DE3409415A1 - Pharmaceutical composition, in particular for inflammations - Google Patents

Abstract

Pharmaceutical composition characterised by containing (A) at least one compound from the group of compounds of the general formula (I) or (II) <IMAGE> in which R, R1, R2, n and X have the meanings stated in Claim 1, and (B) at least one analgesic compound which has, alone or in combination with A, the following properties: it inhibits lipoxygenase predominantly reversibly, it inhibits cyclooxygenase partially reversibly so that sufficient prostaglandin PGE2 can still be produced.

Description

Medicines, especially for inflammation

The invention relates to a medicament which is produced by a combination of active substances of components (A) and (B) is marked. The invention particularly relates to a drug for combating inflammatory rheumatic diseases.

The therapy of chronic inflammatory and degenerative diseases of the human connective tissue and skeletal system, which is caused by reddening, Swelling, overheating, pain and impaired function are characterized is still unsatisfactory, although a large number of drugs have been used for decades is available, such as the cortisone and numerous different from this glucocorticoid by partial synthesis deriving steroids, as well as the non-steroidal Antiphlogistics, such as derivatives of salicylic acid, pyrazolone, 3,5-oxopyrazolidine, the anthranilic acid, the aryl or heteroarylalkanoic acids and oxicams. These drugs All of them have, in some cases, severe side effects, especially when used over a long period of time.

In particular, most of the non-steroidal anti-inflammatory drugs exhibit (NSAIDs) have an undesirable effect closely related to their mechanism of action on.

Arachidonic acid is formed under the influence of cyclooxygenase the labile endoperoxides PGG2 and with elimination of radical oxygen PGH2. From these short-lived intermediate products, depending on the cell type, other, more stable ones emerge Prostaglandins such as PGE2, PGD2, PGF2oCi or thromboxane (TXA2) and prostacyclin (PGI2). Among other things, the prostaglandin, which serves as a protective substance for the gastric mucosa, is also used PGE2 inhibited; According to the current state of knowledge, this prostaglandin is used for ulcerogenic Effect of NSAIDs on the gastric mucosa blamed.

There are a number of therapeutically effective anti-inflammatory drugs and more or less analgesic NSAIDs on the market. With all of these NSAIDs are made aware of the ulcerogenic effect and long-term medication is dangerous, especially for patients with sensitive stomachs. A number of so far Practice-proven anti-inflammatory drugs are available because of the dangerous side effects has recently been the focus of discussion.

There is therefore an urgent need, rheumatics - among them are understood to be patients suffering from chronic inflammatory and degenerative diseases suffer in the connective tissue and skeletal system - to provide a medicine that has both anti-inflammatory and analgesic effects and none or only very little has few side effects, but especially low ulcerogenicity.

The object of the invention is therefore to provide a medicament which the Has the aforementioned properties to make available.

The known, commercially available anti-inflammatory drugs, which the aforementioned Have ulcerogenic side effects, are characterized in the majority by a simultaneous anti-inflammatory and analgesic effects and thus meet the needs of the Against rheumatism. Does the analgesic effect lack or is it only weak pronounced, so there is often a need to use anti-inflammatory agents to combine with an analgesic.

The invention is based on the consideration that according to the current According to biochemical knowledge, the prostaglandins are not the only mediators are responsible for the pathophysiology of inflammation.

Rather, the arachidonic acid is formed by the lipoxygenase Leukotrienes. From today's point of view, they are also important mediators Inflammatory and immune reactions, as well as in some forms of bronchospasm (slow reaction substances, SRS).

A drug that, in therapeutic doses, has an inhibitory effect exhibits on both enzyme systems is not known to the best of our knowledge.

It has now been found that compounds of the formula and the formula in which the radicals have the following meanings: R = H, metal, C1 6 -alkyl, R1 = C1-5-alkyl, n = 0, 1, 2 X = H, CF3, F, C1 have an excellent anti-inflammatory effect, namely in that they reversibly inhibit lipoxygenase and exert only a slight influence on cyclooxygenase.

The consequence is that through these compounds the inflammation mediators be prevented more specifically, while the pain component of the invention is not is reduced to the same extent.

Therefore, according to the invention, the above-mentioned compounds Component B was added to formulas (I) and (II). This should be able to handle the To inhibit prostaglandins to such an extent that the sensation of pain is attenuated is, but prostaglandin PGE2 is still sufficiently produced to cause irritation the gastric mucosa does not occur even with prolonged use.

Another possibility would be the connections of the formulas (I) and (II) to be combined with a centrally acting analgesic. Such a one Combination results in a drug with the desired therapeutic properties, especially for combating rheumatic diseases.

It was found according to the invention that in contrast to most of the known NSAIDs, which inhibit cyclooxygenase, only a small number of none or activating influence on the lipoxygenase have the compounds of the general Formulas (I) or (II) still in concentrations of 10 4 mmol die Lipoxygenase formation inhibit reversibly by more than 50%; and thus also the formation of the leukotrienes (see Applied Chemie, 1982, No. 12, pages 881 to 962).

The cyclic compounds of component (A) also act as Free radical scavengers because they have a high redox potential.

Free radical oxygen is created both during the formation of the leukotrienes as well as with the transition of the endoperoxides of the prostaglandins into secondary products and is toxic to the cell and promotes inflammation.

N "-Phenyl-2-butylmalonic acid monohydrazide, a preferred compound of the general formula (I), inhibits in concentrations of 10-4 to 10-7 mmol Lipoxygenase (> 50%), at the same time, to a lesser extent, cyclooxygenase (<50%) %); part of the prostaglandin formation is therefore retained, in particular the prostaglandins PGE2, which have a protective effect on the gastric mucosa.

The second component (B) in the medicament of the present invention is a Analgesic whose mechanism of action does not necessarily involve the arachidonic acid cascade must be done. It is essential that it is the pain receptors in their sensitivity belittles. Suitable analgesics that have the aforementioned properties, with they also have a more or less pronounced anti-inflammatory effect can exercise are e.g. o-carbamoyl-phenoxyacetic acid ,, Diflunisal, Diclofenac, Paracetamol and certain anthranilic acid derivatives such as mefenamic acid etc.

The active ingredient combination according to the invention makes it possible with comparatively get by with low dosages of the individual active ingredients.

The components can be made into tablets using customary auxiliaries, Capsules, orally administrable solutions, topically applicable preparations or suppositories be formulated. They can also be prepared as injectable solutions.

The compounds of component (A) and component (B) are preferably combined in the following ratio: 1-8 component (A) to 0.1-8 component (B) The active ingredient combination according to the invention has, inter alia the following advantages: It is the desired combinatorial effect with regard to the anti-inflammatory, analgesic and antiulcerogenic mode of action. In the combination is the active ingredients in lower amounts than for each required anti-inflammatory or analgesic effect of the individual components is required. Therefore the effect / side effect relationship of these combinations is (A) + (B) much cheaper. While for the analgesic component, diclophenac, Dosages required for scavenging oxygen radicals and inhibiting lipoxygenase which are above the therapeutic level, k & nn in the inventive Combination containing a diclophenac as a peripheral analgesic drug contain this in much lower quantities.

The synthesis of the compounds of component (A) takes place by itself known procedures.

Compounds of the general formula (I) are obtained by reacting (a) alkylmalonic acids of the general formula where R is a straight-chain, branched or cyclic alkyl or alkenyl radical with up to 7 carbon atoms, X is a halogen, preferably chlorine, and Y is a hydroxyl group or an alkoxy group with up to 6 carbon atoms, or (b) 2-alkylsuccinic acids the general formula in which R, X and Y have the meanings given under (a), or (c) 2-alkylglutaric acids of the general formula wherein R, X and Y have the meanings given under (a), with unsubstituted or substituted phenylhydrazine in the aromatic nucleus (X = CF3, F, C1).

The reaction takes place under reflux and stirring in a solvent, which does not interfere with the reaction and in which the reactants are soluble.

For binding the hydrogen halide released during the reaction a base that does not take part in the reaction is added to the batch. The approach is kept for 2 to 3 hours at the boiling point with constant stirring. To After the reaction mixture has cooled, it is worked up in the usual way: Evaporation of the solvent, taking up the residue in a suitable solvent, repeated recrystallization to a constant melting point.

Example 1 (Compound I) N "Phenyl-n-butylmalonic acid monohydrazide 10.8 g (0.1 mol) phenylhydrazine and 12.0 g (0.12 mol) triaethylamine are dissolved in 150 ml benzene dissolved and the solution heated 4m reflux condenser. 21.0 g are added to this solution (0.1 mol) 2 (ethoxycarbonyl) hexanoic acid chloride within 2 h via a dropping funnel added and the batch was kept in the heat for some time. Then will the solvent is distilled off and the residue is extracted with ethanol. The ethanolic Solution is again evaporated to dryness and the residue from petroleum ether (60-900C) recrystallized.

Yield: 10.9 g (= 62% of theory) of N't-phenyl-2 (ethoxycarbonyl) -hexanoic acid monohydrazide or on 2 (ethoxycarbonyl) hexanoic acid chloride.

Mp: 1030C. The N "phenyl-2 (ethoxycarbonyl) -hexanoic acid chloride becomes dissolved in warm 2N sodium hydroxide solution and 2N hydrochloric acid was added to the clear solution until no more precipitation occurs. The precipitated N "phenyl-2 (carboxyl) -hexanoic acid monohydrazide is recrystallized from ethanol / water (2: 1, v / v).

Yield: 15.2 g (= 50% of theory) of N "phenyl-2 (carboxyl) -hexanoic acid monohydrazide or on 2 (ethoxycarbonyl) hexanoic acid chloride.

Mp: 158-1600C LD50 of N "phenyl-2 (carboxyl) hexanoic acid monohydrazide (Mouse i.p.) 1335 mg / kg.

Example 2 (Compound-II) 1 -Phenyl-4n-butyl-3, 5-oxopyrazolidine 72.0-74.0 g (0.33-0.34 mol) of butylmalonate are in a mixture from sodium ethanolate (0.9-1.02Mol) dissolved in 200 ml of ethanol and with 47.7 g (0.33Mol) Phenylhydrazine hydrochloride is added and the mixture is heated to 120-1400C for 6 hours while gassing with nitrogen. During the implementation of the excess and resulting from the reaction Alcohol continuously distilled off. The solid reaction product becomes after cooling dissolved in 200-300 ml of water and this solution is extracted with ether. After that the aqueous Solution adjusted to pH 3 with 2N hydrochloric acid. The oil that separates out solidifies after a short while in the cold. Wake up washing with dilute sodium bisulfite solution the substance is dissolved in a little ethanol (mixed with sodium bisulfite). By dropwise addition of water until the solution becomes cloudy after a short time Crystallization. The crude product is recrystallized three times in the same way.

Yield: 44.5 g (= 56% of theory) of 1-phenyl-4n-butyl-3,5-oxopyrazolidine or on butylmalonic acid diethyl ester.

Mp: 101 ° C. The LD50 of 1-phenyl-4n-butyl-3,5-oxopyrazolidine (mouse i.p.) 960 mgjkg.

Example 3 (Compound I) N "-Phenyl -n-butylmalon acid monohydra z id 5.1 g (0.2 mol) 1-phenyl-4n-butyl-3t5-oxopyrazolidine, 2 g (0.5 mol) sodium hydroxide, 3.86 g (0.6 mol) of sodium chloride and 30 mg of sodium bisulfite are dissolved in 200 ml of water dissolved and refluxed for 24 h under nitrogen gas. After the batch has cooled down is filtered off from undissolved residue and washed with approx. 200 ml of water. The filtrate is adjusted to pH 2-3 with 2N sulfuric acid. The resulting crystals is suctioned off and washed with water.

Yield: 4.1 g (= 75% of theory) of N "-phenyl-n-butylmalonic acid monohydrazide or to 1-phenyl-4n-butyl-3, 5-oxopyrazolidine.

Mp: 1580C The substance is dissolved in acetone and this solution of undissolved parts separated by glass wool. By blowing off the acetone with The solution can be concentrated with nitrogen; the substance precipitates. To complete Crystallization, about 40-50 ml of water are added to the acetone solution and then suctioned off and washed the precipitate with water.

Yield: 3.2 g (= 59% of theory) of N "-phenyl-n-butylmalonic acid monohydrazide or to 1-phenyl-4n-butyl-3,5-oxopyrazolidine.

M.p .: 1580C Example 4 (Compound I) N "p-Fluorophenyl-2- (carboxyl-methyl) -hexanoic acid monohydrazide, 11.7 g (0.1 mol) of p-fluorophenyl hydrazine and 12.2 g (0.12 mol) of triethylamine are dissolved in 150 ml of toluene and the solution heated to reflux. 23.3 g (0.1 mol) of 2 (ethoxycarbonyl-methyl) -hexanoic acid chloride was added via a dropping funnel within 2 h and the Keep the approach in the warmth for some time. Then the solvent distilled off and the residue extracted with ethanol.

The ethanolic solution is again evaporated to dryness and the The residue was recrystallized from petroleum ether (60-900C).

Yield: 13.1 g (= 75% of theory) of N "p-fluorophenyl-2- (ethoxycarbonyl-methyl) -hexanoic acid monohydrazide The N "p-fluorophenyl-2- (ethoxycarbonyl-methyl) -hexanoic acid monohydrazide is in 2N Sodium hydroxide solution dissolved in the heat and 2N hydrochloric acid was added to the clear solution the precipitation has ended. The crude product is made from ethanol / water (2: 1, v / v) several times recrystallized.

Yield: 11.9 g (= 43% of theory) of N "p-fluorophenyl-2- (carboxYii- ' methyl) -hexanoic acid monohydxazide or on 2 (ethoxycarbonyl-methyl) -hexanoic acid chloride.

M.p .: 170-1720C

Claims (6)

Medicines, especially against inflammation PATENT CLAIMS 1. Medicines, characterized by a content of (A) at least one compound from the group of compounds of the general formula (I) or (11) where: R = H, Cl 6-alkyl, metal, R1 = C15-alkyl, n = 0, 1, 2 X = H, CF31 F, Cl and (B) at least one analgesic compound which, individually or in combination with A, has the following properties: it primarily reversibly inhibits lipoxygenase, it partially reversibly inhibits cyclooxygenase, so that sufficient prostaglandin PGE2 can still be formed. 2. Medicament according to claim 1, characterized in that it is -k e n n z e i c h n e t that the compound (I) in component (A) is N "-phenyl-2-n-butylmalonic acid monohydrazide is. 3. Medicament according to claim 1, characterized in that it is -k e n n z e i c h n e t that component (A) of formula (II) l-phenyl-4-n-butyl-3,5-dioxopyrazolidine is. 4. Medicament according to one of the preceding claims, characterized it is not noted that component (B) is selected from: o-carbamoyl-phenoxyacetic acid, Diflunisal, Diclofenac, anthranilic acid derivatives or aryl resp. Heteroarylalkanoic acids. 5. Medicament according to one of the preceding claims, characterized Note that the weight ratio of component (A) to component (B) is 1-8 to 0.1-8. 6. Use of a medicament according to one of the preceding Claims as an anti-inflammatory agent.