WO1994014431A1 - Gastrocytoprotective pharmaceutical composition and process for the preparation thereof - Google Patents

Gastrocytoprotective pharmaceutical composition and process for the preparation thereof Download PDF

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Publication number
WO1994014431A1
WO1994014431A1 PCT/HU1993/000085 HU9300085W WO9414431A1 WO 1994014431 A1 WO1994014431 A1 WO 1994014431A1 HU 9300085 W HU9300085 W HU 9300085W WO 9414431 A1 WO9414431 A1 WO 9414431A1
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WO
WIPO (PCT)
Prior art keywords
group
general formula
alkyl group
weight ratio
stands
Prior art date
Application number
PCT/HU1993/000085
Other languages
French (fr)
Inventor
János Fischer
György HOFFMANN
Elemér Ezer
Judit MATÚZ
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.
Priority to AU58422/94A priority Critical patent/AU5842294A/en
Publication of WO1994014431A1 publication Critical patent/WO1994014431A1/en

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Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof

Definitions

  • the invention relates to a novel-type gastrocytoprotective pharmaceutical composition as well as a process for the preparation thereof.
  • ranitidine chemically N- ⁇ 2-[[[5- -[(dimethylamino)methyl]-2-furanoyl]-methyl]thio]ethyl ⁇ - -N'-methyl-2-nitro-1,1'-ethenediamine hydrochloride is a highly effective H 2 receptor-blocking agent being therefore a very valuable active agent of pharmaceutical compositions useful against gastric and duodenal ulcers (British patent specification No. 1,565,966 or the equivalent Hungarian patent specification No. 185,001).
  • R means hydrogen or a C 1-4 alkyl group
  • R 1 stands for: hydroxyl group; C 1-4 alkoxy group; or a group of the general formula (A)
  • R 2 means hydrogen or benzyl group
  • R 3 means a C 1-4 alkyl group
  • R 1 stands for a group of the general formula (B)
  • R 4 means a C 1-4 alkyl group
  • the present invention is aimed to develop a pharmaceutical composition combining the advantageous effects of both active agents mentioned above.
  • a mixture containing the compound of general formula (I), wherein the substituents are as defined above, and the compound of formula (II) in a weight ratio of 1:1 proved to be especially advantageous.
  • the present invention relates to a gastrocytoprotective pharmaceutical composition containing as active ingredients a compound of the general formula (I),
  • R means hydrogen or a C 1-4 alkyl group
  • R 1 stands for: hydroxyl group; C 1-4 alkoxy group; or a group of the general formula (A)
  • R 2 means hydrogen or benzyl group
  • R 3 means a C 1-4 alkyl group
  • R 1 stands for a group of the general formula (B)
  • R 4 means a C 1-4 alkyl group
  • ranitidine in a weight ratio of 10:1 to 1:10 together with carriers and auxiliaries known per se.
  • the pharmaceutical composition according to the invention contains as active ingredient methyl 4-(3-carboxy-4-hydroxyphenyl)- -4-oxo-(2E)-butenoate and ranitidine in a weight ratio of 10:1 to 1:10, preferably in a weight ratio of 1:1.
  • the invention furthermore relates to a process for the preparation of a novel gastrocytoprotective pharmaceutical composition, which comprises mixing a compound of the general formula (I),
  • R means hydrogen or a C 1-4 alkyl group
  • R 1 stands for: hydroxyl group; C 1-4 alkoxy group; or a group of the general formula (A)
  • R 2 means hydrogen or benzyl group
  • R 3 means a C 1-4 alkyl group
  • R 1 stands for a group of the general formula (B)
  • R 4 means a C 1-4 alkyl group
  • ranitidine in a weight ratio of 10:1 to 1:10 and supplementing them with carriers and auxiliaries known per se.
  • the invention furthermore relates to a method of healing and/or preventing of ulcerous diseases of mammals including man.
  • This method comprises introducing as active agent one or more therapeutically effective dose(s) of a mixture containing a compound of the general formula (I),
  • R means hydrogen or a C 1-4 alkyl group
  • R 1 stands for: hydroxyl group; C 1-4 alkoxy group; or a group of the general formula (A)
  • R 2 means hydrogen or benzyl group
  • R 3 means a C 1-4 alkyl group
  • R 1 stands for a group of the general formula (B)
  • R 4 means a C 1-4 alkyl group
  • ranitidine in a weight ratio of 10:1 to 1:10 alone or in the form of a pharmaceutical composition to the organism of a patient or animal in neeed of such treatment.
  • the combination of active agents according to the invention exerts also an antibacterial effect (in a concentration of >62 to 250 ⁇ g/ml on Helicobacter phylori).
  • the combination of active agents according to the invention can be formulated to pharmaceutical compositions by mixing them with the commonly used nontoxic, inert, solid or liquid carriers and/or auxiliaries suitable to parenteral or enteral administration.
  • carriers e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, stearic acid, talc as well as vegetable oils such as peanut oil or olive oil may be used.
  • the combination of active agents may be formulated to the usual pharmaceutical compositions, particularly e.g. to solid dosage forms such as rounded or edged tablet, dragee, capsule, e.g. gelatine capsule, pill, suppository or the like.
  • the amount of the active agent combination may be selected within a broad range, e.g. in the range between 25 mg and 1 g.
  • the compounds may optionally contain the usual pharmaceutical auxiliaries, e.g. preserving agents, stabilizers, wetting and emulsifying agents.
  • auxiliaries e.g. preserving agents, stabilizers, wetting and emulsifying agents.
  • compositions can be prepared in the usual ways e.g. by sieving, mixing, granulating and compressing the ingredients for preparing solid compositions.
  • the compositions may be subjected to other usual operations of the pharmaceutical technology, e.g. sterilization.
  • ranitidine 1 g is mixed with -9 g of ethyl N-[4- -(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoyl]- glycinate to obtain 10 g of active agent composition as product.

Abstract

The present invention relates to a gastrocytoprotective pharmaceutical composition containing as active agents a compound of general formula (I), wherein R means hydrogen or a C1-4alkyl group; R1 stands for: hydroxyl group; C¿1-4?alkoxy group; or a group of general formula (A), wherein R?2¿ means hydrogen or benzyl group; and R3 means a C¿1-4?alkyl group; or stands for a group of general formula (B), wherein R?4¿ means a C¿1-4?alkyl group, and ranitidine in a weight ratio of 10:1 to 1:10 together with carriers and auxiliaries known per se, and to a process for the preparation thereof. A favourable active agent of general formula (I) is e.g. methyl 4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate. The combination of the above active agents according to the invention exerts also an antibacterial effect (against the Helicobacter pylori strain).

Description

GASTROCYTOPROTECTIVE PHARMACEUTICAL COMPOSITION AND PROCESS FOR THE PREPARATION THEREOF
The invention relates to a novel-type gastrocytoprotective pharmaceutical composition as well as a process for the preparation thereof.
It is known that ranitidine (chemically N-{2-[[[5- -[(dimethylamino)methyl]-2-furanoyl]-methyl]thio]ethyl}- -N'-methyl-2-nitro-1,1'-ethenediamine hydrochloride is a highly effective H2 receptor-blocking agent being therefore a very valuable active agent of pharmaceutical compositions useful against gastric and duodenal ulcers (British patent specification No. 1,565,966 or the equivalent Hungarian patent specification No. 185,001).
Based on our investigations, it has been stated that salicylic acid derivatives of the general formula (I),
Figure imgf000003_0001
wherein
R means hydrogen or a C1-4alkyl group;
R1 stands for: hydroxyl group; C1-4alkoxy group; or a group of the general formula (A)
Figure imgf000003_0002
wherein
R2 means hydrogen or benzyl group; and
R3 means a C1-4alkyl group; or
R1 stands for a group of the general formula (B)
Figure imgf000004_0001
wherein
R4 means a C1-4alkyl group,
show a gastrocytoprotective effect in themselves, too ( Hungarian patent application No. P 92-4142).
The present invention is aimed to develop a pharmaceutical composition combining the advantageous effects of both active agents mentioned above.
It has surprisingly been observed in the course of our experiments that by mixing any of the compounds of general formula (I), wherein the substituents are as defined above, with ranitidine of the formula (II)
Figure imgf000004_0002
in a weight ratio of 10:1 to 1:10 and mixing them with the usual carriers and auxiliaries, a pharmaceutical composition possessing a strengthened gastrocytoprotective effect is obtained.
A mixture containing the compound of general formula (I), wherein the substituents are as defined above, and the compound of formula (II) in a weight ratio of 1:1 proved to be especially advantageous. Thus, the present invention relates to a gastrocytoprotective pharmaceutical composition containing as active ingredients a compound of the general formula (I),
Figure imgf000005_0001
wherein
R means hydrogen or a C1-4alkyl group;
R1 stands for: hydroxyl group; C1-4alkoxy group; or a group of the general formula (A)
Figure imgf000005_0002
wherein
R2 means hydrogen or benzyl group; and
R3 means a C1-4alkyl group; or
R1 stands for a group of the general formula (B)
Figure imgf000005_0003
wherein
R4 means a C1-4alkyl group,
and the compound of formula (II)
Figure imgf000006_0001
(generic name: ranitidine) in a weight ratio of 10:1 to 1:10 together with carriers and auxiliaries known per se.
According to a preferred embodiment the pharmaceutical composition according to the invention contains as active ingredient methyl 4-(3-carboxy-4-hydroxyphenyl)- -4-oxo-(2E)-butenoate and ranitidine in a weight ratio of 10:1 to 1:10, preferably in a weight ratio of 1:1.
The invention furthermore relates to a process for the preparation of a novel gastrocytoprotective pharmaceutical composition, which comprises mixing a compound of the general formula (I),
Figure imgf000006_0002
wherein
R means hydrogen or a C1-4alkyl group;
R1 stands for: hydroxyl group; C1-4alkoxy group; or a group of the general formula (A)
Figure imgf000006_0003
wherein R2 means hydrogen or benzyl group; and
R3 means a C1-4alkyl group; or
R1 stands for a group of the general formula (B)
Figure imgf000007_0001
wherein
R4 means a C1-4alkyl group,
with a compound of formula (II)
Figure imgf000007_0002
(generic name: ranitidine) in a weight ratio of 10:1 to 1:10 and supplementing them with carriers and auxiliaries known per se.
In the process of the invention it is especially preferable to mix methyl 4-(3-carboxy-4-hydroxyphenyl)-
4-oxo-(2E)-butenoate with ranitidine in a weight ratio of 10:1 to 1:10, preferably in a weight ratio of 1:1 and to supplement them with carriers and auxiliarries known per se.
The invention furthermore relates to a method of healing and/or preventing of ulcerous diseases of mammals including man. This method comprises introducing as active agent one or more therapeutically effective dose(s) of a mixture containing a compound of the general formula (I),
Figure imgf000008_0001
wherein
R means hydrogen or a C1-4alkyl group;
R1 stands for: hydroxyl group; C1-4alkoxy group; or a group of the general formula (A)
Figure imgf000008_0002
wherein
R2 means hydrogen or benzyl group; and
R3 means a C1-4alkyl group; or
R1 stands for a group of the general formula (B)
Figure imgf000008_0004
wherein
R4 means a C1-4alkyl group,
and a compound of formula (II)
Figure imgf000008_0003
(generic name: ranitidine) in a weight ratio of 10:1 to 1:10 alone or in the form of a pharmaceutical composition to the organism of a patient or animal in neeed of such treatment.
Combinations containing as active agents methyl 4- (3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate or ethyl N-[4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)butenoyl]- glycinate or 1-[4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)- butenoyl]-4-(ethoxycarbonyl)piperazine, respectively of the general formula (I) and ranitidine in a weight ratio of 10:1 to 1:10 proved to be peculiarly favourable.
The combination containing methyl 4-(3-carboxy-4- -hydroxyphenyl)-4-oxo-(2E)-butenoate and ranitidine was subjected to a study in detail.
In the course of pharmacological tests, the combination of 1:1 weight ratio inhibited the gastric acid secretion of so-called Shay rats [Gastroenterology 5., page 43 (1945)] in an oral dose of 7.3 mg/kg; as well as it effectively prevented the gastric laesions induced by acid-containing ethanol [Robert: Gastroenterology 77, page 761 (1979)] in a dose of 1.4 mg/kg (this is the so- called gastrocytoprotective action).
The inhibition of the -gastric ulcer induced by aspirin and stress was investigated by using the method of Rainford [Agents Actions 5, page 553 (1975)].
In a dose of 7.5 mg/kg, the above combination was capable to protect against the development of indo- methacin-induced gastric ulcers. This test was carried out in such a way that female RG-Wistar rats previously starved for 24 hours were orally treated with the combination to be tested and, after 30 minutes, with 20 mg/kg of indomethacin. The evaluation was made by comparision to the control group and ED50 values were determined.
The results of this study are summarized in Table 1.
Figure imgf000010_0001
Signs:
A: Methyl 4-(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)- -butenoate
B: Ranitidine
C: Mixture of 1:1 weight ratio of A to B.
Furthermore, the combination of active agents according to the invention exerts also an antibacterial effect (in a concentration of >62 to 250 μg/ml on Helicobacter phylori).
The combination of active agents according to the invention can be formulated to pharmaceutical compositions by mixing them with the commonly used nontoxic, inert, solid or liquid carriers and/or auxiliaries suitable to parenteral or enteral administration.
As carriers e.g. water, gelatine, lactose, starch, pectin, magnesium stearate, stearic acid, talc as well as vegetable oils such as peanut oil or olive oil may be used.
The combination of active agents may be formulated to the usual pharmaceutical compositions, particularly e.g. to solid dosage forms such as rounded or edged tablet, dragee, capsule, e.g. gelatine capsule, pill, suppository or the like.
The amount of the active agent combination may be selected within a broad range, e.g. in the range between 25 mg and 1 g.
The compounds may optionally contain the usual pharmaceutical auxiliaries, e.g. preserving agents, stabilizers, wetting and emulsifying agents.
The compositions can be prepared in the usual ways e.g. by sieving, mixing, granulating and compressing the ingredients for preparing solid compositions. The compositions may be subjected to other usual operations of the pharmaceutical technology, e.g. sterilization.
The invention is illustrated in detail by the following non-limiting Examples.
Example 1
Active agent composition.
5 g of ranitidine are mixed with 5 g of methyl 4- -(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate to give 10 g of active agent composition as product.
Example 2
1 g of ranitidine is mixed with -9 g of ethyl N-[4- -(3-carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoyl]- glycinate to obtain 10 g of active agent composition as product.
Example 3
9 g of ranitidine are mixed with 1 g of 1-[4-(3- -carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoyl]-4-(ethoxy- carbonyl)piperazine to give 10 g of active agent composition as product.

Claims

Claims
1. Gastrocytoprotective pharmaceutical composition, which c o m p r i s e s as active agent a compound of the general formula (I)
Figure imgf000012_0001
wherein
R means hydrogen or a C1-4alkyl group;
R1 stands for: hydroxyl group; C1-4alkoxy group; or a group of the general formula (A)
Figure imgf000012_0002
wherein
R2 means hydrogen or benzyl group; and
R3 means a C1-4alkyl group; or
R1 stands for a group of the general formula (B)
Figure imgf000012_0003
wherein
R4 means a C1-4alkyl group,
and a compound of formula (II)
Figure imgf000013_0001
(generic name: ranitidine) in a weight ratio of 10:1 to 1:10 and as carriers and auxiliaries those known per se.
2. A pharmaceutical composition as claimed in claim 1, which c o m p r i s e s as active agent methyl 4-(3- carboxy-4-hydroxyphenyl)-4-oxo-(2E)-butenoate and ranitidine in a weight ratio of 10:1 to 1:10, preferably in a weight ratio of 1:1.
3. Process for the preparation of a gastrocytoprotective pharmaceutical composition, which c o m p r i s e s mixing a compound of the general formula (I),
Figure imgf000013_0002
wherein
R means hydrogen or a C1-4alkyl group;
R1 stands for: hydroxyl group; C1-4alkoxy group; or a group of the general formula (A)
Figure imgf000013_0003
wherein R2 means hydrogen or benzyl group; and
R3 means a C1-4alkyl group; or
R1 stands for a group of the general formula (B)
Figure imgf000014_0001
wherein
R4 means a C1-4alkyl group,
with a compound of formula (II)
Figure imgf000014_0002
(generic name: ranitidine) in a weight ratio of 10:1 to 1:10 and supplementing them with carriers and auxiliaries known per se.
4. A process as claimed in claim 3, which c o m p r i s e s mixing methyl 4-(3-carboxy-4-hydroxy- phenyl)-4-oxo-(2E)-butenoate with ranitidine in a weight ratio of 10:1 to 1:10, preferably in a weight ratio of 1:1 and supplementing them with carriers and auxiliaries known per se.
5. Method for the healing and/or preventing of ulcerous diseases of mammals including man, which
c o mp r i s e s introducing as active agent one or more therapeutically effective dose(s) of a mixture containing a compound of the general formula (I)
Figure imgf000015_0001
wherein
R means hydrogen or a C1-4alkyl group;
R1 stands for: hydroxyl group; C1-4alkoxy group; or a group of the general formula (A)
Figure imgf000015_0002
wherein
R2 means hydrogen or benzyl group; and
R3 means a C1-4alkyl group; or
R1 stands for a group of the general formula (B)
Figure imgf000015_0003
wherein
R4 means a C1-4alkyl group,
and a compound of formula (II)
Figure imgf000015_0004
(generic name: ranitidine) in a weight ratio of 10:1 to
PCT/HU1993/000085 1992-12-29 1993-12-29 Gastrocytoprotective pharmaceutical composition and process for the preparation thereof WO1994014431A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58422/94A AU5842294A (en) 1992-12-29 1993-12-29 Gastrocytoprotective pharmaceutical composition and process for the preparation thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HUP924143 1992-12-29
HU9204143A HU213101B (en) 1992-12-29 1992-12-29 Process for producing pharmaceutical composition of synergetic gastrocitoprotective activity, containing ranitidine and derivative of the salicylic acid

Publications (1)

Publication Number Publication Date
WO1994014431A1 true WO1994014431A1 (en) 1994-07-07

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HU (1) HU213101B (en)
WO (1) WO1994014431A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2105193A (en) * 1981-09-04 1983-03-23 Glaxo Group Ltd Pharmaceutical compositions containing non-steroidal anti-inflammatory agents
GB2120938A (en) * 1982-05-14 1983-12-14 Richter Gedeon Vegyeszet Anti-ulcer pharmaceutical compositions containing salicylic acid or its salts
EP0321613A1 (en) * 1987-12-18 1989-06-28 Bristol-Myers Company The effect of a combination of a beta-adrenergic agonist and certain histamine H1- and/or H2-receptor blockers on gastrointestinal injury produced by nonsteroidal anti-inflammatory compositions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2105193A (en) * 1981-09-04 1983-03-23 Glaxo Group Ltd Pharmaceutical compositions containing non-steroidal anti-inflammatory agents
GB2120938A (en) * 1982-05-14 1983-12-14 Richter Gedeon Vegyeszet Anti-ulcer pharmaceutical compositions containing salicylic acid or its salts
EP0321613A1 (en) * 1987-12-18 1989-06-28 Bristol-Myers Company The effect of a combination of a beta-adrenergic agonist and certain histamine H1- and/or H2-receptor blockers on gastrointestinal injury produced by nonsteroidal anti-inflammatory compositions

Also Published As

Publication number Publication date
AU5842294A (en) 1994-07-19
HUT72417A (en) 1996-04-29
HU9204143D0 (en) 1993-04-28
HU213101B (en) 1997-02-28

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