IE922391A1

IE922391A1 - Dimethylacetoacetamides, process for their preparation and¹pharmaceuticals

Info

Publication number: IE922391A1
Application number: IE239192A
Authority: IE
Inventors: Rupert Strasser; Rainer J Klauser; Peter Zeiller
Original assignee: Luitpold Pharma Gmbh
Priority date: 1991-07-24
Filing date: 1992-07-23
Publication date: 1993-01-27
Also published as: WO1993002043A1; CA2074568A1; AU2051092A; IL102611A0; FI923360A; DE4124587A1; FI923360A0; JPH05230003A; EP0525686A1

Abstract

The present invention relates to novel dimethylacetoacetic acid amide derivatives, a process for their preparation and pharmaceutical compositions containing them.

Description

Dimethylacetoacetamides, Process for their preparation and pharmaceuticals Description The invention relates to compounds of the general formula I in which R1 denotes a radical of the general formula II CC (II) Ror a heteroaryl radical, R2 denotes a hydrogen atom or a lower alkyl radical, R3 denotes a hydrogen atom, a lower alkyl radical, an aryl-lower alkyl radical or a radical of the general formula II, R*, R5 and R6 independently of one another denote hydrogen atoms, halogen atoms, hydroxyl groups, lower alkyloxy groups, lower alkyl radicals, nitro groups, amino groups substituted by hydrogen or lower alkyl radicals, carboxylic - 2 acid groups, lower a Iky loxy carbonyl groups, sulphonic acid groups or trifluoromethyl groups, X denotes an oxygen atom or an =NR7 group, where R7 denotes a hydrogen atom, a lower alkyl radical, a radical of the general formula II, a heteroaryl radical, a hydroxyl radical or a lower alkyloxy group and their salts with physiologically tolerable acids and bases, excluding N-phenyl-4-methyl-3-oxopentanoic acid amide, N-methyl-N-phenyl-4-methyl-3-oxopentanoic acid amide, and N- (4-bromophenyl) -4-methyl-2-isopropyl-3-oxopentanoic acid amide.

The compounds of the general formula I according to the invention are in general present individually or in a mixture within the meaning of a keto-enol tautomerism or within the meaning of an imino-enamine tautomerism. They can be present in pure form or as a hydrate.

The following explanations apply to the various substituents or radicals in the formulae I and II mentioned in connection with the description of the present application: Examples of lower alkyl radicals are unbranched and branched hydrocarbons having up to 6 carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1methylpropyl, tert.-butyl, n-pentyl, 1-methylbutyl, 2methylbutyl, 3-methylbutyl, 1,1-dimethylpropyl, 2,2dimethylpropyl, 1,2-dimethylpropyl, 1-ethy lpropyl, n30 hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3dimethylbutyl, 1,2-dimethylbutyl, 2,3-dimethylbutyl, 1,3dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, l-ethyl-2-methyl35 propyl or 1-ethyl-l-methylpropyl radicals. Methyl, ethyl, - 3 n-propyl, isopropyl, n-butyl or isobutyl radicals are preferred. If the expression lower alkyl appears alone or in combination with other functional groups (for example lower alkyloxy , lower alkyloxycarbonyl or lower alkylmercapto groups) in the present application, this expression has the abovementioned definitions.

Examples of aryl-lower alkyl radicals in the case of R3 are the lower alkyl radicals defined above, linked to a radical of the general formula II, which is defined as above. Preferred aryl-lower alkyl radicals are benzyl, phenylethyl, 4-fluorobenzyl, 2-(4'-fluorophenyl)ethyl, 4chlorobenzyl, 2-(4'-chlorophenyl)ethyl, 2-hydroxybenzyl, 2- (2'-hydroxyphenyl) ethyl, 3-hydroxybenzyl, 2-(3'hydroxyphenyl) ethyl, 4-hydroxybenzyl, 2-(4'-hydroxy15 phenyl)ethyl, 2-methoxybenzyl, 2-(2'-methoxyphenyl)ethyl, 4-methoxybenzyl, 2-(4'-methoxyphenyl) ethyl, 2,5dimethoxybenzyl, 2,4-dimethoxybenzyl, 4-methylbenzyl, 2(4'-methylphenyl) ethyl, 4-nitrobenzyl, 2—(4'— nitrophenyl)ethyl, 4-(Ν,Ν-dimethylamino)benzyl, 2—(4'— Ν,Ν-dimethylaminophenyl)ethyl, 2-trifluoromethylbenzyl, 3- trifluoromethylbenzyl, 4-trifluoromethylbenzyl, 4methoxycarbonylbenzyl, 4-methylmercaptobenzyl, or 2methoxy-5-methylbenzyl radicals.

Examples of halogen atoms are fluorine, chlorine, bromine and iodine atoms.

Examples of heteroaryl radicals are five- and six-membered aromatic monocyclic ring systems or such ring systems which are fused to benzene in any desired position which contain one, two or three identical or different heteroatoms such as nitrogen atoms, oxygen atoms or sulphur atoms. Particularly to be mentioned are furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, triazinyl, benzofuranyl, benzothienyl, indolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl or isoquinolinyl radicals. The abovementioned heteroaryl radicals can be unsubstituted or substituted by halogen atoms, hydroxyl - 4 groups, lower alkyloxy groups, lower alkyl radicals, nitro groups, amino groups substituted by hydrogen or lower alkyl radicals, carboxylic acid groups, carboxylic acid lower alkyl esters, mercapto groups, lower alkylmercapto groups, sulphonic acid groups or trifluoromethyl groups. Those preferred are the following heteroaryl radicals: 2furanyl, 2-thienyl, 2-imidazolyl, 2-thiazolyl, 2-pyridyl or 2-pyrimidyl radicals. Heteroaryl radicals can be linked to compounds of the general formula I by means of all the carbon atoms in the ring.

The substituents R*, R5 and R6 present on the radical of the general formula II can be in various positions of the phenyl ring such as, for example, in the ortho- and para-position, but also in the meta-position, to the site of linkage of the phenyl ring.

If the compounds according to the invention are present in salt form, these are the salts of physiologically tolerable inorganic or organic bases and acids.

Examples of salts with physiologically tolerable 20 bases are ammonium, sodium, potassium, lithium, magnesium and calcium salts, as well as salts with ethanolamine, triethanolamine, morpholine or piperidine.

Examples of salts with physiologically tolerable acids are citrate-, tartrate-, acetate-, chloride- and bromide-containing salts.

The compounds of the general formula I can be prepared in analogy to methods which are known from the literature and from various patent specifications.

Method 1: Compounds of the general formula I can be prepared from isobutyrylacetic acid esters, for example methyl isobutyrylacetate, (preparation of acetoacetic acid esters analogously to Organikum, Organischchemisches Grundpraktikum, (Basic Practice of Organic Chemistry,) VEB Deutscher Verlag der Wissenschaften, 16th edition, Berlin 1986, p. 480 and p. 478) and aromatic amines in high-boiling aromatic hydrocarbons at - 5 temperatures above 140 °C with or without the use of generally customary acylation catalysts (analogously to L. Knorr; Ann. Chem. 236, 69 (1886); J. Roos; Chem. Ber. 21, 19 (1888); L. Knorr, B. Reuter; Chem. Ber. 27, 1169 (1894)).

Method 2: The reaction of aromatic amines with diketene (for example Chick, Wilsmore; J. Chem. Soc. 1908, 946; Boese; Ind. Eng. Chem. 32, 16 (1940); Williams, Krynitsky; Org. Synth. Coll. Vbl. Ill; 10 (1955)) or with a diketene-acetone adduct (for example M. F. Carrol, A.R. Bader; J. Am. Chem. Soc. 75, 5400 (1953); R. J. Clemens, J. A. Myatt; J. Org. Chem. 50, 2431 (1985)) yields exclusively acetoacetamides where R3 = H. - 6 Starting from this step, transacylation is likewise carried out according to Method 1 to give the isobutyrylacetamides.

Method 3: Another possibility of access to compounds of the general formula I lies in the reaction of a-deprotonated carbonyl compounds with aromatic isocyanates (analogously to A. P. Krapcho, W. P. Stephens; J. Org. Chem. 45, 1106 (1980); N. A. LeBel, R. M. Cherluck, E. A. Curtis; Synthesis 11, 678 (1973)).

Method 4: The deprotonation of N-aromatic amides to give the corresponding dianion and further reaction with methyl isobutyrate likewise leads to compounds of the general formula I (analogously to I. T. Barnish, 20 C. R. Hauser, J. F. Wolfe; J. Org. Chem. 33, 2116 (1968)). 0 0 0 0 ί II 3 2 BuLi -► 1. (CH3)2CHCOOCH3 1 II II 1 H • 2. 1 1, Method 5: The substitution of R3 = H for R3 = lower alkyl or aryl-lower alkyl is carried out in the acyl acetic acid ester step according to Organikum, Organisch-chemisches Grundpraktikum, (Basic Practice of Organic Chemistry,) VEB Deutscher Verlag der Wissenschaften, 16th edition, Berlin 1986, p. 517.

Z = methyl or isopropyl Method 6: Acylacetic acid amides can be alkylated under phase-transfer catalysis analogously to P. S. Raman, M.A. Ashrof; Curr. Sci. 48, 583 (1979). 0 . X PTK p1 0 0 Jin 1 2 R H ► r3x 1 2 R τ R z Z = methyl or isoproyl Method 7s Condensation of acylacetic acid esters with aldehydes or ketones according to Organikum, Organischchemisches Grundpraktikum, (Basic Practice of Organic Chemistry), VEB Deutscher Verlag der Wissenschaften, 16th edition, Berlin 1986, p. 459» and subsequent catalytic hydrogenation likewise yield C-2-substituted acylacetic acid esters which can be reacted further according to Method 1 to give the target compound.

Z = methyl or isopropyl Method 8: This reaction is also described for acylacetic acid amides (Z. H. Khalil, A. S. Yanni; J. Indian Chem. soc. LVIII, 168 and 494 (1981)).

Z = methyl or isopropyl Method 9: Analogously to literature procedures, isobutyryl10 acetamides react with ammonia or with amines to give the corresponding enamine or imino compounds (for example D. Nardi, A. Tajana, R. Pennini; J. Heterocycl. Chem. 12, 139 (1979). With hydroxylamine, hydroxyimino compounds are obtained (for example A. Kettrup, T. Neustadt; Z.

Naturforsch. 28b, 86 (1973), L. Knorr, B. Reuter; Chem. Ber. 27, 1169 (1894)). Lower alkyloxyamines yield lower alkyloxyimino compounds.

Method 10: If, as in Method 4, after deprotonation of aromatic amines the corresponding dianions are treated with isobutyronitrile instead of with isobutyric acid esters, this leads to compounds of the general formula I where X = NH (analogously to I. T. Barnish, C. R. Hauser, J.F. Wolfe; J. Org. Chem. 33, 2116 (1968)).

JV,™ ( Xo/. 2. H3O+ Compounds of the acylacetamide type are known and widely used in chemistry. The compound N-phenyl-4-methyl5 3-oxopentanoic acid amide is known as an intermediate from the booklet Organische Zwischenprodukte (Organic Intermediates), Wacker-Chemie GmbH, March 1989, No. 6.10. It is also described as an intermediate in J. Med. Chem. 33, 61 (1990). The compound N-methyl-N-phenyl-4-methyl10 3-oxopentanoic acid amide should occur as an intermediate in BE-634,930 (in the preparation of the final product No. 15 described therein). Finally, the compound N-(4bromophenyl)-4-methyl-2-isopropyl-3-oxopentanoic acid amide is known from J. Org. Chem. USSR (Engl. Transl.) 14, 1069-1079 (1978). No pharmacological effects were described for any of the three compounds mentioned. Other compounds of the general formula I have not been disclosed.

Pharmacological effects of compounds from the acylacetamide group have hitherto likewise not been disclosed.

The active substances described in US-4,256,759 and EP-A-372,470 are only structurally close to the compounds of the general formula I according to the invention with respect to a part of their basic structure. Because of their compulsorily prescribed cyano group and because of their compulsorily prescribed hetero-aromatic radical in the ^9-position, these a-cyanoj3-oxopropionamide derivatives are not comparable with the compounds of the present invention.

In connection with the present invention, it has surprisingly been found that substances of the general formula I have useful pharmacological properties and can be employed in particular as anti-inflammatory active - ίο substances. In addition to the good tolerability - the LD50 of the compound from Example 1 is, for example, over 1000 mg/kg - compounds of the general formula I are distinguished by useful analgesic and antipyretic proper5 ties. In particular, the compounds according to the invention are suitable for the treatment of inflammatory disorders in humans and animals. The syndromes which can be treated with the compounds according to the invention include all inflammatory conditions, such as, for example, inflammations of the skin such as radiodermatitis, psoriasis, acne, eczema, inflammations of the eye such as, for example, conjunctivitis, inflammations Of the ear, nose and throat such as, for example, catarrhal infections of the upper airways and sinusitis, inflammatory disorders of the vascular system such as thrombophlebitis or vasculitis and inflammations of the nervous system such as, for example, neuralgia or neuritis. Preferred inflammatory disorders to be treated are inflammations in the area of the locomotor apparatus, such as arthritis, osteoarthritis, tendinitis, tendopathies, contusions and distortions, soft tissue rheumatism, gout and lumbago. The compounds according to the invention are also suitable for the treatment of certain diseases or disorders in which pain is predominant. Post-operative pain conditions, pain after tooth extraction and migraine can be mentioned here.

Testing for anti-inflammatory activity (C. A. Winter, E. A. Risley, G. W. Nuss; Proc. Soc. Exp. Biol. Med. Ill, 544 (1962)) was carried out by means of oedema, produced by 0.5 % strength aqueous carrageenan solution, of the right hind paw in groups each containing ten fasting female Wistar rats weighing about 150 g. For this purpose, the volumes of the marked right hind paw were measured with a plethysmometer immediately before and three hours after injection of the carrageenan solution. The substances to be tested were administered p.o. as a suspension in gum arabic by means of a stomach tube 30 minutes before production of oedema. The control group received pure tap water. The individual dose per animal was 200 mg/kg of body weight.

For assessment, the percentage increase in the paw volume for each animal was calculated according to the following formula: Volume of second measurement x 100 --—- - 100 = difference (%) Volume of first measurement then mean values and scatter of all values of a group 10 calculated in this way were determined. The difference between the experimental group treated with the test substance and the corresponding untreated group were determined according to the formula: MW experiment (test substance) x 100 15--100 = % inhibition MW control The statistical assessment was carried out according to the customary methods.

Table 1 shows the anti-inflammatory activity measured in 20 some examples.

TABLE 1: Compound from Example 1 2 % inhibition 52 32 27 26 The compounds according to the invention can be administered in multiple pharmaceutical preparations and various doses, such as, for example, tablets, coated tablets, capsules, liquid preparations to be taken orally, ointments, gels, plasters, injection solutions or sprays, it being possible to use generally used excipients and auxiliaries which are compatible with the - 12 10 compounds according to the invention. The dosages can be 10 to 500 mg of a compound of the general formula I or its salt per dose unit, in the case of administration of one to four dose units per day.

The present invention also relates to pharmaceutical preparations (pharmaceuticals), which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more active substances according to the invention or which consist of one or more active substances according to the invention.

Non-toxic, inert pharmaceutically suitable excipients are to be understood as meaning solid, semisolid or liquid diluents, fillers and formulation auxiliaries of any type.

Preferred pharmaceutical preparations are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders, sprays and aerosols.

In addition to the active substance or substances, tablets, coated tablets, capsules, pills and granules can contain the customary excipients. These include a) fillers and extenders, for example starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders, for example carboxymethylcellulose, alginates, gelatine, polyvinylpyrrolidone, c) humectants, for example glycerol, d) disintegrants, for example agar agar, calcium carbonate e) solution retardants, f) absorption accelerators, example cetyl adsorbents, for lubricants, for and for g) sodium bicarbonate, example paraffin, wetting agents, for alcohol, glycerol monostearate, h) example kaolin and bentonite and i) example talc, calcium stearate and magnesium stearate and solid polyethylene glycols or mixtures of the substances mentioned in a) to i).

The tablets, coated tablets, capsules, pills and granules can be provided with customary coatings optionally containing opacifying agents, for example sugar and - 13 coating varnishes, and can also be composed such that they release the active substance or substances only or preferably in a certain part of the intestinal tract, optionally after a delay, it being possible to use, for example, polymer substances and waxes as embedding materials.

The active substance or substances may optionally be present in microencapsulated form with one or more of the abovementioned excipients.

In addition to the active substance or substances, suppositories can contain the customary watersoluble or water-insoluble excipients, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C14-alcohol with C16-fatty acid or mixtures of these substances).

In addition to the active substance or substances, creams primarily contain, as the oily phase, fatty alcohols, for example lauryl, cetyl and stearyl alcohol, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax and/or hydrocarbons, for example petroleum jelly (petrolatum) or liquid paraffin. Emulsifiers used are preferably those having mainly hydrophilic properties, for example non-ionic emulsifiers such as fatty acid esters of polyalcohols, ethylene oxide adducts thereof such as polyglycerol fatty acid esters or polyoxyethylene sorbitan fatty acid esters (Tweens) or ionic emulsifiers such as alkali metal salts of fatty alcohol sulphates, for example sodium lauryl sulphate, sodium cetyl sulphate or sodium stearyl sulphate. Agents can be added to the water phase which prevent the drying out of the cream, for example polyalcohols such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols.

For ointments, in addition to the active substance or substances, suitable excipients are primarily hydrocarbons, for example petroleum jelly or liquid paraffin, which, for improving the water-binding ability, - 14 preferably contain suitable fatty alcohols or esters thereof, for example cetyl alcohol or wool wax. Emulsifiers are appropriate lipophilic substances such as sorbitan fatty acid esters. Humectants such as, for example, glycerol or propylene glycol can be added to the water phase.

In addition to the active substances or substances, sprays and powders can contain the customary excipients, for example lactose, talc, silicic acid, aluminium hydroxide, calcium silicate and polyamide powder or mixture of these substances. Sprays can additionally contain the customary propellants.

In addition to the active substance or substances, solutions and emulsions can contain the customary excipients such as solvents, solubilisers and emulsifiers, for example water, ethanol, isopropanol, ethyl carbonate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils, in particular cottonseed oil, peanut oil, maize oil, cashew nut oil, castor oil and sesame oil, glycerol, glycerol formal, polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

In addition to the active substance or substances, suspensions can contain the customary excipients such as liquid diluents, for example ethanol, propylene glycol, suspending agents, for example ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar agar or tragacanth or mixtures of these substances.

The said formulation forms can also contain colorants, preservatives and odour- and flavour-enhancing additives, for example peppermint oil and eucalyptus oil and sweeteners, for example saccharin.

The therapeutically effective compounds should preferably be present in the abovementioned pharmaceutical preparations in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95 % by mass of the total - 15 mixture.

In addition to the active substances according to the invention, the abovementioned pharmaceutical preparations can also contain other pharmaceutical active substances.

The abovementioned pharmaceutical preparations are produced in a customary manner by known methods, for example by mixing the active substances with the excipients.

The present active substances or pharmaceutical preparations, which contain one or more active substances, can be employed in human and veterinary medicine for the prevention, amelioration and/or cure of inflammatory diseases .

In general, it proves advantageous in human medicine to administer the active substance or substances according to the invention in total doses of about 10 to about 500 mg, preferably 25 to 500 mg, per dose unit in the case of administration of one to four dose units per day to achieve the desired results.

However, it may be necessary to deviate from the dosages mentioned, in particular depending on the type and body weight of the subject to be treated, the type and the severity of the disorder, the type of preparation and the administration of the pharmaceutical and also the period or interval within which administration takes place. Thus, in some cases it may be adequate to manage with less than the abovementioned amount of active substance, while in other cases the abovementioned amount of active substance must be exceeded.

The following examples illustrate the invention in greater detail, without restricting its extent thereto. - 16 Examples Example 1: N-(2-Methoxyphenyl)-4-methyl-3-oxopentanoic acid amide A solution of 10 g (69.9 mmol) of methyl iso5 butyrylacetate, 7.82 ml (69.4 mmol) of o-anisidine and a few drops of diethanolamine in 50 ml of xylene is heated at 135-150°C until methanol set free in the reaction no longer distils over. After cooling, the solution is extracted several times with dilute sodium hydroxide solution, and the alkaline solution is acidified with dilute acid and back-extracted with ethyl acetate. Washing with dilute sodium chloride solution, drying over sodium sulphate and stripping off the solvent yields an oily crude product. After chromatography (diisopropyl ether/ethyl acetate = 1:1), 9.39 g (58 %) of the title compound are obtained as a clean and oily product. Elemental analysis: % C % H % N calculated: 66.35 7.30 5.95 found: 66.31 7.25 6.09 20 MS: 235 (M+·; 1, 165, 149, 123 (100%), 108, 92, 80, 71, 65, 52.

IR (KBr): 3300, 2965, 1710, 1680, 1643, 1600, 1535, 1487, 1460, 1435, 1335, 1290, 1253, 1220, 1176, 1117, 1045, 1028, 750 cm'1. 251H-NMR (d6-acetone) : δ = 1.12 (d, 6H, 2 x CH3), 2. 83 (dq. IH, -CH(CH3)2), 3.73 (s, 2H, -CH2-), 3.84 and 3. 87 (2s, 3H, OCH3) , 5.43 (s, IH, = =CH-) , 6.76 - 7.08 (m, 3H, Ar-H), 8.15 - 8.45 (m, IH, Ar-H] l, 9. 23 (s, broad, IH, NH) , 13.88 (s, IH, enol-OH); keto: enol =4:1. - 17 Example 2: N-(2-Thiazolyl)-4-methyl-3-oxopentanoic acid amide A solution of 20 g (138.7 mmol) of methyl isobutyrylacetate and 13.9 g (138.7 mmol) of 2-aminothiazole are heated in xylene at an oil bath temperature of 165°C until methanol is not longer set free. The cooled reaction mixture is extracted several times with dilute sodium hydroxide solution, and the alkaline solution is acidified with dilute acid and back-extracted with ethyl acetate. Washing with dilute sodium chloride solution, drying over sodium sulphate and stripping off the solvent yields a dark-brown oil, which is first chromatographed on silica gel using diisopropyl ether/ethyl acetate = 1:1 and then recrystallised in diisopropyl ether. The title compound is thus obtained in 33 % yield as colourless crystals of m.p.: 114-115^(3.

Elemental analysis: % C % H % N % S calculated: 50.92 5.71 13.20 15.11 found: 50.99 5.71 13.14 14.98 MS: 212 (M+), 169, 127, 113, 100 (100%), 71, 58.

IR (KBr): 3120, 2900, 1615, 1550, 1400, 1310, 1270, 1235, 1210, 1185, 1157, 1135, 1005, 920, 790, 778, 748, 720 cm’1. 1H-NMR (d6-DMSO) : δ = 1.05 and 1.08 (d, 6H, 2 x CH3) , 2.73 25 (dq, IH, -CH(CH3)2), 3.76 (s, 2H, -CH2-), 5.38 (s, IH, =CH-), 7.23 (d, IH, Ar-H), 7.48 (d, IH, Ar-H), 12.14 (s, broad, IH, keto-NH), 13.09 (s-broad, IH, enol-NH); keto: enol = 6.5 : 1.

Example 3: N-(4-Methoxyphenyl)-4-methyl-3-oxopentanoic acid amide Preparation is carried out analogously to Example 1: from 20 g (139 mmol) of methyl isobutyrylacetate and - 18 1 eq of para-anisidine, the title compound is obtained in 30 % yield in the form of colourless crystals of m.p.: 40-41°C.

IR (KBr): 3300, 2970, 1725, 1650, 1605, 1545, 1510, 1465, 5 1410, 1340, 1300, 1248, 1176, 1109, 1030, 822 cm'1. 1H-NMR (d6-acetone): S - 1.08 (d, 6H, 2 x CH3) , 2.83 (dq, 1H, -CH(CH3)2, 3.59 (s, 2H, -CH2-) , 3.76 (s, 3H, OCH3), .15 (s, 1H, =CH-), 6.73 - 7.69 (m, 4H, Ar-H), 9.16 (s, broad, 1H, NH); keto : enol = 3.5 : 1.

Example 4: N-(2-Methoxy-5-methylphenyl)-4-methyl-3-oxopentanoic acid amide Preparation is carried out analogously to Example 1: from 20 g (139 mmol) of methyl isobutyrylacetate and 1 eq of 2-methoxy-5-methylaniline, the title compound is obtained in 28 % yield in the form of beige-coloured crystals of m.p.: 50-51°C.

IR (KBr): 3280, 2960, 1703, 1678, 1595, 1545, 1485, 1467, 1428, 1382, 1350, 1329, 1285, 1265, 1225, 1130, 1030, 908, 883, 795, 768, 714 cm'1.

XH-NMR (d6-acetone) : S = 1.13 (d, 6H, 2 x CH3) , 2.26 (s, 3H, Ar-CH3), 2.81 (dq, 1H, -CH(CH3)2, 3.73 (s, 2H, -CH2-), 3.82 and 3.86 (2s, 3H, OCH3), 5.41 (s, 1H, =CH-), 6.87 (s, 2H, Ar-H), 8.20 (s, 1H, Ar-H), 9.15 s, broad), 1H, NH); keto : enol = 4.2 : 1.

Example 5: Recipe for the production of tablets: 1000 tablets are produced from the compounds below in the manner described below. One tablet then contains as active substance 100 mg of N-(2-methoxyIE 922391 - 19 phenyl)-4-methyl-3-oxopentanoic acid amide. 1. N-(2-Methoxyphenyl)-4-methyl-3oxopentanoic acid amide 100 g 2. Lactose 263 g 3. Microcrystalline cellulose 120 g 4. Maize starch 60 g . Magnesium stearate 7 g 1) and 2) are mixed, 3) and 4) are mixed with the mixture, 5) is added finally, and the mixture is mixed and compressed directly. Example 6: Recipe for the production of a cream: The following recipe gives a 5 % N-(2-methoxy- phenyl)-4-methyl-3-oxopentanoic acid amide cream (sub- 15 stance data in % by weight): N-(2-Methoxyphenyl)-4-methyl-3oxopentanoic acid amide 5.00 20 Emulsifier (mixture of sodium glyceryl monostearate, sodium stearyl sulphate and sodium cetyl sulphate) 10,00 Medium chain triglyceride 6.25 Myristyl alcohol 5.00 P0E-12-cetylstearyl alcohol 3.00 25 Preservative q.s. Water to 100.00

Claims

1. Patent Claims

1. Compounds of the general formula I 5 in which R 1 denotes a radical of the general formula II (II) or a heteroaryl radical, R 2 denotes a hydrogen atom or a lower alkyl radical, 10 R 3 denotes a hydrogen atom, a lower alkyl radical, an aryl-lower alkyl radical or a radical of the general formula II, R*, R 5 and R 6 independently of one another denote hydrogen atoms, halogen atoms, hydroxyl groups, lower alkyloxy 15 groups, lower alkyl radicals, nitro groups, amino groups substituted by hydrogen or lower alkyl radicals, carboxylic acid groups, lower alkyl oxycarbonyl groups, mercapto groups, lower alkylmercapto groups, sulphonic acid groups or trifluoromethyl groups, 20 X denotes an oxygen atom or an =NR 7 group, where R 7 denotes a hydrogen atom, a lower alkyl radical, a radical of the general formula II, a heteroaryl radical, a hydroxyl radical or a lower alkyloxy group, and their salts with physiologically tolerable acids and 25 bases, excluding N-phenyl-4-methyl-3-oxopentanoic acid amide, N-methyl-N-phenyl-4-methyl-3-oxopentanoic acid amide, and N-(4-bromophenyl)-4-methyl-2-isopropyl-3-oxopentanoic acid amide.

2. Compounds according to Claim 1, in which X has the meaning oxygen atom.

3. Process for the preparation of compounds according to Claim 1, characterised in that, in a manner known per se, isobutyrylacetic acid esters containing the 10 radical R 3 in the C-2 position are reacted with the appropriate aromatic amines and if appropriate the isobutyrylacetamides obtained are converted into the corresponding 3-imino compounds (X denoting =NR 7 ) with ammonia, amines, hydroxylamine or lower alkyloxyamines. 15

4. Pharmaceuticals for use in humans and animals, consisting of or containing one or more compounds according to Claim 1.

5. A compound according to Claim 1 substantially as described herein in any of the Examples.