WO1993013076A1 - Gastric acid secretion-inhibiting, and gastrocytoprotective pharmaceutical compositions, novel famotidine salts and process for preparing same - Google Patents

Gastric acid secretion-inhibiting, and gastrocytoprotective pharmaceutical compositions, novel famotidine salts and process for preparing same Download PDF

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Publication number
WO1993013076A1
WO1993013076A1 PCT/HU1992/000057 HU9200057W WO9313076A1 WO 1993013076 A1 WO1993013076 A1 WO 1993013076A1 HU 9200057 W HU9200057 W HU 9200057W WO 9313076 A1 WO9313076 A1 WO 9313076A1
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Prior art keywords
acid
famotidine
formula
group
salt
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PCT/HU1992/000057
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French (fr)
Inventor
Tamás FODOR
János Fischer
László Dobay
Ede MÁRVÁNYOS
Katalin SZO^'KE
Ildikó BALLÓ
Ferenc Trischler
Éva PERÉNYI
Katalin GÁSPÁR
Elemér Ezer
Judit MATÚZ
Katalin Sághy
László Szporny
György Hajós
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Richter Gedeon Vegyészeti Gyár Rt.
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Publication of WO1993013076A1 publication Critical patent/WO1993013076A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
    • 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
    • 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
    • C07C323/54—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 acyclic and unsaturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/84—Unsaturated compounds containing keto groups containing six membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/86—Unsaturated compounds containing keto groups containing six-membered aromatic rings and other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or 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 to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or 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 to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/48—Acylated amino or imino radicals by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof, e.g. carbonylguanidines
    • 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 a novel gastric acid secre- tion-inhibiting and gastrocytoprotective pharmaceutical com ⁇ position, which comprises as active ingredient i) a 10:1 to 1:10 mixture by weight of a compound of the formula
  • R stands for a hydrogen atom or a hydroxy, C ⁇ -4al yl or alkoxy group
  • X means oxygen or sulfur or NH group
  • A means a group of the formula
  • Q stands for a hydrogen atom or a phenyl or substi ⁇ tuted phenyl group; m is 0 or 1; n is 0, 1 or 2; p is l when the dotted line represents a chemical bond, or p is 2 when the dotted line means no chemical bond; or means a group of the formula
  • R 1 means methyl, phenyl, substituted phenyl, ⁇ — ⁇ .- alkyl, C ⁇ _ 4 alkoxy or tetrahydronaphthyl group, with the compound of the formula
  • A means a group of the formula A-j , where R and X are as defined above; or
  • A means a group of the formula (A 2 ) , where Q, m, n and p
  • SUBSTITUTESHEET are as defined above; or A means a group of the formula (A 3 ) , where R 1 is as defined above; and _ B+ represents the protonated form of the compound of the
  • famotidine is the generic name of the compound of the for ⁇ 0 mula (III) , chemically N—sulfamyl—3-(2—guanidinothiazol—4- —ylmethylthio)propionamidine] : 1,4-dihydro—4—oxoquinoline—2—carboxylic acid famotidine salt, 4—oxo—4H—1—benzopyran—2—carboxylic acid famotidine salt, 4—oxo—4H—1—benzothiopyran— 2—carboxylic acid famotidine salt, 3—(4-chlorophenylthio)-2(E)—propenoic acid famotidine salt, 3—phenylsulfonyl—2(E)—propenoic acid famotidine salt, 3—(4—fluorophenylsulfon
  • compositions according to the invention may contain as active ingredient a 10:1 to 1:10 mixture by weight of 1,4—dihydro—4—oxoquino ⁇ line—2-carboxylic acid or 4—oxo—4H—1—benzopyran—2—carboxylic acid or 4—oxo—4H—1—benzothiopyran-2—carboxylic acid or 3—(4- - ⁇ hlorophenylthio)—2 (E)-propenoic acid or 3—phenylsulfonyl- —2 (E)-propenoic acid or 3—(4—fluorophenylsulfonyl)—2 (E)—pro ⁇ penoic acid or 3—phenyIsulfony1-2(Z)—propenoic acid or • 3- —benzylsulfony1—2 (E)—propenoic acid or 3—methyIsulfony1- —2(E)—
  • SUBSTITUTESHEET oxo-4—(5,6,7,8—tetrahydro—2—naphthyl)—2(E)—butenoic acid or 4—oxo— 2— entenoic acid, respectively, with famotidine.
  • compositions of the invention are prepared in a known manner, e.g. by a) mixing together a compound of the formula (II) , wherein A is as defined above, and the compound of the for ⁇ mula (III) in a ratio of 10:1 to 1:10 by weight and supple ⁇ menting the mixture obtained with well known additives and carriers; or b) mixing together a compound of the formula (I) , wherein A and B are as defined above, and well known addi ⁇ tives and carriers.
  • a process for the preparation of the new com- pounds of the formula (I) wherein A represents a group of the formula (A-j , (A 2 ) or (A 3 ) , respectively, the meaning of the substituents being the same as defined above, and B+ stands for the protonated form of the compound of the for ⁇ mula (III) , which comprises reacting a compound of the for- mula (II) , wherein A is as defined above, with the compound of the formula (III) .
  • the invention relates to a method of curing and/or preventing the inflammatory and ulcerative diseases of the esophagus, stomach and duodenum of mammals, including humans.
  • This method comprises administering to the patient or to the mammal to be treated (a) therapeutically effective dose(s) of one or more compound(s) of the formula (I) , wherein the substituents (symbols) are as defined above, or (a) therapeutically effective dose(s) of a mixture of 10:1 to 1:10 ratio by weight of a compound of the formula (II) , wherein the substituents are as defined above, with the com ⁇ pound of the formula (III) as such or in the form of the pharmaceutical composition of the invention.
  • Famotidine is a well known gastric acid secretion- inhibiting drug, the effect of which arises from its H 2 receptor-antagonizing action. However, famotidine does not possess any gastrocytoprotective effect.
  • Famotidine salts described till now e.g. famotidine hydrochloride
  • famotidine hydrochloride a known intermediates in the preparation of famotidine
  • the salts of famotidine formed with glutamic or aspartic acid as well as the double salts of these with ascorbic acid are described in the European patent specification No. 277,900.
  • X means oxygen or sulfur or an NH group and R stands for a hydrogen atom or hydroxy, C ⁇ _4alkyl or C 1 —4alkoxy group.
  • Q stands for hydrogen or an optionally substituted phenyl group, where the substituent may be halogen.
  • m is 0 or 1 whereas n is 0 ⁇ 1 or 2.
  • p is 1 when the dotted line symbolizes a further chemical bond whereas the dotted line means no bond when p is 2.
  • R 1 stands for a methyl, optionally substituted phenyl, C ⁇ _4alkoxy or tetra- hydronaphthyl group.
  • the salt formation according to the invention is carried out by reacting the starting compound of the formula
  • Famotidine base can be prepared e.g. according to the Bel ⁇ gian patent specification No. 905,409. The components taken in a substantially stoichiometric ratio are reacted in an inert organic solvent or in a mixture of an inert organic solvent and water and, if desired, the salt formation is completed by a mild heating.
  • Suitable organic solvents are e.g. methanol, ethanol or ethyl acetate.
  • salt formation which is optionally signalized by the clearing up of the reaction mixture
  • the product can be isolated in several well known ways such as: a) through crystallization promoted by cooling; b) by evaporating the solvent and then adding an inert organic solvent in order to promote the precipitation of a crystalline product; or c) by directly filtering off the product from the reac ⁇ tion mixture when the product is very slightly soluble.
  • SUBSTITUTESHEET line—2 carboxylic acid are commercially available.
  • the starting substances of the formula (lib) may be prepared e.g. according to the following literature refer ⁇ ences: L.N. Ower et al: J. Chem. Soc. , 3109 (1949); pub ⁇ lished Japanese patent specification 47—17836 (1969) ; or the Hungarian patent application No. 3572/89.
  • the preparation of the starting substances of the for ⁇ mula (lie) may be carried out by using the method of R. Scheffold [Helv. Chim. Acta 50, 798 (1967)] or 0. Grummitt et al [Org. Synth. Coll. Vol. 2, 109 (1055)].
  • compositions and new compounds, respectively according to the invention were subjected to a detailed pharmaceutical study.
  • the combinations and the new com ⁇ pounds respectively show a gastric acid secretion-inhibit ⁇ ing action in the Shay's test [Gastroenterology 5., 43 (1945)] and a significant cytoprotective effect in the Robert's test [Gastroenterology 77, 761 (1979)].
  • Famotidine salt (Example 5) 1.0 5.4
  • the ED50 value is the oral dose (in mg/kg) causing 50% inhibition.
  • the ED50 value is the oral dose (in mg/kg) causing 50% inhibition.
  • the ED5 0 value is the oral dose (in mg/kg) causing 50% inhibition.
  • Tables 1 to 3 illustrate that the famotidine salts according to the invention excellently inhibit the gastric acid secretion (with an oral ED 50 value of 0.5 to 1 mg/kg) and simultaneously possess a strong gastrocytoprotective effect (with an oral ED5 0 value of 5 to 9.2 mg/kg).
  • the gastrocytoprotective effect of the compound of Example 8 is more favourable than the individual effect of famotidine and the corresponding propenoic acid component.
  • Famotidine salt (Example 11) 1.5 2.7 .5
  • the ED5 0 value is the oral dose (in mg/kg) causing 50% inhibition.
  • xx • bactericidal effect measured in vitro against Helicobacter pylori; MIC means the minimum inhibitory concentration;
  • * means that the dose given of the compound causes an inhibition of the percentage given.
  • the ED 50 value is the oral dose (in mg/kg) causing 50% inhibition.
  • xx bactericidal effect measured in vitro against Helicobacter pylori;
  • MIC means the minimum inhibitory concentration
  • the ED50 value is the oral dose (in mg/kg) causing 50% inhibition; xx bactericidal effect measured in vitro against Helicobacter pylori; MIC means the minimum inhibitory concentration; * means that the dose given of the compound causes an inhibition of the percentage given; ** means that the dose given of the composition aggravates the gastric ulcer.
  • the ED 50 value is the oral dose (in mg/kg) causing 50% inhibition;
  • x means the MIC value (in ⁇ g/ml) , i.e. the minimum inhibitory concentration;
  • Table 7 shows that, while retaining the favourable antiulcer activity of famotidine, the famotidine salts of the formula (I) are excellent gastrocytoprotective sub ⁇ stances, several of which exert a favourable antibacterial effect, too.
  • Famotidine salt of Example 12 10.0 3.2+0.6* 204.4+52.0* 59.2 1.25
  • Famotidine salt of Example 18 1.0 2.3+0.4* 145.0+39.5* 61.4 0.5 .
  • Famotidine salt of Example 6 0.5 3.0+0.6 261.7+59.0* 53.1 0.5
  • MIXTURE (by wt.) : Famotidine/3-(4-fluoro- phenylsulfonyl) -2(E) - -propenoic acid 6:4 (Example 20) 5 0.5 3.6+0.5 273.5+52.7* 44.9
  • Famotidine salt of Example 5 1.0 2.0+0.2 116.9+26.8 62.0 1.03
  • Example 1 The invention is illustrated in detail by the aid of the following non-limiting Examples.
  • Example 1 The invention is illustrated in detail by the aid of the following non-limiting Examples.
  • a suspension containing 1.68 g (5 mmoles) of famotidine in 30 ml of ethanol is mixed with the solution of 1.06 g (5 mmoles) of 3-phenyIsulfony1-2(E)—propenoic acid in 10 ml of ethanol. After heating the mixture to 40°C a homogeneous solution is obtained which is then cooled to start the crys ⁇ tallization. After cooling to 0°C, the mixture is stirred for 2 hours, filtered, washed with ethanol and dried to obtain the title salt in a yield of 2.58 g ((94%), m.p.: 157-158°C.
  • the mixture obtained from the above amounts of ingredi- ents is homogenized and, after adding 15 ml of water, a tab- let-premixture, then tablets are prepared to obtain tablets with a total active " ingredient content of 60 mg each.

Abstract

The invention relates to a novel gastric acid secretion-inhibiting and gastrocytoprotective pharmaceutical composition, which comprises as active ingredient a 10:1 to 1:10 mixture by weight of a compound of formula (II), wherein A means a group of formula (A1), wherein R stands for a hydrogen atom or a hydroxy, C1-4alkyl or alkoxy group; X means oxygen or sulfur or NH group; or A means a group of formula (A2), wherein Q stands for a hydrogen atom or a phenyl or substituted phenyl group; m is 0 or 1; n is 0, 1 or 2; p is 1 when the dotted line represents a chemical bond, or p is 2 when the dotted line means no chemical bond; or A means a group of formula (A3), wherein R1 means methyl, phenyl, substituted phenyl, C-4-alkyl, C¿1-4?alkoxy or tetrahydronaphthyl group with the compound of formula (III) or a new compound of formula (I), wherein A is as defined above and B?+¿ represents the protonated form of the compound of formula (III). The invention furthermore relates to the novel compounds of formula (I), wherein A and B+ are as defined above, and a process for preparing these novel compounds. The compounds of formula (I) and the compositions according to the invention are useful for curing and/or preventing the inflammatory and ulcerative diseases of esophagus, stomach and duodenum of mammal.

Description

GASTRIC ACID SECRETION-INHIBITING AND GASTROCYTOPROTECTIVE •PHARMACEUTICAL COMPOSITIONS, NOVEL FAMOTIDINE SALTS AND PRO- CESS FOR PREPARING SAME
The invention relates to a novel gastric acid secre- tion-inhibiting and gastrocytoprotective pharmaceutical com¬ position, which comprises as active ingredient i) a 10:1 to 1:10 mixture by weight of a compound of the formula
A COOH (II) ,
wherein A means a group of the formula
Figure imgf000003_0001
wherein
R stands for a hydrogen atom or a hydroxy, Cι-4al yl or alkoxy group; X means oxygen or sulfur or NH group; or A means a group of the formula
Figure imgf000003_0002
A 4858-67 MR wherein
Q stands for a hydrogen atom or a phenyl or substi¬ tuted phenyl group; m is 0 or 1; n is 0, 1 or 2; p is l when the dotted line represents a chemical bond, or p is 2 when the dotted line means no chemical bond; or means a group of the formula
10
(A3),
R- - C - CH = CH - wherein
15 R1 means methyl, phenyl, substituted phenyl, ~ —Δ.- alkyl, Cι_4alkoxy or tetrahydronaphthyl group, with the compound of the formula
Figure imgf000004_0001
25 or ii) a new compound of the formula
Figure imgf000004_0002
wherein
A means a group of the formula A-j , where R and X are as defined above; or
'35 A means a group of the formula (A2) , where Q, m, n and p
SUBSTITUTESHEET are as defined above; or A means a group of the formula (A3) , where R1 is as defined above; and _ B+ represents the protonated form of the compound of the
5 formula (III) .
The following novel compounds of the formula (I) may be considered to be as preferred active ingredients [where famotidine is the generic name of the compound of the for¬ 0 mula (III) , chemically N—sulfamyl—3-(2—guanidinothiazol—4- —ylmethylthio)propionamidine] : 1,4-dihydro—4—oxoquinoline—2—carboxylic acid famotidine salt, 4—oxo—4H—1—benzopyran—2—carboxylic acid famotidine salt, 4—oxo—4H—1—benzothiopyran— 2—carboxylic acid famotidine salt, 3—(4-chlorophenylthio)-2(E)—propenoic acid famotidine salt, 3—phenylsulfonyl—2(E)—propenoic acid famotidine salt, 3—(4—fluorophenylsulfonyl)—2(E)—propenoic acid famotidine salt, 3-phenyIsulfony1-2(Z)-propenoic acid famotidine salt, 3—benzylsulfony1—2(E)— ropenoic acid famotidine salt, 3— ethylsulfony1—2(E)—propenoic acid famotidine salt, 3—phenylsulfonylpropionic acid famotidine salt, 4—oxo—4—(5,6,7,8—tetrahydro—2—naphthyl)—2 (E)—butenoic acid famotidine salt, 4—oxo—4—phenyl—2(E)—butenoic acid famotidine salt and 4—oxo—2—pentenoic acid famotidine salt.
In addition to those listed above, the compositions according to the invention may contain as active ingredient a 10:1 to 1:10 mixture by weight of 1,4—dihydro—4—oxoquino¬ line—2-carboxylic acid or 4—oxo—4H—1—benzopyran—2—carboxylic acid or 4—oxo—4H—1—benzothiopyran-2—carboxylic acid or 3—(4- -σhlorophenylthio)—2 (E)-propenoic acid or 3—phenylsulfonyl- —2 (E)-propenoic acid or 3—(4—fluorophenylsulfonyl)—2 (E)—pro¬ penoic acid or 3—phenyIsulfony1-2(Z)—propenoic acid or • 3- —benzylsulfony1—2 (E)—propenoic acid or 3—methyIsulfony1- —2(E)—propenoic acid or 3—phenylsulfonylpropionic acid or 4-
SUBSTITUTESHEET —oxo-4—(5,6,7,8—tetrahydro—2—naphthyl)—2(E)—butenoic acid or 4—oxo— 2— entenoic acid, respectively, with famotidine.
The pharmaceutical compositions of the invention are prepared in a known manner, e.g. by a) mixing together a compound of the formula (II) , wherein A is as defined above, and the compound of the for¬ mula (III) in a ratio of 10:1 to 1:10 by weight and supple¬ menting the mixture obtained with well known additives and carriers; or b) mixing together a compound of the formula (I) , wherein A and B are as defined above, and well known addi¬ tives and carriers.
According to a further aspect of the invention, there is provided a process for the preparation of the new com- pounds of the formula (I) , wherein A represents a group of the formula (A-j , (A2) or (A3) , respectively, the meaning of the substituents being the same as defined above, and B+ stands for the protonated form of the compound of the for¬ mula (III) , which comprises reacting a compound of the for- mula (II) , wherein A is as defined above, with the compound of the formula (III) .
Finally, the invention relates to a method of curing and/or preventing the inflammatory and ulcerative diseases of the esophagus, stomach and duodenum of mammals, including humans. This method comprises administering to the patient or to the mammal to be treated (a) therapeutically effective dose(s) of one or more compound(s) of the formula (I) , wherein the substituents (symbols) are as defined above, or (a) therapeutically effective dose(s) of a mixture of 10:1 to 1:10 ratio by weight of a compound of the formula (II) , wherein the substituents are as defined above, with the com¬ pound of the formula (III) as such or in the form of the pharmaceutical composition of the invention.
The famotidine salts of the formulae (Ia) , (lb) and (Ic) , falling within the scope of the novel compounds of the formula- (I) according to the invention, are new substances
Figure imgf000007_0001
possessing a significant gastrocytoprotective effect in addition to the expected gastric acid secretion-inhibiting action; thus, they are useful not only to treat but also to prevent diseases. These two effects are present not only additively as a sum of the effects of both components form¬ ing the salt, but a substantial synergis can be observed, too.
Famotidine is a well known gastric acid secretion- inhibiting drug, the effect of which arises from its H2 receptor-antagonizing action. However, famotidine does not possess any gastrocytoprotective effect.
Up to the present, no famotidine salts or famotidine- containing compositions have been known from the literature, which could significantly influence the pharmacological spectrum of activity of famotidine. Famotidine salts described till now (e.g. famotidine hydrochloride) are known as intermediates in the preparation of famotidine (see e.g. the Spanish patent specification No. 2,012,735). The salts of famotidine formed with glutamic or aspartic acid as well as the double salts of these with ascorbic acid are described in the European patent specification No. 277,900.
In the compounds of the formula (Ia) X means oxygen or sulfur or an NH group and R stands for a hydrogen atom or hydroxy, Cι_4alkyl or C1—4alkoxy group. In the compounds of the formula (lb) Q stands for hydrogen or an optionally substituted phenyl group, where the substituent may be halogen. The value of m is 0 or 1 whereas n is 0Λ 1 or 2. The value of p is 1 when the dotted line symbolizes a further chemical bond whereas the dotted line means no bond when p is 2.
In the compounds of the formula (Ic) R1 stands for a methyl, optionally substituted phenyl, Cι_4alkoxy or tetra- hydronaphthyl group.
The salt formation according to the invention is carried out by reacting the starting compound of the formula
TIT TE
Figure imgf000009_0001
or
II (lie)
R1 - C - CH = CH - COOH
respectively, with famotidine base of the formula (III) . Famotidine base can be prepared e.g. according to the Bel¬ gian patent specification No. 905,409. The components taken in a substantially stoichiometric ratio are reacted in an inert organic solvent or in a mixture of an inert organic solvent and water and, if desired, the salt formation is completed by a mild heating.
Suitable organic solvents are e.g. methanol, ethanol or ethyl acetate. After salt formation (which is optionally signalized by the clearing up of the reaction mixture) the product can be isolated in several well known ways such as: a) through crystallization promoted by cooling; b) by evaporating the solvent and then adding an inert organic solvent in order to promote the precipitation of a crystalline product; or c) by directly filtering off the product from the reac¬ tion mixture when the product is very slightly soluble.
Methanol, ethanol, ethyl acetate, diethyl ether and acetonitrile proved to be the preferred inert organic sol¬ vents for crystallization of the product.
From the starting substances of the formula (Ila) , 4- —oxo—4H—1—benzopyran-2—carboxylic acid and 4—hydroxyquino-
SUBSTITUTESHEET line—2—carboxylic acid are commercially available. 4-0xo—4H- —1—benzothiopyran—2—carboxylic acid can be prepared by using the method of J. Schmutz et al. [Helv- Chim. Acta 3_4, 769 (1951) ] . The starting substances of the formula (lib) may be prepared e.g. according to the following literature refer¬ ences: L.N. Ower et al: J. Chem. Soc. , 3109 (1949); pub¬ lished Japanese patent specification 47—17836 (1969) ; or the Hungarian patent application No. 3572/89. The preparation of the starting substances of the for¬ mula (lie) may be carried out by using the method of R. Scheffold [Helv. Chim. Acta 50, 798 (1967)] or 0. Grummitt et al [Org. Synth. Coll. Vol. 2, 109 (1055)].
The compositions and new compounds, respectively according to the invention were subjected to a detailed pharmaceutical study. The combinations and the new com¬ pounds, respectively show a gastric acid secretion-inhibit¬ ing action in the Shay's test [Gastroenterology 5., 43 (1945)] and a significant cytoprotective effect in the Robert's test [Gastroenterology 77, 761 (1979)].
Additional investigations were carried out for evalu¬ ating the inhibition of gastric ulcer induced by aspirin and stress [Rainsford: Agents and Actions 5., 553 (1975) ] as well as on the indomethacin-induced gastric ulcer. According to the latter method female RG-Wistar rats, previously starved for 24 hours, were orally treated by the compound to be tested, and then by 20 mg/kg of indometacin after 30 min¬ utes, and the ED50 values were determined. The results are summarized in the following Tables. The data of these Tables unequivocally prove the valuable gastrocytoprotective and significant gastric acid secretion-inhibiting effects of the combinations and the new salts according to the invention. The probable human dose will be between 50 and 500 mg of active agent/kg of body weight.
BSTITUTESHEET Table 1
Comparative pharmacological investigation of famotidine, 3-phenylsulfony1-2 (E)—propenoic acid and of the salt formed therefrom (see Example 5)
Inhibition of the Gastrocytoprotective gastric acid sec¬ effect on the acidic retion on Shay's alcohol model model
ED50 ED50
Famotidine 0.5 83
3-Phenylsulfonyl- -2 (E)-propenoic acid 11
Famotidine salt (Example 5) 1.0 5.4
The ED50 value is the oral dose (in mg/kg) causing 50% inhibition.
Table 2
Comparative pharmacological investigation of famotidine, 3—(4—fluorophenylsulfonyl)—2 (E) -propenoic acid and of the salt formed therefrom (see Example 6)
Inhibition of the Gastrocytoprotective gastric acid sec¬ effect on the acidic retion on Shay's alcohol model model
ED50 ED50
Famotidine 0.5 83
3-(4-Fluorophenylsulfo- nyl) -2 (E) -propenoic acid- 10 3.3
Famotidine salt
(Example 6) 0.5 9.2
The ED50 value is the oral dose (in mg/kg) causing 50% inhibition.
SUBSTITUTE SHEET Table 3 Comparative pharmacological investigation of famotidine, 3—benzylsulfony1—2(E)— ropenoic acid and of the salt formed therefrom (see Example 8)
Inhibition of the Gastrocytoprotective gastric acid sec- effect on the acidic retion on Shay's alcohol model model
ED50 ED50
Famotidine 0.5 83
3-Benzylsulfonyl-2(E)-
-propenoic acid 34 12
Famotidine salt
(Example 8) 0.5 5
The ED50 value is the oral dose (in mg/kg) causing 50% inhibition.
Tables 1 to 3 illustrate that the famotidine salts according to the invention excellently inhibit the gastric acid secretion (with an oral ED50 value of 0.5 to 1 mg/kg) and simultaneously possess a strong gastrocytoprotective effect (with an oral ED50 value of 5 to 9.2 mg/kg). The gastrocytoprotective effect of the compound of Example 8 is more favourable than the individual effect of famotidine and the corresponding propenoic acid component.
E SHEET Table 4 Comparative pharmacological investigation of famotidine, 4-oxo-4-(5, 6,7,8- -tetrahydro-2-naphthyl)-2(E)—butenoic acid and of the salt formed therefrom (see Example 11)
Inhibition of the Gastrocytoprotective Stress Indo ethacin- MICxx gastric acid sec¬ effect on the acidic model induced gastric retion on Shay's alcohol model ulcer model model
ED50 ED 50 ED 50 ED 50 μg/ml
Famotidine 0.5 83 20 (38%)* 0.3 inactive
4-Oxo-4-(4,6,7,8- -tetrahydro-2-naph- thyl) -2 (E) -butenoic acid 43 0.3 50 (25%) 50(61%) 62-125
Famotidine salt (Example 11) 1.5 2.7 .5
The ED50 value is the oral dose (in mg/kg) causing 50% inhibition. xx •= bactericidal effect measured in vitro against Helicobacter pylori; MIC means the minimum inhibitory concentration;
* = means that the dose given of the compound causes an inhibition of the percentage given.
Table 5 Comparative pharmacological investigation of famotidine, 4-oκo-4-phenyl- -2(E)— utenoic acid and of the salt formed therefrom (see Example 12)
Inhibition of the Gastrocytoprotective Stress Indomethacin- MICXX gastric acid sec¬ effect on the acidic model induced gastric retion on Shay's alcohol model ulcer model model
ED50 ED 50 ED50 ED 50 μg/ l
Famotidine 0.5 83 20 (38%)*
4-Oxo-4-phenyl- (E)- -butenoic acid 22 0.5 50 (54%)* 25*ι 31-125
Famotidine salt
(Example 12) 1.2 1.5 0.3
The ED50 value is the oral dose (in mg/kg) causing 50% inhibition. xx = bactericidal effect measured in vitro against Helicobacter pylori;
MIC means the minimum inhibitory concentration;
* means that the dose given of the compound causes an inhibition of the percentage given; ** means that the dose given of the composition aggravates the gastric ulcer,
Figure imgf000015_0001
Table 6 Comparative pharmacological investigation of famotidine, 4-oxo-2 (E)-pente- noic acid and of the salt formed therefrom (see Example 13)
Inhibition of the Gastrocytoprotective Stress Indomethacin- MICXX gastric acid sec¬ efiect on the acidic model induced gastric retion on Shay's alcohol model ulcer model model
C ED50 ED50 ED50 ED50 μg/ml c
Famotidine 0.5 83 20 (38%)* 0.3 inactive
"
4-OXO-2(E)-pente- c -noic acid 17 0.5 50 (35%)* 25** 15-125 m Famotidine salt
0) (Example 13) 0.7 2.2 0.1 125-500
I The ED50 value is the oral dose (in mg/kg) causing 50% inhibition; xx bactericidal effect measured in vitro against Helicobacter pylori; MIC means the minimum inhibitory concentration; * means that the dose given of the compound causes an inhibition of the percentage given; ** means that the dose given of the composition aggravates the gastric ulcer.
Figure imgf000015_0002
It can be seen from tables 4 to 6 that the salts accord¬ ing to the invention retain the favourable gastric acid secretion-inhibiting effect of famotidine and show a promi¬ nent synergetic gastrocytoprotective action.
Figure imgf000017_0001
Table 7 (Summary) Pharmacological effectivity of famotidine and several famotidine salts
3
-\ I in
0)
I
Figure imgf000017_0003
m The ED50 value is the oral dose (in mg/kg) causing 50% inhibition; x means the MIC value (in μg/ml) , i.e. the minimum inhibitory concentration;
* means inhibition;
** means percentual curing.
Figure imgf000017_0002
Table 7 shows that, while retaining the favourable antiulcer activity of famotidine, the famotidine salts of the formula (I) are excellent gastrocytoprotective sub¬ stances, several of which exert a favourable antibacterial effect, too.
Table 8
Tested n Dose Gastric juice Inhibition of material (No. of mg/kg Volume Acid content Inhibition of gastric acid animals) ml/lOOg μmol/100 g acid content content as compared to ED50 control (%) (mg/kg p.o.)
Famotidine 0.25 3.9+0.3 310.5+28.5* 40.6 0.5
Figure imgf000019_0001
8:2 (Example 15) 1.0 3.5+0.3* 188.8+47.1* 67.9
2:8 (Example 17) 1.0 4.3+0.3 330.6+35.6* 43.8
* p < 0.05 in comparison to the control
It can be seen from the above data that, though in com¬ parison to famotidine, 4—oxo—2—pentenoic acid has a much weaker gastric acid secretion-inhibiting effect, both the salt according to Example 13 as well as the mixtures con¬ taining famotidine and 4-oxo—2—pentenoic acid in various ratios inhibit the gastric acid secretion nearly to the same extent as famotidine does.
SUBSTITUTESHEET Table 8 (continuation)
Tested n Dose Gastric juice Inhibition material (No. of mg/kg Volume Acid content Inhibition of gastric aci animals) ml/lOOg μmol/100 g acid content content as compared to ED50 control (%) (mg/kg p.o.
Famotidine 0.25 3.9+0.3 310.5+28.5* 40.6 0.5
Figure imgf000021_0001
Famotidine salt of Example 12 10.0 3.2+0.6* 204.4+52.0* 59.2 1.25
MIXTURE (by wt.) : Famotidine/4-oxo-4- -phenyl-2(E)- -butenoic acid 1.25 2.7+0.5 107.0+38.4* 75 8.2:4.3 (Example 18)
* p < 0.05 in comparison to the control
Table 8 (continuation)
Tested n Dose Gastric juice Inhibition material (No. of mg/kg Volume Acid content Inhibition of gastric aci animals) ml/lOOg μmol/100 g acid content content as compared to ED50 control (%) (mg/kg p.o.)
Famotidine 0.25 3.9+0.3 310.5+28.5* 40.6 0.5
3-Benzylsulfonyl-2 (E) -propenoic acid 25.0 4.9+0.6* 200.5+46.0 29.2 34.0
Famotidine salt of Example 18 1.0 2.3+0.4* 145.0+39.5* 61.4 0.5 .
MIXTURE (by wt.) : Famotidine/3-benzyl- -sulfonyl-2(E)- -propenoic acid 1.0 2.8+0.5* 210.4+62.2 51.7 O 6:4 (Example 19)
3-(4-Fluorophenyl- -sulfonyl) -2 (E) -pro¬ penoic acid 10.0 5.9+0.3 265.7+30.4* 48.3 10.0
Famotidine salt of Example 6 0.5 3.0+0.6 261.7+59.0* 53.1 0.5
MIXTURE (by wt.) : Famotidine/3-(4-fluoro- phenylsulfonyl) -2(E) - -propenoic acid 6:4 (Example 20) 5 0.5 3.6+0.5 273.5+52.7* 44.9
* p < 0.05 in comparison to tho control
It is obvious from the above Table that, though in com¬ parison to famotidine, both 3-benzylsulfonyl-2 (E)-propenoic acid and 3-(4-fluorophenylsulfonyl)-2(E)-propenoic acid exert a much weaker acid secretion-inhibiting effect, both the salts according to Examples 8 and 6 inhibit the gastric acid secretion nearly to the same extent as famotidine. The mixtures of 6:4 ratio of famotidine/3—benzylsulfony1—2 (E)- —propenoic acid or famotidine/3-(4-fluorophenylsulfonyl)- —2(E)-propionic acid, respectively, proved to be similarly strong inhibitors of the gastric acid secretion.
SUBSTITUTE SHEET Table 8 (continuation)
Tested n Dose Gastric juice Inhibition o material (No. of mg/kg Volume Acid content Inhibition of gastric acid animals) ml/ioog μmol/100 g acid content content as compared to ED50 control (%) (mg/kg p.o.)
Famotidine 0.25 3.9+0.3 310.5+28.5* 40.6 0.5
3-Phenylsulfonyl-2 (E) -propenoic acid 1.0 6.0+0.4 650.1+74.0 7.3 11,0
Famotidine salt of Example 5 1.0 2.0+0.2 116.9+26.8 62.0 1.03
MIXTURE (by wt.) : Famotidine/3-phenyl- -sulfonyl-2 (E)- -propenoic acid 1.0 3.3+0.5 155.0+54.9* 54.2 6.1:3.9 (Example 21)
* p < 0.05 in comparison to the control
It can be seen from the above data that 3-phenyl- sulfonyl-2(E)-propenoic acid is a much weaker inhibitor of the gastric acid secretion than famotidine. In contrast, both the salt according to Example 5 or a 6.1:3.9 mixture by weight of famotidine with 3-phenylsulfonyl-2(E)-propenoic acid show a gastric acid secretion-inhibiting action resembling that of famotidine.
The invention is illustrated in detail by the aid of the following non-limiting Examples. Example 1
Preparation of l,4-dihydro-4-oxoquinoline-2-carboxylic acid famotidine salt
To a suspension of 3.4 g (0.01 mole) of famotidine in 200 ml of ethanol, a suspension containing 1.9 g (0.01 mole) of l,4-dihydro-4-oxoquinoline-2-carboxylic acid in 200 ml of ethanol is added portionwise while stirring, then the mix¬ ture is stirred at room temperature for 24 hours. After filtering the product and washing it with ethanol, the title salt is obtained in a yield of 5.0 g (96%), m.p. : 162-165°C. Example 2
Preparation of 4-oxo-4H-l-benzopyran-2-carboxylic acid famotidine salt
A suspension containing 3.4 g (0.01 mole) of famotidine in 20 ml of methanol is added to the suspension of 1.9 g (0.01 mole) of 4-oxo-4H-benzopyran-2-carboxylic acid in a mixture containing 20 ml of methanol and 20 ml of ethyl ace¬ tate. The suspension is boiled under reflux for 2 hours and then stirred at 10°C for a few additional hours. After fil¬ tering, the product is washed with ethyl acetate and dried at 90°C to give the title salt in a yield of 4.5 g (85%) , m.p.: 154-156°C (with decomposition). Example 3
Preparation of 4-oxo-4H-l-benzothiopyran-2-carboxylic acid famotidine salt After dissolving 2.0 g (0.01 mole) of 4-oxo-4H-l—benzo- thiopyran—2—carboxylic acid and 3.37 g of famotidine in a
SUBSTITUTE SHEET hot mixture containing 100 ml of methanol and 50 ml of water, the solution is filtered as hot and the title salt is let to crystallize out from the filtrate under cooling. After filtering the crystalline precipitate is washed with a small volume of cold ethanol and then diethyl ether to obtain the title salt in a yield of 3.8 g (70%), m.p.: 150- 153°C.
Example 4
Preparation of 3-(4-chlorophenylthio)—2(E)—propenoic acid famotidine salt
A solution containing 2.14 g (0.01 mole) 3—(4—chloro- phenylthio)—2(E)—propenoic acid in 20 ml of ethanol is added to the suspension of 3.37 g (0.01 mole) of famotidine in 30 ml of ethanol under stirring. The mixture is stirred at 50°C for 2 hours, then at room temperature for 3 hours, filtered and the precipitate is washed with ethanol to give the title salt in a yield of 5.3 g (96%), m.p.: 169-172°C. Example 5
Preparation of 3-phenyIsulfony1-2(E)—propenoic acid famotidine salt
A suspension containing 1.68 g (5 mmoles) of famotidine in 30 ml of ethanol is mixed with the solution of 1.06 g (5 mmoles) of 3-phenyIsulfony1-2(E)—propenoic acid in 10 ml of ethanol. After heating the mixture to 40°C a homogeneous solution is obtained which is then cooled to start the crys¬ tallization. After cooling to 0°C, the mixture is stirred for 2 hours, filtered, washed with ethanol and dried to obtain the title salt in a yield of 2.58 g ((94%), m.p.: 157-158°C. Example 6
Preparation of 3-(4-fluorophenylsulfonyl)—2(E)—prope¬ noic acid famotidine salt
After adding a solution containing 2.3 g (0.01 mole) of 3-(4-fluorophenylsulfonyl)—2(E)—propenoic acid in 20 ml of methanol to the suspension of 3.37 g (0.01 mole) of famoti¬ dine in 40 ml of methanol, the reaction mixture is stirred
T at room temperature for 1 hour, then the solvent is evapor¬ ated. After adding 50 ml of ethanol to the residue, the pre¬ cipitated crystals are filtered and washed with chloroform to obtain the title salt in a yield of 5.14 g (95%), m.p.: 137°C (with decomposition) . Example 7
Preparation of 3-phenylsulfony1-2(E)— ropenoic acid famotidine salt
After adding 1.06 g (5 mmoles) of 3-phenylsulfonyl- —2(Z)—propenoic acid dissolved in 20 ml of methanol to a suspension containing 1.68 g (5 mmoles) of famotidine in 30 ml of methanol, the reaction mixture is stirred for 1 hour, then 100 ml of chloroform are added, the crystalline precipitate is filtered, washed with diethyl ether and dried to give the title salt in a yield of 2.5 g (91%), m.p.: 119- 122°C.
Example 8
Preparation of 3-benzylsulfony1—2(E)—propenoic acid famotidine salt The suspension containing 3.37 g (0.01 mole) of famo¬ tidine in 40 ml of methanol is reacted with the solution of 2.26 g (0.01 mole) of 3-benzylsulfony1—2(E)—propenoic acid in 20 ml of methanol for 2 hours under stirring. After eva¬ porating the solvent, the residue is crystallized by adding 50 ml of ethanol to obtain the title salt in a yield of 5.18 g (92%), m.p.: 164-165°C. Example 9
Preparation of 3-methylsulfony1-2(E)-propenoic acid famotidine salt After suspending 3.37 g (0.01 mole) of famotidine in 40 ml of methanol and adding the solution of 1.5 g (0.01 mole) of '3-methylsulfonyl-2(E)-propenoic acid in 10 ml of metha¬ nol, crystals begin to precipitate from the solution within a short time. The precipitate is filtered, washed with methanol and dried to give the title salt in a yield of 4.6 g (94%), m.p.: 135°C (with decomposition).
BSTITUTE SHEET Example 10
Preparation of 3-phenylsulfonylpropionic acid famoti¬ dine salt
A solution containing 2.14 g (0.01 mole) of 3- henyl- sulfonylpro ionic acid in 20 ml of ethanol is added to a suspension of 3.37 g (0.01 mole) of famotidine in 50 ml of ethanol. After stirring for 2 hours, the suspension is fil¬ tered, washed with ethanol and dried to give the title salt in a yield of 5.5 g (99%), m.p.: 159-160°C. Example 11
Preparation of 4-oxo-4-(5,6,7,8-tetrahydro—2-naphthyl)- — 2(E)—butenoic acid famotidine salt
The suspension of 3.37 g (0.01 mole) of famotidine in 20 ml of ethanol is added portionwise to the solution con- taining 2.3 g (0.01 mole) of 4-oxc—4-(5,6,7,8-tetrahydro—2- —naphthyl)—2(E)—butenoic acid in 50 ml of ethanol. After stirring for 2 hours, the precipitate is filtered to obtain the title salt in a yield of 5.0 g (88%), m.p.: 158-159°C. Example 12 Preparation of 4-oxo-4-phenyl—2(E)—butenoic acid famo¬ tidine salt
After dissolving 1.76 g (0.01 mole) of 4-oxo-4-phenyl- —2(E)—butenoic acid and 3.37 g (0.01 mole) of famotidine in 50 ml of methanol at 60°C temperature and then stirring the reaction mixture for 1 hour, the mixture is cooled to room temperature and crystallized. The precipitate is filtered, washed with acetonitrile and dried at 40°C to obtain the title salt in a yield of 4.1 g (80%), m.p.: 129°C (with decomposition) . Example 13
Preparation of 4-oxo—2—pentenoic acid famotidine salt After stirring 1.14 g (0.01 mole) of acetylacrylic acid with 3.37 g (0.01 mole) of famotidine in 50 ml of methanol at 60°C for 1 hour, the solution is cooled, the precipitate is filtered, washed with acetonitrile and dried at 40°C to obtain the title salt in a yield of 3.5 g (77%), m.p.: 156-
TITUTESHEET 157°C (with decomposition) . Example 14
Preparation of an active agent combination 7.5 g of famotidine are mixed with 2.5 g of 4-oxo-2- —pentenoic acid to give 10 g of the active agent combina¬ tion.
Example 15
Preparation of an active agent combination 8 g of famotidine are mixed with 2 g of 4-oxo-2—pente- noic acid to give 10 g of the active agent combination. Example 16
Preparation of an active agent combination 6 g of famotidine are mixed with 4 g of 4-oxo-4- —(5,6,7,8—tetrahydro-2-naphthyl)-2(E)—butenoic acid to give 10 g of the active agent combination. Example 17
Preparation of an active' agent combination 2 g of famotidine are mixed with 8 g of 4-oxo-2—pente¬ noic acid to give 10 g of the active agent combination. Example 18
Preparation of an active agent combination 8.2 g of famotidine are mixed with 4.3 g of 4-oxo-4- —pheny1-2(E)—butenoic acid to give 12.5 g of the active agent combination. Example 19
Preparation of an active agent combination 6 g of famotidine are mixed with 4 g of 3—benzylsulfo¬ ny1—2(E)—propenoic acid to give 10 g of the active agent combination. Example 20
Preparation of an active agent combination 6 g of famotidine are mixed with 4 g of 3-(4-fluoro¬ phenylsulfonyl)-2(E)—propenoic acid to obtain 10 g of the active agent combination. Example 21
Preparation of an active agent combination
SUBSTITUTESHEET 6.1 g of famotidine are mixed with 3.9 g of 3—phenyl- sulfonyl—2(E)—propenoic acid to obtain 10 g of the active agent combination. Example 22 Preparation of a pharmaceutical composition Ingredients: Amount in Q
4-Oxo-4H-l-benzopyran-2-carboxylic acid 40 Famotidine 20
Magnesium stearate 100 Polyvinylpyrrolidone 40
Talc 60
Starch 100
Lactose 200
The mixture obtained from the above amounts of ingredi- ents is homogenized and, after adding 15 ml of water, a tab- let-premixture, then tablets are prepared to obtain tablets with a total active"ingredient content of 60 mg each.
TITUTE SHEET

Claims

Claims:
1. Novel compounds of the formula
θ
Figure imgf000031_0001
wherein A means a group of the formula
Figure imgf000031_0002
wherein
R stands for a hydrogen atom or a hydroxy, C;j__4alkyl or alkoxy group; X means oxygen or sulfur or NH group; or means a group of the formula
Figure imgf000031_0003
wherein
Q stands for a hydrogen atom or a phenyl or substi¬ tuted phenyl group; m is 0 or 1; n is 0, 1 or 2;
P is 1 when the dotted line represents a chemical bond, or p is 2 when the dotted line means no
SUBSTITUTE SHEET chemical bond; or A means a group of the formula
0
Figure imgf000032_0001
wherein
R3- means methyl, phenyl, substituted phenyl, C—4- alkyl, Cι_ lkoxy or tetrahydronaphthyl group: 10 B+ represents the protonated form of the compound of the formula
Figure imgf000032_0002
2. A compound selected from the group consisting of 0 1,4— ihydro—4—oxoquinoline—2—carboxylic acid famotidine salt, 4—oxo— H—1—benzopyran—2-carboxylic acid famotidine salt, 4—oxo— H—1—benzothiopyran—2—carboxylic acid famotidine salt, 3—(4—chlorophenylthio)—2(E)—propenoic acid famotidine salt, 5 3— iienylsulfony1—2(E)—propenoic acid famotidine salt, ■
3—(4—fluorophenylsulfonyl)—2(E)—propenoic acid famotidine salt, 3—phenyIsulfony1—2(Z)—propenoic acid famotidine salt, 3—benzylsulfony1—2(E)—propenoic acid famotidine salt, Q 3—methylsulfony1—2(E)—propenoic acid famotidine salt, 3— henylsulfonylpropionic acid famotidine salt, 4—oxo—4—(5,6,7,8—tetrahydro—2—naphthyl)—2(E)—butenoic acid famotidine salt, 4—oxo—4— henyl—2(E)—butenoic acid famotidine salt and 4—oxo—2—pentenoic acid famotidine salt.
3. A process for the preparation of the novel compounds of the formula θ
Figure imgf000033_0001
wherein A means a group of the formula
Figure imgf000033_0002
wherein
R stands for a hydrogen atom or a hydroxy, Cι_4alkyl or alkoxy group; X means oxygen or sulfur or NH group; or means a group of the formula
Figure imgf000033_0003
wherein
Q stands for a hydrogen atom or a phenyl or substi¬ tuted phenyl group; is 0 or 1; is 0, 1 or 2; is 1 when the dotted line represents a chemical bond, or p is 2 when the dotted line means no chemical bond; or means a group of the formula , K (A3 )
Rl - C - CH = CH - wherein R1 means methyl, phenyl, substituted phenyl, C—4- alkyl, Cι_4alko y or tetrahydronaphthyl group: B+ represents the protonated form of the compound of the formula
Figure imgf000034_0001
which comprises reacting a compound of the formula
COOH (II) ,
wherein A is as defined above, with the compound of the for¬ mula (III) .
4. A gastric acid secretion-inhibiting and gastrocyto- protective pharmaceutical composition, which comprises as active ingredient a therapeutically effective amount of a 10:1 to 1:10 mixture by weight of a compound of the formula (II) , wherein A is as defined in claim 1, and the compound of the formula (III) ; or a new compound of the formula (I) , wherein A and B are as defined in claim 1.
5. A pharmaceutical composition as claimed in claim 4, which comprises as active ingredient a therapeutically effective amount of a 10:1 to 1:10 mixture by weight of 1,4- —dihydro—4—oxoquinoline—2-carboxylie acid or 4—oxo—4H—1— en¬ zopyran—2—carboxylic acid or 4—oxo-4H—1—benzothiopyran—2-
SHEET —carboxylic acid or 3—(4—chlorophenylthio)—2 (E)—propenoic acid or 3—phenyIsulfony1—2(E)—propenoic acid or 3—(4—fluoro¬ phenylsulfonyl)—2(E)-propenoic acid or 3— henylsulfonyl- —2(Z)—propenoic acid or 3—benzylsulfony1—2(E)—propenoic acid 5 or 3—methylsulfony1-2(E)—propenoic acid or 3—phenylsulfonyl¬ propionic acid or 4-oxo—4-(5,6,7,8—tetrahydro—2-naphthyl)- —2(E)—butenoic acid or 4-oxo-2-pentenoic acid, respectively, with famotidine.
6. A pharmaceutical composition as claimed in claim 4, 10 which comprises as active ingredient a therapeutically effective amount of 1,4-dihydrc—4—oxoquinoline—carboxylic acid famotidine salt or 4-oxo-4H-l—benzothiopyran-2—carboxy¬ lic acid famotidine salt or 3-(4—chlorophenylthio)-2(E)—pro¬ penoic acid famotidine salt or 3—phenyIsulfony1—2(E)—prope-
15 onic acid famotidine salt or 3—(4—fluorophenylsulfonyl)- —2(E)— ropenoic acid famotidine salt or 3—benzylsulfony1— —2(E)— ropenoic acid famotidine salt or 3—methylsulfonyl- —2(E)—propenoic acid famotidine salt or 3—phenylsulfonylpro¬ pionic acid famotidine salt or 4—oxo—4—(5 ,6 , 1 ,8—tetrahydro- 0 —2—naphthyl)—2(E)-butenoic acid famotidine salt or 4—oxo—4- —phenyl—2 (E)—butenoic acid famotidine salt or 4—oxo—2—pente¬ noic acid famotidine salt, respectively.
7. Method for curing and/or preventing inflammatory and ulcerative diseases of esophagus, stomach and duodenum of 5 mammals, including humans, characterized by administering to the mammal to be treated a therapeutically effective amount of a new compound of the formula (I) , wherein A and B+ are as defined in claim 1, or a 10:1 to 1:10 mixture by weight of a compound of the formula (II) , wherein A is as defined 0 in claim 1, with the compound of the formula (III) as such or in the form of a pharmaceutical composition.
'5
SUBSTITUTESHEET
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Cited By (6)

* Cited by examiner, † Cited by third party
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
WO2013144077A1 (en) * 2012-03-30 2013-10-03 Nestec S.A. 4-oxo-2-pentenoic acid and brain health
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Cited By (17)

* Cited by examiner, † Cited by third party
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
WO2013144077A1 (en) * 2012-03-30 2013-10-03 Nestec S.A. 4-oxo-2-pentenoic acid and brain health
WO2013144080A1 (en) * 2012-03-30 2013-10-03 Nestec S.A. 4-oxo-2-pentenoic acid and cardiovascular health
WO2013144085A1 (en) * 2012-03-30 2013-10-03 Nestec S.A. 4-oxo-2-pentenoic acid and liver disorders
WO2013144083A1 (en) * 2012-03-30 2013-10-03 Nestec S.A. 4-oxo-2-pentenoic acid and the health of the digestive tract
WO2013144079A1 (en) * 2012-03-30 2013-10-03 Nestec S.A. 4-oxo-2-pentenoic acid and skin pigmentation
CN104220056A (en) * 2012-03-30 2014-12-17 雀巢产品技术援助有限公司 4-oxo-2-pentenoic acid and brain health
JP2015512903A (en) * 2012-03-30 2015-04-30 ネステク ソシエテ アノニム 4-oxo-2-pentenoic acid and cardiovascular health
JP2015517987A (en) * 2012-03-30 2015-06-25 ネステク ソシエテ アノニム 4-Oxo-2-pentenoic acid and skin pigmentation
JP2015518371A (en) * 2012-03-30 2015-07-02 ネステク ソシエテ アノニム 4-oxo-2-pentenoic acid and liver damage
JP2015519873A (en) * 2012-03-30 2015-07-16 ネステク ソシエテ アノニム 4-oxo-2-pentenoic acid and brain health
JP2015519874A (en) * 2012-03-30 2015-07-16 ネステク ソシエテ アノニム 4-Oxo-2-pentenoic acid and gastrointestinal health
US9238015B2 (en) 2012-03-30 2016-01-19 Nestec S.A. 4-oxo-2-pentenoic acid and cardiovascular health
US9259404B2 (en) 2012-03-30 2016-02-16 Nestec S.A. 4-oxo-2-pentenoic acid and brain health
US9486425B2 (en) 2012-03-30 2016-11-08 Nestec S.A. 4-oxo-2-pentenoic acid and liver disorders
US9693942B2 (en) 2012-03-30 2017-07-04 Nestec S.A. 4-oxo-2-pentenoic acid and skin pigmentation
CN104220056B (en) * 2012-03-30 2017-11-03 雀巢产品技术援助有限公司 The penetenoic acid of 4 oxo 2 and brain health

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HU914068D0 (en) 1992-03-30

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