HU211216B - Process for producing novel salts of indometaching and the pharmaceutical compositions comprising them - Google Patents

Abstract

Indomethacin salts of formula (III) are new. In (III), R1 is 1-4C alkyl gp. and dotted lines represent single or double bonds.

Description

SUMMARY OF THE INVENTION The present invention relates to the preparation of novel indomethacin salts having particularly advantageous biological properties and pharmaceutical compositions thereof.

As used herein, in the formulas, R ¹ is C 1 -C 4 alkyl, the dotted line being an optional bond.

It is known that 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3-acetic acid or 1- (p-chlorobenzoyl) -5-methoxy-2-methyl-3- indolyl acetic acid (commonly known as indomethacin), one of the most widely used anti-inflammatory agents, having both antipyretic and analgesic activity (U.S. Patent No. 3,161,654). Certain salts of indomethacin are also known, such as the alkali metal salts and the noluminium salt (Merck Index 1989, p. 787). However, the drugs have the disadvantage that they have certain side effects - thus, prolonged use of the effective dose may cause ulcerative symptoms in certain patients. The anticoagulant and antithrombotic effect of indomethacin / Arzneimittel Forsch is also known. 33 (I), No. 1, p.150 (1983); Boll.Chim. Farm. 725 p 387 (1986).

The object of the present invention was to provide derivatives which do not have the above disadvantages.

The present invention is based on the discovery that salts of indomethochine with the isoquinoline derivatives of formula (I) and mixtures of defined ratios, while retaining the beneficial toxicity properties of both indomethacin and isoquinoline derivatives, have an increased anti-inflammatory effect, have both indomethacin and commercial salts and commercially available forms of isoquinoline derivatives.

Due to their advantageous properties above, these compounds are useful as active ingredients of medicaments in the treatment of arthritis, rheumatic and other inflammatory diseases.

The isoquinoline derivatives of formula (I) may be present in the form of a benzyl or benzene derivative, as appropriate. Our application relates to both isomers, both starting materials and end products. However, based on our physicochemical studies to date, it is believed that the salts of the present invention have the formula (ΙΠ).

The smooth muscle anticonvulsant, circulatory, antihypertensive activity of the isoquinoline derivatives of formula I is known. This group includes a number of long-known drug agents, such as papaverine and perparin, their di- and tetrahydro derivatives, and their benzal isomers (U.S. Patent No. 150,535). A variety of their salts have been described for this effect, such as the halogen, sulfate, phosphate, borate salts mentioned in U.S. Pat. Hungarian Patent Specification. Also known is the salt of drotaverine with theophylline-7-acetic acid, which has been patented for gerontological use based on the above properties and for the treatment of pathological conditions resulting from impaired microcirculation of blood (Hungarian Patent No. 197,207).

SUMMARY OF THE INVENTION The present invention relates to salts of isoquinoline derivatives of formula (I) with indole acetic acid derivatives of formula (Π). Salts which are substituted on the isoquinoline ring system with a methoxy or ethoxy group and contain the isoquinoline and acid groups in a 1: 1 ratio are particularly important.

The salts of the present invention have not yet been described in the literature. Their physico-chemical analysis was performed and their structure was confirmed.

The present invention also provides a process for the preparation of salts of isoquinoline derivatives of formula I with indomethacin by reacting the isoquinoline derivative or salt thereof with indomethacin II.

Alternatively, the indomethacin may be used in the form of a salt (e.g., borate or formate), or the isoquinoline derivative may be reacted in the form of a salt or both components and the reaction carried out by exchange.

The salt-forming reaction is preferably carried out in the presence of an apolar organic solvent at a temperature of 10-100 ° C. Halogenated hydrocarbons such as dichloromethane, dichloroethane, carbon tetrachloride are preferred. If the salt is formed in solution, the residue which remains after the mixture has been folded down can be crystallized initially, often at low temperatures, initially with a gummy material. Crystallization can be carried out more rapidly in the presence of a polar solvent, preferably in alcohols e.g. in absolute ethanol.

The novel compounds of the present invention may be prepared, e.g. are: papaverine indomethacin salt, perparin indomethacin salt, drotaverine indomethacin salt, dihydropapaverine indomethacin salt, dihydroperpar indomethacin salt.

The present invention also relates to compositions comprising as active ingredient salts or mixtures of isoquinoline derivatives of the formula I with indomethacin. The molar ratios of the active compounds in the mixtures are isoquinolinoneomethacin = 1: 0.8-1.5. These formulations may contain additional additives commonly used in the manufacture of pharmaceuticals to provide better dosage, easier handling, increased stability, and promote proper absorption and absorption within the body. The products may be administered orally, intraperitoneally, rectally or transdermally, for both human and veterinary use.

The toxicity of the new formulations is very favorable.

The present invention also relates to the use of indomethacin salts or mixtures of the isoquinoline derivatives of the formula I in the treatment of human or veterinary therapeutics for the prevention or prophylaxis of inflammatory diseases, in particular joints, for the treatment of pain or for the treatment or prevention of blood aggregation.

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In the treatment process, the active ingredient may be used in the form of capsules, tablets, sustained release tablets or dragees, transdermal formulations or the like.

In addition to inert, non-toxic carriers and excipients, combinations may also be used in the pharmaceutical compositions, i.e., additional biologically active substances such as muscle relaxants, cardiac drugs, vitamins, and enhancers may be added.

Details of our procedure are set forth in the Examples, but are not intended to be limiting.

Examples

/. Chemical examples

Ll. example

To a solution of 8.7 g (0.02 mol) of drotaverine hydrochloric acid in 100 ml of dichloromethane is added 50 ml of water, followed by a solution of 1 g (0.025 mol) of sodium hydroxide and 20 ml of water. The two phases are separated. The organic phase is washed with neutral water with deionized water. (The pH of the first aqueous portion is above 10.) It is dried over sodium sulfate and then filtered. To the resulting crude solution was added 7.1 g (0.02 mol) of indomethacin. The bright yellow solution was rotaversed in vacuo to remove solvent. 16.0 g of a solidifying gum are obtained, which is dissolved in 20 ml of absolute ethanol while hot. The crystalline salt precipitated from the solution is filtered after cooling, washed with cold absolute ethanol and dried. 14.62 g of the dihydropperparine indomethacin salt are obtained. 90-94 ° C.

Yield 96.9%. After recrystallization from ethanol:

96-98 'C. Elemental analysis: C ₄₃ H ₄₇ ClN ₂ O ₈ M, 754.5 calculated: C, 68.39; H, 6.23; N, 3.71; % Cl 4.71 found: C, 68.14; H, 6.23; N, 3.47. Cl, 4.65

By titration with perchloric acid: 98.8%. According to the alkaline titration: 101%. The product was also identified by UV and NMR.

1.2. example

To a solution of 22.6 g (0.06 mol) of papaverine hydrochloric acid in 150 ml of dichloromethane is added 100 ml of water followed by a solution of 3 g (0.075 mol) of sodium hydroxide and 50 ml of water. The two phases are separated. The organic phase is washed neutral with deionized water (pH of the first aqueous portion is above 10). It is dried over sodium sulfate and then born. To the resulting crude solution was added 21.48 g (0.06 mol) of indomethacin. The bright yellow solution was rotaversed in vacuo. 46 g of gum are obtained, which are dissolved in 70 ml of absolute ethanol while hot. The crystalline salt precipitated from the solution is filtered after cooling, washed with cold absolute ethanol and dried. 35.85 g of papaverine indomethacin salt are obtained, m.p. 99-102 ° C. Yield: 41.79 g, Yield: 85.8%.

It can be recrystallized from absolute ethanol.

Elemental analysis: C ₃₉ H ₃₇ ClN ₂ O ₄ M, = 696.5

calculated: C, 67.19; N, 4.02; H, 5.31; Cl%: 5.10 Found: C, 67.21; H, 5.27; N, 4.12; Cl, 5.14

Based on perchloric acid titration: 98.7%,

By alkaline titration: 101.0%

The product was identified by its ultraviolet and infrared spectra.

Biological examples

1. Ulcerogenic effect:

It is known that non-steroidal anti-inflammatory drugs have significant gastrointestinal side effects. The most common gastrointestinal side effects are gastric ulcer and gastric bleeding. Indomethacin is a representative representative of these substances and has a significant gastric ulcer inducing effect. At doses above 10 mg / kg, it already has a significant ulcerative effect in rats. The ulcerative effect of indomethacin, drotaverine, a mixture of both substances and salts was investigated.

indometha- tin 0.07 mM / kg drotaverin 0.07 mM / kg 1: 1 mixture of indomethacin and drotaverine New salt obtained according to Example 1 ulcus index 4.8 0 4 2.2

The results indicate that the salt-forming effect of indomethacin was significantly reduced by the salt formation.

2. Anti-aggregation effect:

Both substances, drotaverine and indomethacin, inhibit platelet aggregation, although their mechanism of action is different. Indomethacin acts by blocking the platelet cyclooxygenase enzyme system. The inhibitory effect of the phosphodiesterase enzyme is crucial in the anti-aggregation effect of drotaverine.

Material inhibition% drotaverin 20 μΜ 15 indomethacin 20 μΜ 10 drotaverin 20 μΜ + indomethacin 20 μΜ 21 Example 1 salt 20 μ 20 95

The results show that the anti-aggregation effect is significantly enhanced by salt formation. It can be seen that this is not a simple aggregation of effects, but a new type of effect, the compounds potentiating each other.

3. Phosphodiesterase inhibitory effect

The activity of the compounds was investigated with phosphodiesterase enzyme isolated from rabbit platelets.

ΙΟ ₅₀ (μΜ) drotaverine 62 Example 1 Salt 44 indomethacin 100

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From the results, it can be clearly seen that the new salt of Chemical Example 1 has the advantageous properties of indomethacin in the tests tested.

Claims (5)

PATENT CLAIMS A process for the preparation of a salt of an isoquinoline derivative of the Formula I, wherein R ¹ is a C 1 -C 4 alkyl group, the dashed line represents an optional bond with an indole acetic acid derivative of the Formula II: reacting an isoquinoline derivative of the Formula I or a salt thereof, wherein R ¹ and the dotted line are as defined above, with an indole acetic acid derivative of the Formula II or a salt thereof. Process according to claim 1, characterized in that the reaction is carried out in the presence of a non-polar solvent, preferably a halogenated hydrocarbon. 3. The process according to claim 1, wherein the salt is crystallized in the presence of a polar solvent, preferably an alkanol. 4. Process according to any one of claims 1 to 3, characterized in that papaverine, perparin, dihydropapaverine or dihydroperpararin or salts thereof are reacted with indomethacin. 5. A process for the preparation of a pharmaceutical composition, characterized in that an isoquinoline derivative of the formula I, wherein R ¹ and the dashed line are as defined in claim 1, is formed with an indole acetic acid derivative of the formula II as defined in claim 1. One or more salts thereof prepared by the method of formula (I) together with physiologically acceptable excipients, diluents and excipients are converted into the pharmaceutical composition by conventional methods of formulation.