WO1993012787A1 - New pharmaceutical compositions inhibiting gastric acid secretion and exerting gastrocytoprotective effect - Google Patents
New pharmaceutical compositions inhibiting gastric acid secretion and exerting gastrocytoprotective effect Download PDFInfo
- Publication number
- WO1993012787A1 WO1993012787A1 PCT/HU1992/000059 HU9200059W WO9312787A1 WO 1993012787 A1 WO1993012787 A1 WO 1993012787A1 HU 9200059 W HU9200059 W HU 9200059W WO 9312787 A1 WO9312787 A1 WO 9312787A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- general formula
- cimetidine
- hydrogen
- atom
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
-
- 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
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- 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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C317/00—Sulfones; Sulfoxides
- C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/24—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
Definitions
- the invention relates to new pharmaceutical compositions inhibiting gastric acid secretion and exerting gastrocytoprotective effect which contain as active ingredient a 10:1-1:10 (w/w) mixture of a compound of general formula (II) ,
- X represents an oxygen or sulfur atom
- R represents a hydrogen atom, a hydroxy
- R 1 represents a hydrogen or halogen atom, and a compound of general formula (IV) ,
- A represents a group of general formulas (V) or (VI) ,
- the invention relates particularly to new pharmaceutical compositions which contain as active ingredient a 10:1-1:10 (w/w) mixture of 4-oxo-4H-l- benzopyrane-2-carboxylic acid, 4-oxo-4H-l-benzothio- pyrane-2-carboxylic acid or 3-(4-chlorophenylsulfonyl) - acrylic acid and cimetidine; or 4-oxo-4H-l-benzopyrane- 2-carboxylic acid cimetidine salt; or 4-oxo-4H-l- benzothiopyrane-2-carboxylic acid cimetidine salt; or 3- (4-chlorophenylsulfonyl) acrylic acid cimetidine salt.
- the invention relates furthermore to processes for preparing the above pharmaceutical compositions and the new compounds of general formula. (I) , wherein A and B have the same meaning as above.
- X represents an oxygen or sulfur atom
- R represents a hydrogen atom, a hydroxy
- SUBSTITUTESHEET similarly selected from the compounds of general formula (I) , R 1 represents a hydrogen or halogen atom.
- Cimetidine-l-cyano-2-meth 1-3-[2-/(5- methylimidazol-4-yl)methyl/thioethyl]guanidine - is a well known H 2 receptor blocker. It inhibits the secretion of gastric acid but exerts rather poor gastrocytoprotective effect, thus it is the drug of choice for the treatment of gastric ulcer or gastritis but is unsuitable for prophylactic purposes.
- Several cimetidine salts are reported in the literature but neither of the derivatives proved to be more potent than the base.
- 277,900 describes the salts of cimetidine formed with aspartic acid and glutamic acid as well as the double salts of cimetidine aspartate and cimetidine glutamate formed with ascorbic acid. It is assumed that the salts neutralize the toxic side effects of cimetidine.
- European Patent Specification No. 255,376 reports several simple salts of cimetidine, i. e. acetate, sul te, hydrochloride, fu arate, maleinate, etc. The reaction of these salts with ammonia enables the production of polymorphic cimetidine B.
- Cimetidine salts of general formulas (la) and (lb) of compounds of general formula (I) of the invention are new, they exert significant gastro ⁇ cytoprotective effect in addition to their assumed gastric antisecretory action, thus they are suitable not only for the treatment of ulcerous conditions but also for prophylactic purposes. These two effects are exerted not as a simple additive action but significant synergistic effects are observed, too.
- Salt formation is performed from the starting compounds of general formulas (II) or (III) , wherein R, X and R 1 have the same meaning as above, and from
- the cimetidine base can be prepared according to the British Patent Specification No. 2,103,206. Stoichiometric amounts of the components are reacted in an inert organic solvent or in a mixture of an inert organic solvent and water, and salt formation is promoted with heating, or, if required, by refluxing.
- Methanol or a mixture of ethanol and ethyl acetate are preferred organic solvents.
- the solvent is evaporated and the residual crude product is purified by recrystalizing from an inert organic solvent or a mixture of an inert organic solvent and water.
- Acetonitrile, acetone, methane1 and diethyl ether are preferred inert organic solvents.
- 4-oxo-4H-l-benzopyran-2- carboxylic acid is a commercial product while 4-oxo-4H- l-benzothiopyran-2-carboxylic acid can be prepared according to J. Schmutz et al. (Helv. Chim. Acta 34, 769, 1951).
- the new pharmaceutical compositions of the invention can be prepared by mixing in a ratio of 10:1- 1:10 (w/w) a compound of general formula (II), wherein R and X have the same meaning as above, or a compound of general formula (III) , wherein R 1 has the same meaning as above, with cimetidine of general formula (IV) , and admixing it to known carriers or additives usually applied in the art.
- the new pharmaceutical compositions can also be prepared by admixing a compound of general formula
- compositions according to the invention have been submitted to detailed pharmacological testing.
- Table 1 demonstrates that the most advantage ⁇ ous properties of cimetidine and of 4-oxo-4H-l- benzopyran-2-carboxylic acid are combined in the compound of Example 1. While 4-oxo-4H-l-benzopyran-2- carboxylic acid only poorly inhibits gastric acid secretion and the gastrocytoprotective effect of cimetidine is rather low, the compound of Example 1 inhibits gastric acid secretion at a rate similar to cimetidine, and its gastrocytoprotective effect is at the level of 4-oxo-4H-l-benzopyran-2-carboxylic adid.
- Table 2 demonstrates that the compound of Example 2 possesses, similarly to 4-oxo-4H-l-benzothio- pyran-2-carboxylic acid, and, unlike cimetidine, significant gastrocytoprotective effect.
- Table 2 demonstrates that the compound of Example 2 possesses, similarly to 4-oxo-4H-l-benzothio- pyran-2-carboxylic acid, and, unlike cimetidine, significant gastrocytoprotective effect.
- the compound of Example 2 possesses, similarly to 4-oxo-4H-l-benzothio- pyran-2-carboxylic acid, and, unlike cimetidine, significant gastrocytoprotective effect.
- SUBSTITUTESHEET 2 retains the antiulcer effect of cimetidine, but , unlike 4-oxo-4H-l-benzothiopyran-2-carboxylic acid , fails to promote aspirin+stress induced ulcer .
- Table 3 demonstrates that the compound of Example 3 is superior both as regards its inhibitory action on gastric acid secretion and its gastrocyto-
- Gastric juice Inhibition ED 50 Compound n Dose Volume Acid content of acid sec. mg/kg mg/kg ml/100 g umole/100 g compared p.o.+ p. o. to control
- Cimetidine 5 12.5 2.5 ⁇ 0.5 171.9 ⁇ 61.2 25.9 25
- Table 4 demonstrates that the salt of Example 3 as well as the various mixtures of cimetidine and 3- (4-chlorophenylsulfonyl)acrylic acid are inhibiting gastric acid secretion to a significantly higher degree than either cimetidine or the respective acrylic acid derivative alone.
- the rate of inhibition caused by the various mixtures is approximately similar.
- SUBSTITUTE SHEET Lactose 20 g is homogenized, then a tablet-premix is prepared with 15 ml of water and the tablets are pressed.
- One tablet has an active ingredient content of 132 mg.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to new pharmaceutical compositions inhibiting gastric acid secretion and exerting gastrocytoprotective effect which contain as active ingredient a 10:1-1:10 (w/w) mixture of a compound of general formula (II), wherein X represents an oxygen or sulfur atom, and R represents a hydrogen atom, a hydroxy, C1-4 alkyl or C1-4 alkoxy group, or a compound of general formula (III), wherein R1 represents a hydrogen or halogen atom, and a compound of general formula (IV), or a compound of general formula (I), wherein A represents a group of general formulas (V) or (VI), wherein X, R and R1 have the same meaning as above, and B is the protonated form of the compound of general formula (IV), in admixture with carriers and additives known in the art, furthermore to processes preparing the same and to a treatment method for the therapy and/or prophylaxis of mammals - including men - suffering from inflammatory and ulcerous diseases of the esophagus, stomach and duodenum.
Description
NEW PHARMACEUTICAL COMPOSITIONS INHIBITING GASTRIC ACID SECRETION AND EXERTING GASTROCYTOPROTECTIVE EFFECT
The invention relates to new pharmaceutical compositions inhibiting gastric acid secretion and exerting gastrocytoprotective effect which contain as active ingredient a 10:1-1:10 (w/w) mixture of a compound of general formula (II) ,
(II)
wherein X represents an oxygen or sulfur atom, and R represents a hydrogen atom, a hydroxy,
Cι_4 al yl or Cχ-/_ alkoxy group, or a compound of general formula (III) ,
( HI )
wherein
R1 represents a hydrogen or halogen atom, and a compound of general formula (IV) ,
SUBSTITUTE SHEET
or a compound of general formula (I) ,
wherein
A represents a group of general formulas (V) or (VI) ,
0
( V ) ( VI )
wherein
X, R and R1 have the same meaning as above, and
B is the protonated form of the compound of general formula (IV) ,
SUBSTITUTE SHEET
in admixture with carriers and additives known in the art.
The invention relates particularly to new pharmaceutical compositions which contain as active ingredient a 10:1-1:10 (w/w) mixture of 4-oxo-4H-l- benzopyrane-2-carboxylic acid, 4-oxo-4H-l-benzothio- pyrane-2-carboxylic acid or 3-(4-chlorophenylsulfonyl) - acrylic acid and cimetidine; or 4-oxo-4H-l-benzopyrane- 2-carboxylic acid cimetidine salt; or 4-oxo-4H-l- benzothiopyrane-2-carboxylic acid cimetidine salt; or 3- (4-chlorophenylsulfonyl) acrylic acid cimetidine salt.
The invention relates furthermore to processes for preparing the above pharmaceutical compositions and the new compounds of general formula. (I) , wherein A and B have the same meaning as above.
In the salts of general formula (la) ,
Cι_4 alkyl or Cι_4 alkoxy group while in the salts of general formula (lb) ,
SUBSTITUTESHEET
similarly selected from the compounds of general formula (I) , R1 represents a hydrogen or halogen atom.
Cimetidine-l-cyano-2-meth 1-3-[2-/(5- methylimidazol-4-yl)methyl/thioethyl]guanidine - is a well known H2 receptor blocker. It inhibits the secretion of gastric acid but exerts rather poor gastrocytoprotective effect, thus it is the drug of choice for the treatment of gastric ulcer or gastritis but is unsuitable for prophylactic purposes. Several cimetidine salts are reported in the literature but neither of the derivatives proved to be more potent than the base. The European Patent Specification No. 277,900 describes the salts of cimetidine formed with aspartic acid and glutamic acid as well as the double salts of cimetidine aspartate and cimetidine glutamate formed with ascorbic acid. It is assumed that the salts neutralize the toxic side effects of cimetidine.
European Patent Specification No. 255,376 reports several simple salts of cimetidine, i. e. acetate, sul te, hydrochloride, fu arate, maleinate, etc. The reaction of these salts with ammonia enables the production of polymorphic cimetidine B.
Cimetidine salts of general formulas (la) and (lb) of compounds of general formula (I) of the invention are new, they exert significant gastro¬ cytoprotective effect in addition to their assumed gastric antisecretory action, thus they are suitable not only for the treatment of ulcerous conditions but also for prophylactic purposes. These two effects are exerted not as a simple additive action but significant synergistic effects are observed, too.
Salt formation is performed from the starting compounds of general formulas (II) or (III) , wherein R, X and R1 have the same meaning as above, and from
SUBSTITUTESHEET
cimetidine base. The cimetidine base can be prepared according to the British Patent Specification No. 2,103,206. Stoichiometric amounts of the components are reacted in an inert organic solvent or in a mixture of an inert organic solvent and water, and salt formation is promoted with heating, or, if required, by refluxing.
Methanol or a mixture of ethanol and ethyl acetate are preferred organic solvents. After the salt formation - which is indicated also by the clearing up of the heterogeneous system the solvent is evaporated and the residual crude product is purified by recrystalizing from an inert organic solvent or a mixture of an inert organic solvent and water.
Acetonitrile, acetone, methane1 and diethyl ether are preferred inert organic solvents.
From the starting materials of the compounds of general formula (II) 4-oxo-4H-l-benzopyran-2- carboxylic acid is a commercial product while 4-oxo-4H- l-benzothiopyran-2-carboxylic acid can be prepared according to J. Schmutz et al. (Helv. Chim. Acta 34, 769, 1951).
From the starting materials of general formula (III) 3-phenylsulfonylacrylic acid and its substituted derivatives can be prepared according to the Hungarian Patent Application No. 3572/89.
The new pharmaceutical compositions of the invention can be prepared by mixing in a ratio of 10:1- 1:10 (w/w) a compound of general formula (II), wherein R and X have the same meaning as above, or a compound of general formula (III) , wherein R1 has the same meaning as above, with cimetidine of general formula (IV) , and admixing it to known carriers or additives usually applied in the art.
The new pharmaceutical compositions can also be prepared by admixing a compound of general formula
SUBSTITUTE SHEET
(I) , wherein A and B have the same meaning as above, with known carriers or additives.
The active ingredients of the compositions according to the invention have been submitted to detailed pharmacological testing.
The combinations as well as the new compositions inhibited the gastric acid secretion in the Shay test (Shay et al. : Gastroenterology 5_, 43, 1945), and exerted significant gastrocytoprotective effect in rats in the Robert test (A. Robert: Gastroenterology 77, 761, 1979) .
In further studies the inhibition of gastric ulcer, induced by aspirin and stress (K. D. Rainsford: Agents and Actions 5_, 553, 1975), as well as by indomethacin, was measured. In the latter study female RG- istar rats, starved for 24 hours, were treated with the test compound, then, after 30 minutes, with 20 mg of indomethacin, p.o. and the ED50 values were calculated. The results are presented in the following tables. These data distinctly prove the valuable effect of both the combinations and the new salts according to the invention. In the pharmacological tests they proved to inhibit significantly gastric acid secretion and exert gastrocytoprotective effect. The expected human dose can be in the range of 50-500 mg/kg body weight active ingredient.
SUBSTITUTESHEET
Table 1
Inhibition Gaεtro- Aspirin+ Indomethacin of gastric cyto- stress induced acid prot- model gastric secretion ective (Rainsford) ulcer
Compound (Shay test) effect- Dose: model acid 50 mg/kg alcohol model (Robert)
ED50 ED50 ED50 ED50
Cimetidine 25 170 40% ulcer inhibition
4-Oxo-4H-l- benz yran- 25 mg/kg 2-carboxylic promotes acid 95 No effect ulcer
Compound of 36% ulcer example 1 12 inhibition
ED50 in mg/kg p.o.
Table 1 demonstrates that the most advantage¬ ous properties of cimetidine and of 4-oxo-4H-l- benzopyran-2-carboxylic acid are combined in the compound of Example 1. While 4-oxo-4H-l-benzopyran-2- carboxylic acid only poorly inhibits gastric acid secretion and the gastrocytoprotective effect of cimetidine is rather low, the compound of Example 1 inhibits gastric acid secretion at a rate similar to cimetidine, and its gastrocytoprotective effect is at the level of 4-oxo-4H-l-benzopyran-2-carboxylic adid.
SUBSTITUTE SHEET
Table 2
Inhibition Gastro- Aspirin-f- Indomethacin of gastric cyto- stress induced acid prot- model gastric secretion ective (Rainsford) ulcer Compound (Shay test) effect- model acid alcohol model (Robert) ED50 ED50 ED50 ED50
Cimetidine 25 170 40% lcer inhibition at a dose of 50 mg/kg
4-0xo-4H-l- benzothio- No effect Stress pyran-2- at a dose of promoted by carboxylic 50 mg/kg 5,4 25 mg/kg 64 acid
Compound of No effect Example 2 20 at a dose of 50 mg/kg
ED50 in mg/kg p.o.
Table 2 demonstrates that the compound of Example 2 possesses, similarly to 4-oxo-4H-l-benzothio- pyran-2-carboxylic acid, and, unlike cimetidine, significant gastrocytoprotective effect. In the indomethacin induced ulcer test the compound of Example
SUBSTITUTESHEET
2 retains the antiulcer effect of cimetidine, but , unlike 4-oxo-4H-l-benzothiopyran-2-carboxylic acid , fails to promote aspirin+stress induced ulcer .
Table 3
Inhibition Gastro- Aspirin+ Indomethacin of gastric cyto- stress induced acid prot- model gastric secretion ective (Rains 3rd) ulcer
Compound (Shay test) effect- model acid alcohol model (Robert) ED50 ED50 ED50 ED50
Cimetidine 25 170 40% ulcer inhibition at a dose of 50 mg/kg
3-(4-Chloro- Ulcer phenyl- promoted sulfonyl)- by dose of acrylic acid 16 1, 19 25 mg/kg
Compound of No effect Example 3 4.2 22 at a dose of 50 mg/kg
ED50 in mg/kg p.o.
Table 3 demonstrates that the compound of Example 3 is superior both as regards its inhibitory action on gastric acid secretion and its gastrocyto-
SUBSTITUTE SHEET
protective effect as well as its antiulcer effect measured in the aspirin+stress model compared to the effect of either of its constituents [cimetidine and 3- (4-chlorophenylsulfonyl)acrylic acid] determined alone.
Table 4
Gastric juice Inhibition ED50 Compound n Dose Volume Acid content of acid sec. mg/kg mg/kg ml/100 g umole/100 g compared p.o.+ p. o. to control
Cimetidine 5 12.5 2.5±0.5 171.9±61.2 25.9 25
3-(4-chloro- phenyl- sulfonyl)- acrylic acid 5 10.0 5.8±0.2 345.8±54.5 1.1 16
Salt of
Example 3 5 10.0 4.1±0.1 368.9±21.3* 34.0 8
Mixtures (w/w)++: 5.1:4.9 Example 4) 5 10.0 4.4±0.3 266.5±44.0* 50.9
2:8 Example 5) 5 10.0 5.~7±0.3* 291.5±18.3* 47.8
8:2
Example 6) 5 10.0 3.9±0.4* 315.7±62.2* 43.5
continued
SUBSTITUTESHEET
Table 4 continued...
* p<0.05 compared to actual control n Number of animals
+ Based on the inhibition of gastric acid secretion ++ Mixtures of cimetidine and 3-(4-chlorophenyl- sμlfonyl)acrylic acid
Table 4 demonstrates that the salt of Example 3 as well as the various mixtures of cimetidine and 3- (4-chlorophenylsulfonyl)acrylic acid are inhibiting gastric acid secretion to a significantly higher degree than either cimetidine or the respective acrylic acid derivative alone.
The rate of inhibition caused by the various mixtures is approximately similar.
The following examples are illustrating but not limiting the scope of the invention.
Example l 4-Oxo-4H-l-benzopyran-carboxylic acid cimetidine salt dihydrate
5.7 g (0.03 mole) of 4-oxo-4H-l-benzopyran-2— carboxylic acid are suspended in a mixture of 60 ml of methanol and 40 ml of ethyl acetate then a solution of 7.57 g (0.03 mole) of cimetidine base in 60 ml of methanol are added. The initially heterogeneous system rapidly becomes a solution which is evaporated after refluxing for 2 hours. The residue is dissolved in 10 ml of aceto- nitrile under heating and is crystallized by the addition of water. The filtered product is dried at
60°C.
Yield: 10.5 g (76 %) M.p.: 105-107°C, decomp. at 114°C. Analysis for C20H 22 N 6°4 S-2H 2° (478.52).
SUBSTITUTESHEET
Calculated: C% 50.20; H% 5.47; N% 17.56 Found: C% 50.40; H% 5.89; N% 17.51.
Example 2 4-Oxo-4H-l-benzothiopyran-2-carboxylic acid cimetidine salt
2.52 g (0.01 mole) of cimetidine base are dissolved in a hot mixture of 200 ml of water and 30 ml of methanol, then a suspension of 2.06 g (0.01 mole) of 4-oxo-4H-l-benzothiopyran-2-carboxylic acid in 30 ml of methanol are added. The mixture is heated to boiling, decolorized with charcoal, filtered and the filtrate is evaporated at reduced pressure. The residue crystallizes upon cooling, then a mixture of 30 ml "of acetone and 10 ml of methanol is added, the white crystals are filtered and washed with diethyl ether. Yield: 3.52 g (77 %) . M.p. : 146-148°C (decomp.).
Example 3
3-(4-Chlorophenylsulfonyl)acrylic acid cimetidine salt
1.23 g (5 mmole) of 3-(4-chlorophenyl- sulfonyl)-acrylic acid and 1.26 g (5 mmole) of cime¬ tidine base are dissolved in 20 ml of methanol. The solution is left to stand for one hour, then it is evaporated and the residue is crystallized with diethyl ether. Yield: 2.1 g (84 %) .
M.p.: 84-90°C (decomp.).
Example 4
Active ingredient composition
SUBSTITUTESHEET
5.1 g of cimetidine is mixed with 4.9 g of 4- oxo-4H-l-benzopyran-2-carboxylic acid. Yield: 10 g.
Example 5
Active ingredient composition
20 g of cimetidine is mixed with 80 g of 3-(4-chlorophenylsulfonyl)acrylic acid. Yield: 100 g.
Example 6
Active ingredient composition
80 g of cimetidine is mixed with 20 g of 3-(4- chlorophenylsulfonyl)acrylic acid. Yield: 100 g.
Example 7 Active ingredient composition
60 g of cimetidine is mixed with 40 g of 3-(4-chlorophenylsulfonyl)acrylic acid. Yield: loo g.
Example 8
Pharmaceutical composition
A mixture of the following ingredients 4-Oxo-4H-l-benzopyran-2-carboxylic acid 5.7 g
Cimetidine 7.5 g
Magnesium stearate 10 g
Polyvinylpyrrolidone 4 g
Talc 6 g Starch 10 g
SUBSTITUTE SHEET
Lactose 20 g is homogenized, then a tablet-premix is prepared with 15 ml of water and the tablets are pressed. One tablet has an active ingredient content of 132 mg.
SUBSTITUTESHEET
Claims
1. Pharmaceutical composition inhibiting gastric acid secretion and exerting gastrocytoprotective effect which contains as active ingredient a 10:1-1:10 (w/w) mixture of a compound of general formula (II) ,
(II-)
wherein
X represents an oxygen or sulfur atom, and R represents a hydrogen atom, a hydroxy, or Cι_4 alkyl or C^_4 alkoxy grc^D, or a compound of general formula (III) ,
( 111 )
wherein
R1 represents a hydr- en or halogen atom, and a compound of general -..ormula (IV) ,
SUBSTITUTESHEET 
or a compound of general formula (I) ,
wherein
A represents a group of general formulas (V) or (VI),
(V) (VI)
wherein X, R and R1 have the same meaning as above, and B is the protonated form of the compound of general formula (IV) , in admixture with carriers and additives known in the art.
2. Pharmaceutical composition as claimed in claim 1, w h i c h c o m p r i s e s applying as
B TT active ingredient a 10:1-1:10 (w/w) mixture of 4-oxo-4H- l-benzopyran-2-carboxylic acid and cimetidine.
3. Pharmaceutical composition as claimed in claim 1, w h i c h c o m p r i s e s applying as active ingredient 4-oxo-4H-l-benzopyran-2-carboxylic acid cimetidine salt.
4. Pharmaceutical composition as claimed in claim 1, w h i c h c o m p r i s e s applying as active ingredient a 10:1-1:10 (w/w) mixture of 4-oxo-4H- l-benzothiopyran-2-carboxylic acid and cimetidine.
5. Pharmaceutical composition as claimed in claim 1, w h i c h c o m p r i s e s applying as active ingredient 4-oxo-4H-l-benzothiopyran-2-carboxylic acid cimetidine salt.
6. Pharmaceutical composition as claimed in claim 1, w h i c h c o m p r i s e s applying as active ingredient a 10:1-1:10 (w/w) mixture of 3-(4- chlorophenylsulfonyl)acrylic acid and cimetidine.
7. Pharmaceutical composition as claimed in claim 1, w h i c h c o m p r i s e s applying as active 'ingredient 3-(4-chlorophenylsulfonyl)acrylic acid cimetidine salt.
8. Compound of general formula (I),
wherein A represents a group of general formulas (V) or (VI) - wherein X represents an oxygen or sulfur atom,
SUBSTITUTESHEET R represents a hydrogen atom, a hydroxy, or Cι_4 alkyl or C±-4 alkoxy group, and R1 represents a hydrogen or halogen atom - and B represents the protonated form of the compound of general formula (IV) .
9. 4-Oxo-4H-l-benzopyran-2-carboxylic acid cimetidine salt dihydrate.
10. 4-Oxo-4H-l-benzothiopyran-2-carboxylic acid cimetidine salt dihydrate.
11. 3-(4-Chlorophenylsulfonyl)acrylic acid cimetidine salt.
12. Process for the preparation of a pharmaceutical composition inhibiting gastric acid secretion and exerting gastrocytoprotective effect w h i c h c o m p r i s e s a) mixing in a ratio of 10:1-1:10 (w/w) a compound of general formula (II) - wherein X represents an oxygen or sulfur atom, and R represents a hydrogen atom, a hyd¬ roxy, or Cι_ alkyl or C^-ύ. alkoxy group - or a compound of general formula (III) - wherein R1 represents a hydrogen or halogen atom - with cimetidine, then supp¬ lementing the mixture with carriers and additives known in the art, or b) mixing a compound of general formula (I) , wherein A represents a group of general formulas (V) or (VI) - wherein X represents an oxygen or sulfur atom, R represents a hydrogen atom, a hydroxy, or Cχ_4 alkyl or c l-4 alkoxy group, and R1 represents a hydrogen or halogen atom - and B represents the protonated form of the compound of general formula (IV) with carriers and additives known in the art.
13. Process for preparing compounds of general formula (I) , wherein A represents a group of general formulas (V) or (VI) - wherein X represents an oxygen or sulfur atom, R represents a hydrogen atom, a hydroxy, or Cι_4 alkyl or Cι_ alkoxy group, and R1 represents a
SUBSTITUTESHEET hydrogen or halogen atom - and B represents the protonated form of the compound of general formula (IV) , w h i c h c o m p r i s e s reacting a compound of general formula (II) - wherein X represents an oxygen or sulfur atom, and R represents a hydrogen atom, a hydroxy, or Cι_4 alkyl or Cι_4 alkoxy group or a compound of general formula (III) - wherein R1 represents a hydrogen or halogen atom - with a compound* of general formula (IV) .
14. Method of treatment for the therapy and/or prophylaxis of mammals - including humans - suffering from inflammatory and ulcerous diseases of the esopha¬ gus, stomach and duodenum, w h i c h c o m p r i s e s administering .to the animals or individuals a therapeu- tically effective dose(s) of a pharmaceutical composi¬ tion containing a 10:1—1:10 (w/w) mixture of a compound of general formula (II) - wherein X represents an oxygen or sulfur atom, and R represents a hydrogen atom, a hydroxy, or Cχ_4 alkyl or Cι_4 alkoxy group - or a compound of general formula (III) - wherein R1 represents a hydrogen or halogen atom - and a compound of general formula (IV) , or of a compound of general formula (I) , wherein A represents a group of general formulas (V) or (VI) - wherein X, R and R1 have the same meaning as above - and B represents the protonated form of the compound of general formula (IV) - and carriers and additives known in the art.
SUBSTITUTE SHEET
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| HU406791A HU209245B (en) | 1991-12-20 | 1991-12-20 | Process for producing new cimetidine derivatives, as well as new gastric acid secretion inhibiting and gastrocytoprotective pharmaceuitcal compositions |
| HU4067/91 | 1991-12-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1993012787A1 true WO1993012787A1 (en) | 1993-07-08 |
Family
ID=10966768
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/HU1992/000059 WO1993012787A1 (en) | 1991-12-20 | 1992-12-18 | New pharmaceutical compositions inhibiting gastric acid secretion and exerting gastrocytoprotective effect |
Country Status (4)
| Country | Link |
|---|---|
| CN (1) | CN1075255A (en) |
| HU (1) | HU209245B (en) |
| TW (1) | TW232015B (en) |
| WO (1) | WO1993012787A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997049679A1 (en) * | 1996-06-27 | 1997-12-31 | Ono Pharmaceutical Co., Ltd. | Aryl (sulfide, sulfoxide and sulfone) derivatives and drugs containing the same as the active ingredient |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0040489A1 (en) * | 1980-05-17 | 1981-11-25 | FISONS plc | Mixtures, salts, packages and pharmaceutical compositions containing 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid or a derivative thereof and an H2 receptor antagonist antihistamine |
| EP0156233A2 (en) * | 1984-03-19 | 1985-10-02 | Merck & Co. Inc. | Use of leukotriene antagonists for producing cytoprotective pharmaceutical compositions and process for producing cytoprotective pharmaceutical compositions |
| WO1990002741A1 (en) * | 1988-09-14 | 1990-03-22 | Biota Scientific Management Pty Ltd. | Chromone derivatives |
| EP0408108A2 (en) * | 1989-07-14 | 1991-01-16 | Richter Gedeon Vegyeszeti Gyar R.T. | Pharmaceutical compositions containing acrylic acid derivatives and their use in the medicine |
-
1991
- 1991-12-20 HU HU406791A patent/HU209245B/en not_active IP Right Cessation
-
1992
- 1992-12-18 WO PCT/HU1992/000059 patent/WO1993012787A1/en active Application Filing
- 1992-12-19 CN CN 92115369 patent/CN1075255A/en active Pending
- 1992-12-21 TW TW81110294A patent/TW232015B/zh active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0040489A1 (en) * | 1980-05-17 | 1981-11-25 | FISONS plc | Mixtures, salts, packages and pharmaceutical compositions containing 5-(2-hydroxypropoxy)-4-oxo-8-propyl-4H-1-benzopyran-2-carboxylic acid or a derivative thereof and an H2 receptor antagonist antihistamine |
| EP0156233A2 (en) * | 1984-03-19 | 1985-10-02 | Merck & Co. Inc. | Use of leukotriene antagonists for producing cytoprotective pharmaceutical compositions and process for producing cytoprotective pharmaceutical compositions |
| WO1990002741A1 (en) * | 1988-09-14 | 1990-03-22 | Biota Scientific Management Pty Ltd. | Chromone derivatives |
| EP0408108A2 (en) * | 1989-07-14 | 1991-01-16 | Richter Gedeon Vegyeszeti Gyar R.T. | Pharmaceutical compositions containing acrylic acid derivatives and their use in the medicine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997049679A1 (en) * | 1996-06-27 | 1997-12-31 | Ono Pharmaceutical Co., Ltd. | Aryl (sulfide, sulfoxide and sulfone) derivatives and drugs containing the same as the active ingredient |
Also Published As
| Publication number | Publication date |
|---|---|
| TW232015B (en) | 1994-10-11 |
| HU209245B (en) | 1994-04-28 |
| HUT63955A (en) | 1993-11-29 |
| CN1075255A (en) | 1993-08-18 |
| HU914067D0 (en) | 1992-03-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP2008509953A (en) | 4-[[(7R) -8-cyclopentyl-7-ethyl-5,6,7,8-tetrahydro-5-methyl-4-6-oxo-2-piperidinyl] amino] -3-methoxy-N- ( 1-methyl-4-piperidinyl) benzamide hydrates and polymorphs, processes for their preparation and their use as drugs | |
| DE60304599T2 (en) | PYRIDOPYRIMIDINONE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEREOF | |
| JPS6229566A (en) | Novel guanidinomthylbenzoic acid derivative | |
| US4443459A (en) | α-Tocopheryl ester of 5-substituted picolinic acid and hypotensive composition containing it | |
| DE3035086A1 (en) | CYCLOHEXANCARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEANS CONTAINING THEM | |
| DE69223835T2 (en) | New aminophenol derivatives and pharmaceutical compositions containing them | |
| WO1989005799A1 (en) | Novel tetrahydropyridine derivatives, pharmaceutical compositions containing them and process for preparing same | |
| US4233310A (en) | Antiarteriosclerotic N-(mercaptoacyl)-histidines | |
| US4297357A (en) | N-Phenethylacetamide compounds and process for preparation thereof | |
| CH663616A5 (en) | 1,4-DIHYDROPYRIDINE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THE SAME. | |
| WO1993012787A1 (en) | New pharmaceutical compositions inhibiting gastric acid secretion and exerting gastrocytoprotective effect | |
| EP0106276B1 (en) | 1,4-dihydropyridine derivatives | |
| DE3023717A1 (en) | NEW SULFURIZED ISOCHINOLINE DERIVATIVES, THE PHARMACEUTICAL PREPARATIONS CONTAINING THESE COMPOUNDS, AND METHOD FOR PRODUCING THE NEW COMPOUNDS | |
| IE59653B1 (en) | Pyrrolo[1,2-a][4,1]benzoxyzepine derivatives, process for their preparation, compounds and their therapeutic use | |
| JPH0339513B2 (en) | ||
| HU210154B (en) | Process for producing new famotidin-salts and pharmaceutical compositions of gastro-acid-secretion-inhibiting and gastro-citoprotective activity, containing them | |
| EP0301245B1 (en) | 3-sulfonyl-3,7-diazabicyclo-(3,3,1)nonane compounds, processes for their preparation, and medicaments containing these compounds | |
| EP0017352A2 (en) | Chromanone derivatives, a process for their preparation, compositions containing them | |
| US4320128A (en) | Chromanone derivatives and compositions containing them | |
| US5451584A (en) | N-alkynyl carboxamides as sertonergic agents | |
| US4316899A (en) | Chromanone derivatives, a process for their preparation and compositions containing them | |
| EP0101633B1 (en) | Pyridinecarboxylic esters of dopamine and of its n-alkyl derivatives | |
| US3812135A (en) | Pyrroloindole and pyridoindole derivatives | |
| US5169859A (en) | Thiazolidinone derivatives, pharmaceutical compositions containing them and process for preparing same | |
| DE2605824A1 (en) | N-ACYLANILINE, THE METHOD OF MANUFACTURING IT AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| AK | Designated states |
Kind code of ref document: A1 Designated state(s): CA JP US |
|
| AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE |
|
| DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
| EX32 | Extension under rule 32 effected after completion of technical preparation for international publication |
Ref country code: KZ |
|
| LE32 | Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b) |
Ref country code: KZ |
|
| LE32 | Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b) |
Ref country code: BY |
|
| EX32 | Extension under rule 32 effected after completion of technical preparation for international publication |
Ref country code: BY |
|
| LE32 | Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b) |
Ref country code: KZ |
|
| LE32 | Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b) |
Ref country code: BY |
|
| LE32 | Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b) |
Ref country code: KZ |
|
| LE32 | Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b) |
Ref country code: BY |
|
| LE32 | Later election for international application filed prior to expiration of 19th month from priority date or according to rule 32.2 (b) |
Ref country code: BY |
|
| 122 | Ep: pct application non-entry in european phase | ||
| NENP | Non-entry into the national phase |
Ref country code: CA |