WO1994014751A1 - Substituted butenoic acid derivatives and pharmaceutical compositions containing them - Google Patents
Substituted butenoic acid derivatives and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- WO1994014751A1 WO1994014751A1 PCT/HU1993/000075 HU9300075W WO9414751A1 WO 1994014751 A1 WO1994014751 A1 WO 1994014751A1 HU 9300075 W HU9300075 W HU 9300075W WO 9414751 A1 WO9414751 A1 WO 9414751A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- hydroxy
- nitrophenyl
- oxo
- formula
- butenoic acid
- 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.)
- Ceased
Links
- QJBNQTXMGMPRID-ONEGZZNKSA-N [O-][N+](c1cc(C(/C=C/C(O)=O)=O)ccc1N=O)=O Chemical compound [O-][N+](c1cc(C(/C=C/C(O)=O)=O)ccc1N=O)=O QJBNQTXMGMPRID-ONEGZZNKSA-N 0.000 description 1
- UGCDTJCFWLWCOM-ARJAWSKDSA-N [O-][N+](c1cc(C(/C=C\C(O)=O)=O)ccc1O)=O Chemical compound [O-][N+](c1cc(C(/C=C\C(O)=O)=O)ccc1O)=O UGCDTJCFWLWCOM-ARJAWSKDSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/49—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups
- C07C205/56—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by carboxyl groups having nitro groups bound to carbon atoms of six-membered aromatic rings and carboxyl groups bound to acyclic carbon atoms of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
- C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
Definitions
- the invention relates to the novel , therapeutically active 4- (4-hydroxy-3-nitrophenyl) -4-oxo- (2E) -butenoic acid and 4- (4-hydroxy-3-nitrophenyl) -4-oxo- (2Z) -butenoic acid of the formula
- the invention relates to a process for the preparation of the above compounds and compositions.
- the compounds of formula (I) possess valuable pharmacological activ- ities such as gastric acid secretion inhibitory and gastocytoprotective effects. Thus, they are useful for the prevention and/or healing of various ulcerous diseases of the oesophagus, stomach and duodenum.
- the invention relates also to a method for the prevention and/or healing of various ulcerous diseases of the oesophagus, stomach and duodenum in a mammal including man by administering one or more therapeutically effective dose(s) of the compound of formula (I) or a salt thereof with a H2 receptor anta- gonist, preferably Famotidine, to said mammal.
- a H2 receptor anta- gonist preferably Famotidine
- the oral ED5 0 value of the compound prepared as described in Example 1 was found to be 3.5 mg/kg of body weight in the above test.
- Cimetidine a known drug was found to be 50 mg/kg of body weight according to the test carried out under the same conditions as described above.
- the gastrocytoprotective effect was expressed by the percentage of the average total length of longit- udinal bleedings in relation of the average total length measured in the control group treated with acidic alcohol alone.
- the oral ED5 0 value of the compound prepared as described in Example 1 was found to be 0.6 mg/kg of body weight in the above test.
- the ED 50 value of Sucralfate a known drug was found to be 150 mg/kg of body weight in the above test used for determination of the gastrocytoprotective effect.
- the activity of the compounds of formula (I) according to the invention significantly exceeds the activity of the reference drugs.
- the therapeutic dose may be varied in a range of 20 to 100 mg/day.
- the active agents of the formula (I) can be transformed to pharmaceutical compositions by mixing them with non-toxic, inert, solid or liquid carriers and/or other auxiliaries commonly used in pharma ⁇ ceutical formulations for parenteral or enteral administration.
- Useful carriers are e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, talc, vegetable oils such as peanut oil, olive oil and the like.
- the active agent can be formulated to usual pharmaceutical compositions, particularly solid compositions, e.g. rounded or edged tablets, dragees or capsules such as gelatine capsules, pills, suppositories and the like.
- the amount of the solid active agent may be varied a broad range, preferably it is between about 25 mg and 1 g per unit dose (i.e. tablet, capsule, one unit of the formulated solution, etc.).
- these compositions may also contain other conventional pharmaceutical auxili ⁇ aries, e.g. stabilizers, preservatives, wetting agents, emulsifying agents and the like.
- the compositions can be prepared in a known manner, e.g.
- compositions may be subjected to other usual operations of the pharmaceutical tech ⁇ nology, e.g. sterilization.
- the dose level to be used can be varied within broad limits depending on the body weight and the individual response of the patient or animal being treated, sever ⁇ ity of the condition to be influenced as well as the frequency and the particular route of administration.
- the amount of the suitable dose can easily be determined by a physician skilled in the art.
- the condensation reaction of the compound of formula (II) with glyoxylic acid is catalyzed by an acid; thus, it is preferable to carry out this reaction in an acid, e.g. glacial acetic acid or phosphoric acid.
- an acid e.g. glacial acetic acid or phosphoric acid.
- the reaction is carried out by heating in 85% phosphoric acid at a temperature between 80 °C and 100 °C for 8 to 10 hours. Under these conditions the compound of the formula (I) having (E) configuration can be obtained in a yield of about 70%.
- the compound of the formula (I) having (Z) config ⁇ uration can be prepared by photoisomerization of the (E) isomer.
- the photoisomerization can be achieved by irradia ⁇ tion with a high-pressure mercury vapour lamp in an inert organic solvent, preferably acetone at room tem ⁇ perature by adding a catalytic amount of an acid catalyst, preferably methanesulfonic acid to the reac- tion mixture. In the absence of an acid catalyst, the progress of the photoisomerization is only partial.
- the starting substance 4-hydroxy-3-nitroacetophenone of the formula (II) is prepared by a slight modification of the method known from the literature [J. Am. Chem. Soc. .80. / page 5808 (1958)], which will be described in Example 5 hereinafter.
- Glyoxylic acid monohydrate is a commercially available product.
- Famotidine salts of the formula (la) may be formed from stoichiometric amounts of the compounds of the for- mula (I) and Famotidine base in an inert organic sol ⁇ vent, preferably ethanol at room temperature. The optimum reaction time is about 24 hours in average. The salts of the formula (la) can be obtained in a pure state in a yield of about 95%. Famotidine, chemically 3-[[ [2-[ (amino-iminomethyl)- amino]thiazoly1]methyl]thio]-N-(aminosulfony1)propane- imide amide, can be prepared according to the Belgian Patent Specification No. 905,409.
- Example 1 The invention is illustrated in detail by the following non-limiting Examples.
- Example 1 The invention is illustrated in detail by the following non-limiting Examples.
- a suspension containing 3.7 g (0.02 mol) of 4- hydroxy-3-nitroacetophenone and 1.8 g (0.02 mol) of glyoxylic acid monohydrate in 30 ml of 85% phosphoric acid is stirred at a temperature of 80 °C to 100 °C for 8 to 10 hours.
- the starting substances are gradually dissolved while the product gradually precipitates.
- the reaction mixture is poured into 120 ml of water under stirring, stirred at room temperature for 4 to 5 hours, then cooled, filtered and the product is washed with water.
- 3.4 g (72%) of crude product are obtained, which is purified as follows.
- the crude product is suspended in 200 ml of benzene.
- Example 3 Preparation of the Famotidine salt of 4-(4-hydroxy- 3-nitrophenyl)-4-oxo-(2E)-butenoic acid To a solution containing 2.4 g (0.01 mol) of 4-(4- hydroxy-3-nitrophenyl)-4-oxo-(2E)-butenoic acid prepared as described in Example 1 in 100 ml of ethanol, a suspension of 3.4 g (0.01 mol) of Famotidine in 100 ml of ethanol is added at room temperature. After stirring at room temperature for 24 hours, the reaction mixture is filtered and the precipitate is washed with ethanol to give 5.4 g (95%) of the title salt, m.p.: 161-168 °C.
- Famotidine salt of 4-(4-hydroxy- 3-nitrophenyl)-4-oxo-(2Z)-butenoic acid A suspension of 1.11 g (3.3 mmol) of Famotidine in 20 ml of ethanol is added to the solution of 0.78 g (3.3 mmol) of 4-(4-hydroxy-3-nitrophenyl)-4-oxo-(2Z)-butenoic acid prepared as described in Example 2 in 20 ml of ethanol at room temperature. The mixture is stirred at room temperature for 24 hours, then filtered and the precipitate is washed with ethanol to obtain 1.8 g (95%) of title compound, m.p.: 134-138 °C.
- Tablets weighing 150 or 300 mg, respectively each are compressed from the powder mixture with the composi ⁇ tion defined under a) or under b) , respectively in the usual manner by wet granulation and compression.
- Each tablet contains 5 or 50 mg, respectively of active ingredient.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
There are provided novel, therapeutically active 4-(4-hydroxy-3-nitrophenyl)-4-oxo-(2E)-butenoic acid and 4-(4-hydroxy-3-nitrophenyl)-4-oxo-(2Z)-butenoic acid of formula (I), as well as their salts formed with H2 receptor antagonists, preferably their Famotidine salt, and pharmaceutical compositions containing these compounds. Furthermore, processes are described for the preparation of the above compounds and compositions, respectively. The compounds of formula (I) and salts thereof possess significant gastric acid secretion inhibitory and gastrocytoprotective activities. Thus, they are useful for the prevention and/or healing of various ulcerous disease of the oesophagus, stomach and duodenum.
Description
Substituted butenoic acid derivatives and pharmaceutical compositions containing them .
The invention relates to the novel , therapeutically active 4- (4-hydroxy-3-nitrophenyl) -4-oxo- (2E) -butenoic acid and 4- (4-hydroxy-3-nitrophenyl) -4-oxo- (2Z) -butenoic acid of the formula
as well as their salts formed with H2 receptor antagonists, preferably their Famotidine salt of the formula
(la)
and pharmaceutical compositions containing these compounds.
Furthermore, the invention relates to a process for the preparation of the above compounds and compositions.
Surprisingly, it has been found that the compounds of formula (I) possess valuable pharmacological activ- ities such as gastric acid secretion inhibitory and gastocytoprotective effects. Thus, they are useful for the prevention and/or healing of various ulcerous diseases of the oesophagus, stomach and duodenum.
Accordingly, the invention relates also to a method for the prevention and/or healing of various ulcerous diseases of the oesophagus, stomach and duodenum in a mammal including man by administering one or more therapeutically effective dose(s) of the compound of formula (I) or a salt thereof with a H2 receptor anta- gonist, preferably Famotidine, to said mammal.
The biological activity of the compounds according to the invention is illustrated by the tests described hereinafter.
1) Assay of the gastric acid secretion inhibitory effect by pylorus ligature
The method of Shay et al. [Gastroenterology 5 , pages 43 to 61 (1945)] was used.
Female Hannover- istar rats weighing 120 to 150 g each were starved for 24 hours then, pylorus ligature was carried out in the animals. Active agents of the formula (I) were orally (p.o.) administered to the animals 30 minutes before the pylorus ligation. Four hours after the surgery the animals were killed and the acid content of gastric juice was determined. The gastric acid secretion inhibitory activity of the compounds tested was determined in relation to the acid content measured in the gastric juice of the untreated control animals.
The oral ED50 value of the compound prepared as described in Example 1 was found to be 3.5 mg/kg of body
weight in the above test.
The ED50 value of Cimetidine, a known drug was found to be 50 mg/kg of body weight according to the test carried out under the same conditions as described above.
2) Effects on the gastric lesion induced by acid- containing alcohol The method of A. Robert [Gastroenterology 11_, pages 761 to 767 (1979)] was followed. Female rats weighing 120 to 150 g each fasted for 24 hours were used. A mixture containing 1 ml of con¬ centrated hydrochloric acid and 50 ml of abs. ethanol administered in a dose of 0.5 ml/100 g of body weight was employed as necrotizing agent. The compounds of the formula (I) were administered to the stomach 30 minutes before administration of the acidic alcohol. One hour following the administration of the acidic alcohol the animals were killed. The length of longitudinal bleedings induced by the acidic alcohol treatment on the glandular part of the stomach was measured and the average total length per stomach cal¬ culated.
The gastrocytoprotective effect was expressed by the percentage of the average total length of longit- udinal bleedings in relation of the average total length measured in the control group treated with acidic alcohol alone.
The oral ED50 value of the compound prepared as described in Example 1 was found to be 0.6 mg/kg of body weight in the above test.
The ED50 value of Sucralfate, a known drug was found to be 150 mg/kg of body weight in the above test used for determination of the gastrocytoprotective effect.
In tests showing the gastric acid secretion inhibit- ory and gastrocytoprotective effects, the activity of
the compounds of formula (I) according to the invention significantly exceeds the activity of the reference drugs. For adult human patients the therapeutic dose may be varied in a range of 20 to 100 mg/day. The active agents of the formula (I) can be transformed to pharmaceutical compositions by mixing them with non-toxic, inert, solid or liquid carriers and/or other auxiliaries commonly used in pharma¬ ceutical formulations for parenteral or enteral administration. Useful carriers are e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, talc, vegetable oils such as peanut oil, olive oil and the like. The active agent can be formulated to usual pharmaceutical compositions, particularly solid compositions, e.g. rounded or edged tablets, dragees or capsules such as gelatine capsules, pills, suppositories and the like. The amount of the solid active agent may be varied a broad range, preferably it is between about 25 mg and 1 g per unit dose (i.e. tablet, capsule, one unit of the formulated solution, etc.). Optionally, these compositions may also contain other conventional pharmaceutical auxili¬ aries, e.g. stabilizers, preservatives, wetting agents, emulsifying agents and the like. The compositions can be prepared in a known manner, e.g. by sieving, mixing, granulating and compressing the ingredients in the case of solid compositions. The compositions may be subjected to other usual operations of the pharmaceutical tech¬ nology, e.g. sterilization. The dose level to be used can be varied within broad limits depending on the body weight and the individual response of the patient or animal being treated, sever¬ ity of the condition to be influenced as well as the frequency and the particular route of administration. The amount of the suitable dose can easily be determined
by a physician skilled in the art.
According to the invention the novel substituted butenoic acid derivatives of the formula
and their salts can be prepared by reacting 4-hydroxy-3- nitroacetophenone of the formula
with glyoxylic acid in the presence of an acid catalyst to obtain the compound of the formula (I) having (E) configuration and, if desired, irradiating the (E) iso er by using a high-pressure mercury vapour lamp, if desired, in the presence of an acid catalyst to obtain the corresponding (Z) isomer, and, if desired, reacting the butenoic acid derivative of the formula (I) having (E) or (Z) configuration, respectively with a H2 receptor antagonist to obtain a salt thereof.
The condensation reaction of the compound of formula (II) with glyoxylic acid is catalyzed by an acid; thus, it is preferable to carry out this reaction in an acid,
e.g. glacial acetic acid or phosphoric acid. Suitably, the reaction is carried out by heating in 85% phosphoric acid at a temperature between 80 °C and 100 °C for 8 to 10 hours. Under these conditions the compound of the formula (I) having (E) configuration can be obtained in a yield of about 70%.
The compound of the formula (I) having (Z) config¬ uration can be prepared by photoisomerization of the (E) isomer. The photoisomerization can be achieved by irradia¬ tion with a high-pressure mercury vapour lamp in an inert organic solvent, preferably acetone at room tem¬ perature by adding a catalytic amount of an acid catalyst, preferably methanesulfonic acid to the reac- tion mixture. In the absence of an acid catalyst, the progress of the photoisomerization is only partial.
The starting substance 4-hydroxy-3-nitroacetophenone of the formula (II) is prepared by a slight modification of the method known from the literature [J. Am. Chem. Soc. .80./ page 5808 (1958)], which will be described in Example 5 hereinafter. Glyoxylic acid monohydrate is a commercially available product.
Famotidine salts of the formula (la) may be formed from stoichiometric amounts of the compounds of the for- mula (I) and Famotidine base in an inert organic sol¬ vent, preferably ethanol at room temperature. The optimum reaction time is about 24 hours in average. The salts of the formula (la) can be obtained in a pure state in a yield of about 95%. Famotidine, chemically 3-[[ [2-[ (amino-iminomethyl)- amino]thiazoly1]methyl]thio]-N-(aminosulfony1)propane- imide amide, can be prepared according to the Belgian Patent Specification No. 905,409.
The invention is illustrated in detail by the following non-limiting Examples.
Example 1
Preparation of 4-(4-hydroxy-3-nitrophenyl)-4-oxo-
(2E)-butenoic acid
A suspension containing 3.7 g (0.02 mol) of 4- hydroxy-3-nitroacetophenone and 1.8 g (0.02 mol) of glyoxylic acid monohydrate in 30 ml of 85% phosphoric acid is stirred at a temperature of 80 °C to 100 °C for 8 to 10 hours. The starting substances are gradually dissolved while the product gradually precipitates. Thereafter, the reaction mixture is poured into 120 ml of water under stirring, stirred at room temperature for 4 to 5 hours, then cooled, filtered and the product is washed with water. Thus, 3.4 g (72%) of crude product are obtained, which is purified as follows. The crude product is suspended in 200 ml of benzene. Then, under heating it is dissolved by adding 20 ml of methanol, thereafter it is clarified by using charcool and after evaporating 50 ml of solvent the product is crystallized. 2.4 g (51%) of title product are obtained, m.p. : 178-183 °C, Rf = 0.81 (ethyl acetate/glacial acetic acid 10:1) . Example 2 Preparation of 4-(4-hydroxy-3-nitrophenyl)-4-oxo- (2Z)-butenoic acid
The solution of 4.8 g (0.02 mol) of 4-(4-hydroxy-3- nitrophenyl)-4-oxo-(2E)-butenoic acid (prepared as described in Example 1 in 420 ml of acetone is irradiated in a photoreactor by using a high-pressure mercury vapour lamp in the presence of one drop of methanesulfonic acid as catalyst for 20 hours. Subsequently, acetone is distilled off by heating in a water bath of at most 30 °C temperature. The residue is crystallized by using diethyl ether. Thus, 3.4 g (71%) of title product are obtained,
m.p.: 141-145 °C, Rf = 0.95 (acetone/glacial acetic acid 20:1). In comparison, the Rf value of the (E) isomer is 0.88.
Example 3 Preparation of the Famotidine salt of 4-(4-hydroxy- 3-nitrophenyl)-4-oxo-(2E)-butenoic acid To a solution containing 2.4 g (0.01 mol) of 4-(4- hydroxy-3-nitrophenyl)-4-oxo-(2E)-butenoic acid prepared as described in Example 1 in 100 ml of ethanol, a suspension of 3.4 g (0.01 mol) of Famotidine in 100 ml of ethanol is added at room temperature. After stirring at room temperature for 24 hours, the reaction mixture is filtered and the precipitate is washed with ethanol to give 5.4 g (95%) of the title salt, m.p.: 161-168 °C. Example 4
Preparation of the Famotidine salt of 4-(4-hydroxy- 3-nitrophenyl)-4-oxo-(2Z)-butenoic acid A suspension of 1.11 g (3.3 mmol) of Famotidine in 20 ml of ethanol is added to the solution of 0.78 g (3.3 mmol) of 4-(4-hydroxy-3-nitrophenyl)-4-oxo-(2Z)-butenoic acid prepared as described in Example 2 in 20 ml of ethanol at room temperature. The mixture is stirred at room temperature for 24 hours, then filtered and the precipitate is washed with ethanol to obtain 1.8 g (95%) of title compound, m.p.: 134-138 °C. Example 5
Preparation of 4-hydroxy-3-nitroacetophenone used as starting substance [according to J. Am. Che . Soc, 80, 5808 (1958)] After cooling 30 ml of fuming nitric acid to
-20 °C, 6.8 g (0.05 mol) of 4-hydroxyacetophenone are added. After addition of the last portion, the reaction mixture is poured into ice-water, stirred for 1 hour, then filtered, and the precipitate is washed with water. Thus, 8.6 g (95%) of crude product are obtained, which
is recrystallized from 100 ml of ethanol to give 6.7 g (74%) of title product, m.p.: 124-127 °C, Rf = 0.69 (benzene/methanol 14:3). Example 6 Preparation of tablets a) Tablets weighing 150 mg containing 5 mg of active ingredient each
Ingredients g
Active ingredient 5 Gelatine 3
Magnesium stearate 2
Talc 5
Potato starch 40
Lactose 95 b) Tablets weighing 300 mg containing 50 mg of active ingredient each
Ingredients g
Active ingredient 50
Polyvidone 6 Magnesium stearate 3
Talc 9
Potato starch 84
Lactose 148
Tablets weighing 150 or 300 mg, respectively each are compressed from the powder mixture with the composi¬ tion defined under a) or under b) , respectively in the usual manner by wet granulation and compression. Each tablet contains 5 or 50 mg, respectively of active ingredient.
Claims
C l a i m s
1) 4-(4-Hydroxy-3-nitrophenyl)-4-oxo-(2E)-butenoic acid and 4-(4-hydroxy-3-nitrophenyl)-4-oxo-(2Z)-butenoic acid of the formula
and their salts formed with H2 receptor antagonists
2) 4-(4-Hydroxy-3-nitrophenyl) -4-oxo-(2E) -butenoic acid.
3) A pharmaceutical composition, which c o m p r i s e s as active ingredient a therapeutical- ly effective amount of 4-(4-hydroxy-3-nitrophenyl)-4- oxo-(2E) -butenoic acid or 4-(4-hydroxy-3-nitrophenyl) - 4-oxo-(2Z) -butenoic acid of the formula (I) or their salt(s) formed with H2 receptor antagonists in admixture with non-toxic, inert, solid or liquid carriers and/or additives commonly used in pharmaceuticals for enteral or parenteral administration.
4) Process for the preparation of the novel 4-(4- hydroxy-3-nitrophenyl) -4-oxo-(2E) -butenoic acid and 4- (4-hydroxy-3-nitrophenyl)-4-oxo-(2Z)-butenoic acid of the formula
as well as of their salts formed with H2 receptor anta¬ gonists, which c o m p r i s e s reacting 4-hydroxy-3- nitroacetophenone of the formula
with glyoxylic acid in the presence of an acid catalyst to obtain the compound of formula (I) having (E) con¬ figuration and, if desired, irradiating the (E) isomer by using a high-pressure mercury vapour lamp, if de¬ sired, in the presence of an acid catalyst to obtain the corresponding (Z) isomer, and, if desired, reacting the butenoic acid derivative of the formula (I) having (E) or (Z) configuration, respectively with a H2 receptor antagonist to obtain a salt thereof.
5) The process accoridng to claim 4, which c o m p r i s e s forming the Famotidine salt of a compound of the formula (I) having (E) or (Z) configuration, respectively. 6) The process according to claim 4 or claim 5,
which c o m p r i s e s carrying out the reaction in a solvent being inert under the reaction condi¬ tions) .
7) The process according to any of the claims 4 to 6, which c o m p r i s e s carrying out the reaction of 4-hydroxy-3-nitroacetophenone of the formula (II) with glyoxylic acid in phosphoric acid.
8) The process according to any of the claims 4 to 6, which c o m p r i s e s carrying out the isomerization in the presence of methanesulfonic acid as catalyst.
9) A process for the preparation of a pharmaceutical composition, which c o m p r i s e s mixing as active ingredient a therapeutically effective amount of the novel 4-(4-hydroxy-3-nitrophenyl -4-oxo-(2E)-butenoic acid or 4-(4-hydroxy-3-nitrophenyl)-4-oxo-(2Z)-butenoic acid of the formula
or their salt(s) formed with H2 receptor antagonists, with non-toxic, inert, solid or liquid carriers and/or additives commonly used in pharmaceuticals for enteral or parenteral administration and converting the mixture to a pharmaceutical composition.
10) A method for the prevention and/or healing of various ulcerous diseases of oesophagus, stomach or duodenum in a mammal including man, which c o m p r i s e s administering to said mammal one
or more therapeutically effective dose(s) of 4-(4- hydroxy-3-nitrophenyl)-4-oxo-(2E)-butenoic acid or 4- (4-hydroxy-3-nitrophenyl)-4-oxo-(2Z)-butenoic acid, of the formula
or their salts with H2 receptor antagonists alone or in the form of a pharmaceutical composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HUP9204116 | 1992-12-23 | ||
| HU9204116A HU210698B (en) | 1992-12-23 | 1992-12-23 | Process to prepare the novel 4-(4-hidroxy-3-nitro-phenyl)-4-oxo butenic acid and its salt and pharmaceutical compositions to prepare them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1994014751A1 true WO1994014751A1 (en) | 1994-07-07 |
Family
ID=10982768
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU1993/000075 Ceased WO1994014751A1 (en) | 1992-12-23 | 1993-12-17 | Substituted butenoic acid derivatives and pharmaceutical compositions containing them |
Country Status (2)
| Country | Link |
|---|---|
| HU (1) | HU210698B (en) |
| WO (1) | WO1994014751A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0240338A1 (en) * | 1986-04-01 | 1987-10-07 | Richter Gedeon Vegyeszeti Gyar R.T. | Butenoic acid derivatives |
| EP0309261A2 (en) * | 1987-09-25 | 1989-03-29 | Richter Gedeon Vegyeszeti Gyar R.T. | Butenoic acid amides, their salts, pharmaceutical compositions containing them and process for preparing same |
| EP0309262A2 (en) * | 1987-09-25 | 1989-03-29 | Richter Gedeon Vegyeszeti Gyar R.T. | Novel salicylates, their salts, pharmaceutical compositions containing them and process for preparing same |
-
1992
- 1992-12-23 HU HU9204116A patent/HU210698B/en unknown
-
1993
- 1993-12-17 WO PCT/HU1993/000075 patent/WO1994014751A1/en not_active Ceased
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0240338A1 (en) * | 1986-04-01 | 1987-10-07 | Richter Gedeon Vegyeszeti Gyar R.T. | Butenoic acid derivatives |
| EP0309261A2 (en) * | 1987-09-25 | 1989-03-29 | Richter Gedeon Vegyeszeti Gyar R.T. | Butenoic acid amides, their salts, pharmaceutical compositions containing them and process for preparing same |
| EP0309262A2 (en) * | 1987-09-25 | 1989-03-29 | Richter Gedeon Vegyeszeti Gyar R.T. | Novel salicylates, their salts, pharmaceutical compositions containing them and process for preparing same |
Non-Patent Citations (1)
| Title |
|---|
| EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, Vol. 23, issued 1988, (Elsevier, Paris), M. BIANCHI et al., "Gastric Anti-Secretory, Anti-Ulcer and Cytoprotective Properties of Substituted (E)-4-Phenyl- and Heteroaryl-4-Oxo-2-Butenoic Acids", pages 45-52. * |
Also Published As
| Publication number | Publication date |
|---|---|
| HU210698B (en) | 1995-08-28 |
| HU9204116D0 (en) | 1993-04-28 |
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