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 PDF

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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
Application number
PCT/HU1992/000059
Other languages
English (en)
French (fr)
Inventor
László Dobay
János Fischer
Ede MÁRVÁNYOS
Tamás FODOR
Ferenc Trischler
Éva PERÉNYI
Katalin GÁSPÁR
Elemér Ezer
Judith Matuz
Katalin Sághy
László Szporny
György Hajós
Original Assignee
Richter Gedeon Vegyészeti Gyár Rt.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Richter Gedeon Vegyészeti Gyár Rt. filed Critical Richter Gedeon Vegyészeti Gyár Rt.
Publication of WO1993012787A1 publication Critical patent/WO1993012787A1/en

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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.

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  • 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)
PCT/HU1992/000059 1991-12-20 1992-12-18 New pharmaceutical compositions inhibiting gastric acid secretion and exerting gastrocytoprotective effect WO1993012787A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU4067/91 1991-12-20
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

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 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
HU (1) HU209245B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
TW (1) TW232015B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)
WO (1) WO1993012787A1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997049679A1 (fr) * 1996-06-27 1997-12-31 Ono Pharmaceutical Co., Ltd. Derives d'aryle (sulfure, oxyde sulfonique et sulfone) et medicaments les contenant en tant que principe actif

Citations (4)

* Cited by examiner, † Cited by third party
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

Patent Citations (4)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997049679A1 (fr) * 1996-06-27 1997-12-31 Ono Pharmaceutical Co., Ltd. Derives d'aryle (sulfure, oxyde sulfonique et sulfone) et medicaments les contenant en tant que principe actif

Also Published As

Publication number Publication date
HU914067D0 (en) 1992-03-30
TW232015B (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 1994-10-11
CN1075255A (zh) 1993-08-18
HUT63955A (en) 1993-11-29
HU209245B (en) 1994-04-28

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