DE2416143A1 - ANTIULCUS AGENT - Google Patents

Description

2416H3

Case 5/627
Dr.Fl./Kp.

DR. KARL THOMAE GMBH., BIBERACH AN DER RISS

Antiulcer agents

The subject of the present application is a new antiulcus agent, which as active substance one or more compounds of the general formula I,

CH ₉ - N

R ₂

(I)

Nile

Hal

in the

Shark a chlorine or bromine atom,

Usually a hydrogen, chlorine or bromine atom, Rp is an optionally substituted by I-3 hydroxyl groups branched alkyl radical with 3 to 5 carbon atoms, a

Cyclohexyl or hydroxycyclohexyl _{radical and R 11 is} a straight-chain or branched alkyl radical with 1 to 4 carbon atoms or a hydrogen atom if R _{2 is} a hydroxycyclohexyl radical or an optionally through

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1 to 3 hydroxyl groups substituted branched alkylreat with 3 to 5 carbon atoms, or their physiologically acceptable acid addition salts with inorganic ones or contains organic acids.

For pharmaceutical use, the compounds of the above general formula I or their physiologically tolerable acid addition salts can be incorporated with inorganic or organic acids into the customary preparation forms such as tablets, coated tablets, capsules or solutions. The new antiulcer agent is applied to humans expediently 3 to 4 times a day in a dosage of 25 to 100 mg, but preferably 30 to 60 mg. The daily dose is therefore ^75-1 IOO mg, but preferably 90 - ¹ mg 2 IO.

For example, the connections were

A = N-Cyclohexy1-3 »S-dibromo ^ -hydroxy-N-methyl-benzylamine hydrochloride,

B - 3,5-dibromo-2-hydroxy-N- (trans- ¹ J-hydroxy-cyclohexyl) -benzylami n-hy dr ο ch Io ri d,

C = N-ethyl-N-cyclohexyl ^^ - dibromo ^ -hydroxy-benzylamine hydrochloride and

D = ^{3,5-dibromo-1} l-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylaminhydrochlorid

examined with regard to their anti-ulcer effect as follows:

The effect of the substance to be examined on ulcera was after the method of K. Tagaki et al. (Jap. J. Pharmac. 19, 418 (1969)) certainly. For this purpose, female rats with a body weight between 220 and 350 g were opened and the abdominal cavity under ether anesthesia the stomach exposed. After that, between the muscularis mucosae

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and the submucosa of the stomach at one point 0.05 ml of a 5 lb. Acetic acid solution injected. The abdominal cavity was closed again after the injection. The after 3 to 5 days at the application site in The ulcers arising on the mucous membrane were treated for 3 weeks by adding the substance to be investigated in the doses of 50 and 100 mg / kg treated to the putter (5 to 8 animals / dose). The control animals received the powdered putter only.

After 3 weeks of treatment, the animals were sacrificed, the stomach was removed and the ulcers were determined by measuring the length and width of the ulcer. The effect of the substance against controls (100 %) was determined:

treatment Dose mg / kg
po Reduction of the ulcers
in % compared to control control powder putter 0 Substance A 50
100 - 73
- 82 Substance B 50
100 - 59
- 78 Substance C 50
100 - 39
- 54 Substance D 50
100 - 11
- 29

The indicative acute toxicity of the substances was determined in groups of 5 white mice after administration of a dose of 5,000 mg / kg p.o. determined per animal (observation time: 72 hours):

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substance > 5 000 mg / kg acute Toxicity from 5 Animals died) A. > 5 000 mg / kg p.o. (1 from VJl Animals died) B. > 5 000 mg / kg p.o. (0 from VJI Animals died) C. > 5 000 mg / kg p.o. (0 from 5 Animals died) D. p.o. (0

The compounds of the general formula I can be per se produce known methods, for example by implementing a Compound of general formula II,

Shark

CH ₂ - R ₆

(II)

in the

R ₁ and Hai are as defined at the outset and

Rg is a hydroxyl group, a chlorine, bromine or iodine atom, an acyloxy, Means sulfonyloxy, alkoxy, aryloxy or aralkoxy group, with an amine of the general formula III,

H-N

(III)

in the
R _? and

. as defined at the beginning.

The reaction is expediently carried out in a solvent such as acetone, carbon tetrachloride, chloroform, ethanol, tetrahydrofuran, benzene, toluene, dioxane, tetralin or in excess of the amine of the general formula III used and depending on the reactivity of the radical Rg at temperatures between -70 and 200 ° C. However, the implementation can also be done without

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_ 5 -

Solvent to be carried out. If Rg is, for example, a halogen atom, the reaction is preferably carried out at temperatures between 0 and 150 ⁰ C, for example at the boiling point of the solvent used, and expediently in the presence of a hydrogen halide binding agent, for example an inorganic base such as sodium carbonate or sodium hydroxide, an ion exchange, or carried out a tertiary organic base such as triethylamine or pyridine. A tertiary organic base used can also serve as a solvent at the same time.

The following examples are intended to explain the invention in more detail:

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Example A.

yl-35 5-dibromo-2-hydroxy-benzylamine-hydrochloride

17 g of 3,5-dibromo-2-hydroxy-benzyl bromide and 12.7 g of N-ethyl-cyclohexylamine are refluxed in 150 ml of ethanol for 3 hours. It is then evaporated to dryness. The residue is shaken with 150 ml of chloroform and 200 ml of water. The chloroform phase will separated, filtered and concentrated to dryness. The residue is dissolved in ethanol and acidified with ethanolic hydrochloric acid. The N-ethyl-N-cyclohexyl-3,5-dibromo-2-hydroxybenzylamine hydrochloride crystallizes from a melting point of 193-19 ° C (decomp.).

The following connections can be established analogously to example A:

N-ethyl-N-cyclohexyl-3,5-dibromo- ^i- l-hydroxy-benzylamine. Melting point of the hydrochloride: 180-18l ° C (decomp.).

3-Bromo-2-hydroxy-N- (trans-4-hydroxy-cyclohexyl) -benzylamine Melting point of the hydrochloride: 19 ^ - 196 ° C (decomp.).

3-Bromo-5-chloro-N-cyclohexyl-4-hydroxy-N-methyl-benzylamine Melting point: 136-138 ° C.

3,5-Dibromo-N- (dihydroxy-tert-butyl) -2-hydroxy-benzylamine Melting point of the hydrochloride: I87 - 189 ⁰ C.

3,5-dichloro-N- (dihydroxy-t-butyl) -4-hydroxy-benzylamine Melting point of the hydrochloride: I66 - 169 ⁰ C. (Zar.).

3,5-dibromo-2-hydroxy-M-tert-pentyl-benzylamine Melting point of the hydrochloride: 202-2O6 ° C (dec.).

3,5-dibromo-4-hydroxy-N- (trans-3-hydroxy-cyclohexyl) -benzylamine Melting point of the hydrochloride: 215-215.5 ° C (dec.).

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SiS-dibromo- ^ - hydroxy-N-Ctrans-il-hydroxy-cyclohexyD-benzylamine Melting point of the hydrochloride: 212 - 218 ° C (dec.)

3,5-dibromo-4-hydroxy-N- (cis-3-hydroxy-cyclohexyl) -benzylamine Melting point of the hydrochloride: 216-218 ⁰ C (dec.).

N-cyclohexyl-3,5-dibromo-2-hydroxy-N-methyl-benzylamine Melting point of the hydrochloride: I89 - 191 ⁰ C (dec.).

example 1

Tablets with 50 mg of N-cyclohexyl-3,5-dibromo-2-hydroxy-N- methylbenzylamine hydrochloride

Composition: anhydrous 50.0 mg 1 tablet contains: 120.0 mg Active ingredient 10.0 mg Calcium phosphate sec., 30.0 mg Aerosil 5.0 mg Cornstarch 20.0 mg Polyvinyl pyrrolidone 3.0 mg Potato starch 2.0 mg Maleic acid Magnesium stearate

240.0 mg Manufacturing process:

The mixture of the active substance with calcium phosphate, Aerosil and corn starch is with a 10 ^ igen solution of the polyvinylpyrrolidone in ethanol, which also contains maleic acid dissolved, granulated through a sieve 1.5 mm, dried at 45 ° C and again through the above Grated sieve. The granules obtained in this way are mixed with potato starch and magnesium stearate and pressed into tablets.

Tablet weight: 20 mg
Rubber stamp: . 9 mm 0

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- 8 Example 2

Dragees with 30 mg of N-cyclohexyl ^ ii-dibromo ^ -hydroxy-N- methylbenzylamine hydrochloride

Composition: 30.0 mg 1 dragee contains: 100.0 mg Active ingredient 10.0 mg Calcium phosphate sec., Anhydrous 20.0 mg Aerosil 5.0 mg Cornstarch 3.0 mg Polyvinyl pyrrolidone 10.0 mg Maleic acid 2.0 mg Potato starch Magne s i ums t e ar at

180.0 mg

Production of the cores analogous to the drageing example:

According to a known method, the cores are covered with a shell, which consists essentially of talc and sugar.

Example 3

Hard gelatine capsules with 50 mg N-cyclohexyl-3,5-dibromo-2-hydroxy- N-methyl-benzylamine hydrochloride

1 capsule contains:

Active substance 50.0 mg

Potato starch 40.0 mg Talc IQ ₅ mg O

100.0 mg

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- 9 manufacturing processes:

The substances are mixed intensively and placed in hard gelatin capsules Bottled of suitable size.

Capsule filling: 100 rag.

Example 4

Juice with 50 mg of N-Cyclohexy1-3,5-dibromo-2-hydroxy-N-methyl-benzylamine hydrochloride

Composition:

Active ingredient

sugar

Tartaric acid

sec. Sodium phosphate. 2H _? 0

Saccharin sodium p-oxybenzoic acid methyl ester propyl p-oxybenzoate Eucalyptus Menthol Essence Raspberry Essence

Pure ethanol

Dist. Water ad

Production method:

Approx. 50 ml of water are heated to 80 ° C and the p-oxybenzoic acid ester, Sugar, sodium saccharin, tartaric acid, sec. Sodium phosphate and the active substance dissolved. Then the solution of eucalyptus menthol essence and raspberry essence stirred into ethanol. It is then filtered clear.

10 ml of juice contain 50 mg of active substance

0.5 G 70.0 G 0.3 G 1.2 G 0.2 G 0.07 G 0.03 G 0.1 S. 0.02 G 2.0 G 100.0 G

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Claims (3)

Claims in the Shark a chlorine or bromine atom, R _{1 is} a hydrogen, chlorine or bromine atom, R _{2 is} a branched alkyl radical with 3 to 5 carbon atoms optionally substituted by 1 to 3 hydroxyl groups, a cyclohexyl or hydroxycyclohexyl radical and R |, a straight-chain or branched alkyl radical with 1 to 4 carbon atoms or a hydrogen atom, if Rp is a hydroxycyclohexyl radical or an optionally represent branched alkyl radicals with 3 to 5 carbon atoms substituted by 1 to 3 hydroxyl groups, or their physiologically compatible acid addition salts with inorganic or organic acids. 509842/0848 24Ί6Η3 2. Antiulcus agent according to claim 1, characterized in that this 25 to 100 mg, but preferably 30 to 60 mg, one Compound of the above general formula I contains as an active ingredient. 3. Method of making a new antiulcer agent, thereby characterized in that one or more compounds of the general formula I, (D shark in the Shark a chlorine or bromine atom, Usually a hydrogen, chlorine or bromine atom, Rp is an optionally substituted by 1 or 3 hydroxyl groups branched alkyl radical with 3 to 5 carbon atoms, a cyclohexyl or hydroxycyclohexyl radical and R ₁ . a straight-chain or branched alkyl radical with 1 to 4 carbon atoms or a hydrogen atom, if R _{2 represents} a hydroxycyclohexyl radical or a branched alkyl radical with 3 to 5 carbon atoms optionally substituted by 1 to 3 hydroxyl groups, as well as their physiologically acceptable acid addition salt> with inorganic or organic acids be incorporated into the usual pharmaceutical preparation forms. 509842/0848 24Ί6Η3 Method according to claim 3j characterized in that 25 to 100 mg, but preferably 30 to 60 mg, of one or more compounds of the above general formula I as active substance be incorporated into the usual pharmaceutical preparation forms. ee fciulousiels retroactively 509842/0848