid of the formula:: H2N-B-CH2COR3 wherein R3 is hydroxy or alkoxy (Cr s) and B is straight alkylene (Cr s) (said alkylene being unsubstituted or substituted with phenyl), and carnosine.
4. A salt of sulfodehydroabietic acid of the formula:
with a metal selected from lithium, potassium, magnesium, calcium and aluminium; a metal hydroxide selected from aluminium monohydroxide and aluminium dihydroxide; or an amine selected from alkyl(C, s)amine, di-alkyl(C1-5)amine, tri-alkyl(C1-5)amine, cycloalkyl(C3-6)amine, dialkyl(C-15)amino-alkyl(C1-5)amine, alkoxy(C, s)-alkyl(C, s)amine, hydroxy-alkyl(C1-5)amine, alkylene (C26)diamine, aralkyl(C78)amine, alkyl(C1-5) N-piperidinoacetyl-p-aminobenzoate, alkyl(C1 s) Nprolyl-p-aminobenzoate, alkyl(C1 s) N-pipecolyl-p-aminobenzoate, morpholine, piperazine, 3-(3,4dihydroxyphenyl)-8,8-dimethyl-1,8-diazoniaspiro[4.5]decane, 1 -(2-dimethylaminoethyl)-4-phenyl 2-pyrrolidone, homocysteine thio-lactone, an a-amino acid of the formula:
wherein R1 is amino, guanidino, carbamoyl, dimethyl-thionia, 4-imidazolyl, mercapto or methylthio, R2 is hydroxy, alkoxy(C1-5), amino, alkyl (C18)amino, di-alkyl(C1 s)amino, cycloalkyl (C3-6)amino or p-alkoxy(C1-5)anilino, and A is straight alkylene (C1-5), a w-amino acid of the formula: H2N-B-CH2COR3 wherein R3 is hydroxy or alkoxy (C1 s) and B is straight alkylene (C1 s) (said alkylene being unsubstituted or substituted with phenyl), and carnosine.
5. A process for preparing a salt of sulfodehydroabietic acid of the formula:
with a metal selected from lithium, potassium, magnesium, calcium and aluminium; a metal hydroxide selected from aluminium monohydroxide and aluminium dihydroxide; or an amine selected from alkyl(C1-5)amine, di-alkyl(C15)amine, tri-alkyl(C1 5)amine, cycloalkyl(C36)amine, dialkyl(C1-5)amino-alkyl(C1-5)amine, alkoxy(C1-5)-alkyl(C1-5)amine, hydroxyalkyl(C1-5)amine, alkylene (C26)diamine, aralkyl(C78)amine, alkyl(C, 5) N-piperidinoacetyl-p-aminobenzoate, alkyl(C,5) Nprolyl-p-aminobenzoate, alkyl(C1 -5) N-pipecolyl-p-aminobenzoate, morpholine, piperazine, 3-(3,4 dihydroxyphenyl)-8,8-dimethyl-l ,8-diazoniaspiro[4.5] decane, 1 -(2-dimethylaminoethyl)-4-phenyl-2-pyrrolidone, homocysteine thiolactone, an a-amino acid of the formula:
wherein R' is amino, guanidino, carbamoyl, dimethylthionia, 4-imidazolyl, mercapto or methylthio, R2 is hydroxy, alkoxy(C1-5), amino alkyl(C,8)amino, di-alkyl(C1-5)amino, cycloalkyl-(C3-6)am- ino or p-alkoxy(C1-5) anilino, and A is straight alkylene (Cr 5) a amino acid of the formula: H2N-B-CH2COR3 wherein R3 is hydroxy or alkoxy(C, s) and B is straight alkylene (Ca s) (said alkylene being unsubstituted or substituted with phenyl), and carnosine, which comprises:: (A) neutralising sulfodehydroabietic acid (I) with a hydroxide, carbonate or bicarbonate of said metal or with said amine or give a salt of sulfodehydroabietic acid (I) with said metal or said amine; or (B) reacting sulfodehydroabietic acid (I) with an aluminium alkoxide in the presence of water to give a salt of sulfodehydroabietic acid (I) with aluminium monohydroxide or aluminium dihydroxide; or (C) reacting a sodium salt of sulfodehydroabietic acid (I) with a halide, sulfate or nitrate of said metal to give a salt of sulfodehydroabietic acid (I) with said metal; or (D) reacting a silver salt of sulfodehydroabietic acid (I) with a halide of said metal or with a hydrohalide or quaternary salt of said amine to give a salt of sulfodehydroabietic acid with said metal or said amine.
6. A pharmaceutical composition which comprises a theratpeutically effective amount of sulphodehydroabietic acid or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier therefor.
7. A pharmaceutical composition as claimed in claim 6 and substantially as hereinbefore described with reference to any one of Examples 49 to 51.
8. A salt as claimed in claim 4 and substantially as hereinbefore described with reference to Examples 1 to 48.
9. A process as claimed in claim 5 and substantially as hereinbefore described with reference to Examples 1 to 48.
GB08131856A 1981-10-22 1981-10-22 Treatment of gastro-intestinal diseases Withdrawn GB2107584A (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
GB08131856A GB2107584A (en) 1981-10-22 1981-10-22 Treatment of gastro-intestinal diseases
EP82305594A EP0078152B1 (en) 1981-10-22 1982-10-21 Salts of sulfodehydroabietic acid and treatment of gastro-intestinal diseases
DE8282305594T DE3271037D1 (en) 1981-10-22 1982-10-21 Salts of sulfodehydroabietic acid and treatment of gastro-intestinal diseases
IT49332/82A IT1196554B (en) 1981-10-22 1982-10-21 SULFODEHYDROABIETIC ACID SALT AND PHARMACEUTICAL COMPOSITION CONTAINING IT
DK198204675A DK172690B1 (en) 1981-10-22 1982-10-21 Analogous process for the preparation of salts of sulfodehydroabietic acid or hydrates thereof
JP57185883A JPS5877814A (en) 1981-10-22 1982-10-21 anti-ulcer agent
GB08230027A GB2114975B (en) 1981-10-22 1982-10-21 Salts of sulfodehydroabietic acid and treatment of gastro-intestinal diseases
DE19823239172 DE3239172A1 (en) 1981-10-22 1982-10-22 SALTS OF SULFODEHYDROABIETIC ACID AND MEDICINAL PRODUCTS CONTAINING THEM
FR8217722A FR2515039A1 (en) 1981-10-22 1982-10-22 SULFODEHYDROABIETIC ACID SALTS AND THEIR USE FOR THE TREATMENT OF GASTROINTESTINAL DISEASES
US06/621,124 US4529602A (en) 1981-10-22 1984-06-14 Method for treatment or prophylaxis of gastro-intestinal disease
JP62282659A JPS63165361A (en) 1981-10-22 1987-11-09 Novel sulfodehydroabietate
SG107/88A SG10788G (en) 1981-10-22 1988-02-06 Salts of sulfodehydroabietic acid and treatment of gastro-intestinal diseases
HK415/88A HK41588A (en) 1981-10-22 1988-06-02 Salts of sulfodehydroabietic acid and treatment of gastro-intestinal diseases
JP1273358A JPH02167258A (en) 1981-10-22 1989-10-19 Salt of novel sulfodehydroabietic acid

Applications Claiming Priority (1)

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GB08131856A GB2107584A (en) 1981-10-22 1981-10-22 Treatment of gastro-intestinal diseases

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CN103772241A (en) * 2014-01-07 2014-05-07 珠海亿邦制药股份有限公司 Method for preparing sulfonated dehydroabietic acid salt
CN111377836A (en) * 2018-12-29 2020-07-07 四川科瑞德制药股份有限公司 Crystal form of ecabet sodium and preparation method thereof

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JP3059092B2 (en) 1995-11-15 2000-07-04 田辺製薬株式会社 Agent for preventing and treating dry eye and diseases caused by dry eye
TW585762B (en) * 1999-11-11 2004-05-01 Tanabe Seiyaku Co Pharmaceutical composition for prophylaxis or treatment of inflammatory bowel diseases
WO2007040005A1 (en) * 2005-09-06 2007-04-12 Kyoto University ACTIVATOR FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPARα) AND COMPOSITION CONTAINING THE ACTIVATOR FOR PREVENTING OR AMELIORATING SPECIFIC SYMPTOM
JP4839460B1 (en) * 2011-04-28 2011-12-21 丸一株式会社 Release wire connection structure of remote-controlled drain plug device

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US2121032A (en) * 1936-03-24 1938-06-21 G & A Lab Detergent and wetting agent and process of producing the same

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1430892A4 (en) * 2001-09-27 2006-03-01 Tanabe Seiyaku Co PREPARATION OF AQUEOUS ECABET SODIUM SOLUTION
CN103772241A (en) * 2014-01-07 2014-05-07 珠海亿邦制药股份有限公司 Method for preparing sulfonated dehydroabietic acid salt
CN103772241B (en) * 2014-01-07 2015-08-26 珠海亿邦制药股份有限公司 A kind of preparation method of sulfonated dehydro sylvate
CN111377836A (en) * 2018-12-29 2020-07-07 四川科瑞德制药股份有限公司 Crystal form of ecabet sodium and preparation method thereof

Also Published As

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JPS6323174B2 (en) 1988-05-16
JPS63165361A (en) 1988-07-08
JPH0231070B2 (en) 1990-07-11
JPS5877814A (en) 1983-05-11

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