HU194816B - Process for producing 1-/2-hydroxy-aryl/-1-alkanon-oxim derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

Pharmaceutical compsn. contains an oxime of formula (I) as active ingredient. R = 1-18C alkyl or aralkyl; R1 and R3 = H, 1-12C alkyl or Cl; R2 = H, 1-12C alkyl or OR4; Z = H, 1-12C alkyl, COR5 or CONHR5; R4 = 1-18C alkyl, 3-8C cycloalkyl or aralkyl; R5 = aromatic or aliphatic gp. The following (I) are new cpds. Z-2-OH-caprophenone oxime; 5-Me-2-OH-caprophenone (N-phenylcarbamoyl) oxime; Z'-2-OH-laurophenone oxime; 4-Z''-2-OH- acetophenone oxime; 4-n-butoxy 5-n-hexyl-2-OH acetophenone oxime and 4-Z'''-2-OH-propiophenone oxime. (Z = 3- or 5-Cl, 4- or 5-Me or 4-(n-pentoxy or n-decyloxy); Z'=3- or 5-Cl; 5-Me or 4-(n-octyloxy or n-decyloxy); Z'' = n-butoxy, n-pentoxy, n-decyloxy, n-hexadecyloxy, n-octadecyloxy or benzyloxy; Z'''=n-decyloxy, n-dodecyloxy or cyclohexyl.

Description

The invention also relates to the preparation of some known compounds of formula I as pharmaceuticals. These known compounds also have the formula I, but the substituents have the following meanings:

R is methyl or undecyl,

R ^{1 is} hydrogen or methyl,

R ^{2 is} hydrogen or hexadecyloxy, while R ³ and Z are hydrogen.

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The present invention relates to novel 1- (2-hydroxyaryl) -1-alkanone oxime derivatives of the formula I and to pharmaceutical compositions containing such compounds. In the general formula (I)

R ^{1 is} hydrogen or chloro or C 1-9 alkyl,

R is R ² - in case of R ³ = Z = hydrogen, C7-14 alkyl, with the proviso that when R is alkyl of 11 carbon atoms, ^R1 is not methyl, or R

R 1 is C 1 -C 14 alkyl and R ^{2 is} hydrogen or -OR ⁴ where

R ^{4 is} C 1 -C ₁₈ alkyl, except C ₁₆ alkyl, or C 4 -C 8 cycloalkyl, or alkyl-C 1 -C 4 phenylalkyl or naphthylalkyl, and

R ^{3 is} hydrogen or halo, while

Z is hydrogen or -CONHR ⁵ wherein R ^{5 is} phenyl or naphthyl.

The above novel compounds have lipoxygenase inhibitory, anti-asthma, anti-allergic, thrombotic and arteriosclerotic, anti-inflammatory and gastroprotective properties.

The invention also relates to a pharmaceutical preparation comprising methyl or undecyl, ^R1 is hydrogen or methyl, ^R2 is hydrogen or hexadeciloxicsoportot, and R, and the compound of formula (I) wherein Z is hydrogen, wherein R is an active ingredient.

These compounds are known (British Patent No. 1,441,174, German Patent Publication No. 2,342,878, German Patent Publication No. 2,305,694, Syntheses 1982), but their pharmacological activity is unknown.

The preparation of ketoximes is described in detail in the literature; processes for the production of letoximes can be found in all organic synthesis manuals (see, for example, Weygand-Hilgetag: Organischchemische Experimentierkunst). Various methods have been described in the literature for the reaction of 1-artI-1-alkanone derivatives with hydroxylamine hydrochloride, but the reaction conditions, such as reaction time and base quality, are often not the most favorable, depending on the structure of the starting ketone. way.

Of the I-aryl-1-alkanone oxime derivatives, particular attention has been paid to 1- (2-hydroxyphenyl) -1-alkanone oxime derivatives as they are reagents in the analysis of metals and in liquid metallurgy. They can be used as selective metal extraction agents for extractions (German Patent Publication No. 2,342,878). 5-Isonyl-2-hydroxyacetophenone oxime has gained industrial importance for the isolation of copper. (This compound is Shell Chemicals SME 529) (Extr. Metall Copper Int. Symp. 1976, 1039). However, the use of these compounds in human or veterinary medicine has not yet been described.

It is an object of the present invention to provide compounds of therapeutic value, in particular anti-asthma, anti-anaphylactic, anti-inflammatory, anti-rheumatic, antihypertensive, antispasmodic and anti-thrombotic.

Surprisingly, it has been found that the compounds of formula (I) of the present invention have valuable pharmacological activity, particularly against asthma and rheumatism, as well as anti-anaphylactic, anti-inflammatory, antihypertensive, antispasmodic and thrombotic, and consequently in bronchial asthma and other allergic diseases, as well as various types of inflammatory and rheumatic diseases and thrombosis.

The pharmacological effects of the compounds of the invention are based on the inhibition of the lipoxygenase enzyme.

The invention also relates to pharmaceutical compositions containing the compounds of the invention as active ingredients.

The compounds of formula (I) according to the invention are prepared by reacting an aliphatic carboxylic acid of the formula C _n H ₂ r _{+ 1} CO ₂ H or a suitable derivative thereof, preferably the acid chloride, under conditions of Fries rearrangement or the like. with a substituted phenol. If the ketone thus obtained contains an additional hydroxyl group, it is converted to the ether with an alkylating agent such as an alkyl halide, aralkyl or cycloalkyl bromide or chloride, preferably an alkyl bromide. The ketone is then converted to the oxime in a basic manner in a known manner with hydroxylamine hydrochloride or other suitable hydroxylamine salt. Inorganic or organic bases may be used. Suitable bases include, for example, sodium or potassium hydroxide or calcium hydroxide; sodium or potassium carbonate; sodium hydrogencarbonate; sodium or potassium acetate and sodium formate; and pyridine, piperidine, morpholine, N-methylpiperazine and diethanolamine. The etherification and oxime forming reaction is carried out in organic solvents: for the etherification reaction, it is preferable to use acetone or a lower aliphatic alcohol and to add one of the basic substances mentioned above, in particular potassium carbonate or sodium hydroxide. Preferred oxime formation is an aliphatic lower alcohol or glycol, 3

-3194816 acetonitrile or dioxane, preferably ethanol or a mixture of these solvents with water is used. Preferably, the temperature is between 50 ° C and 130 ° C. The alkylation reaction lasts for 15-30 hours; the oxime-forming reaction time is from 15 minutes to 3 hours.

The present invention also provides novel compounds not previously described in the literature which have been characterized by elemental analysis, melting point and infrared imaging properties. These data are summarized in Table 1.

. Spreadsheet

Novel 1- (2-hydroxyaryl) -alkanone oxime derivatives

The chemical name of the compound op. C \ / KBr; cm ' ¹ v max / OH / / C = N / / N = 0 /

2-Hydroxy-5-methyl-kaprofenon- / N

phenylcarbamoyl / oxime 117-120 2-Hydroxy-3-chloro-oxime carprofen 102-103 3390 1638 975 2-Hydroxy-4-pentyloxy-oxime 66-67 3420 1640 980 2-Hydroxy-4- / decyloxy / acetophenone oxime 69-70 3425 * 1628s 975 2-Hydroxy-4- / phenylmethoxy / acetophenone oxime 143 3350 3360 1630 962 2-Hydroxy-4- / decyloxy / propiophenone oxime 58-59 3390 1632 990 2-Hydroxy-4-butoxy-5- (n-hexyl) -acetophenone oxime 62 3410 * 1640s 970 2-Hydroxy-4-pentyloxy-carprofen oxime 80 3360 1640 985 2-Hydroxy-4- / decyloxy / -kapro- butoxide oxime 57 3430 1648 980 2-Hydroxy-4- / octyloxy / -laurofenon oxime 60-63 3430 * 1640s 985 2-Hydroxy-4- / cyclohexyloxy / propiophenone oxime 65-69 3440 1640 988 2-Hydroxy-3-chloro-oxime laurofenon 96 3395 1640 972 2-Hydroxy-5-chloro-oxime laurofenon 97 3380 1635 970 2-Hydroxy-4-butoxyacetophenone oxime 87 3422 1640 988 2-Hydroxy-4- (dodecyloxy) -propionic enone oxime 63 3395 1635 988

2-Hydroxy-4- / octadecyloxy / -aceto-

butoxide oxime 90 3410 3360s ^X 1627 980 2-Hydroxy-4- / decyloxy / -laurofe- Non-oxime 64-69 3430 1648 987

* s = spectrum shows commitment

Surprisingly, it has been found that the compounds of formula (I) according to the invention exhibit pronounced anti-asthma and allergy and anti-anaphylactic (anti-anaphylactic) effects in vitro and in vivo in experimental animals. 4

These pharmacologic properties of the compounds of the present invention have been partially demonstrated by measurement methods described in the literature, but modified. For the purposes of these _β assays, isolated guinea pig trachea, isolated guinea pig lung 4194816 and arachidonic acid-induced contraction of the isolated lung strip (see Example 16) and arachidonic acid-induced contraction of the pulmonary artery (see Example 18) and , specifically allergic-induced bronchoconstriction of guinea pig anesthetized and artificially ventilated guinea pig ("Guinea pig asthma" and "guinea pig anaphylactic behavior") (see Example 17) [MW Drazen et al., J. Clin. Invest. 63: 1 (1979); MW Schneider and JM Drazen: Amer. Resp. Dis. 121,835 (1980)

S. S. Yen and W. Kreutner, Agents and Actions 10, 274 (1980); S. S. Yen; Prostaglandins 22, 183 (1981); J.J. Adcock and L.G. Gariand: Brit. J. Pharmacol. 69, 167 (1980); W. Diamantis et al., Europ. J. Pharmacol. 56: 407 (1979); and P. Andersson, Brit. J. Pharmacol. 77, 301 (1982)].

The compounds of the present invention completely inhibit the asthmatic response of ovalbumin sensitized guinea pig. It is noteworthy that all control animals died after a single intraperitoneal administration of ovalbumin (40 μg / kg body weight) following a persistent, extremely severe asthma reaction (anaphylactic shock) with respiratory paralysis; in contrast, animals pre-treated with a compound of the invention (e.g., 2-hydroxy-5-methyl-laurophenone oxime) also underwent three consecutive injections of 40 pg of ovalbumin without any bronchoconstriction reaction. This type of activity against allergic asthma is comparable to that of ketotifen, a modern anti-asthma agent, but with a mechanism of action different from that of the compounds of the present invention (see below). The compounds of the invention are superior to ketotifen because they have a broader range of indications: they are also effective against non-allergic forms of bronchial asthma. The inhibitory effect of arachidonic acid-induced contraction in the isolated pulmonary arteries of rabbits (see Example 18) may be consistent with their antihypertensive and antispasmodic activity.

This experimental method provides an appropriate model in experimental animals for forms of bronchial asthma that are a consequence of IgE and IgG mediated allergic reactions [R. Andersson: Brit. J. Pharmacol. 77, 301 (1982)]. From this it can be concluded that the compounds of the invention also have anti-inflammatory activity. This conclusion was reached in a suitable animal model, carrageenin-induced rat foot edema, using the method of Winter et al. Winter et al., Proc. Soc Exp Bioi. Med. Ili, 544 (1962)] (see Example 19).

It has been shown that inhibition of the lipoxygenase enzyme is responsible for the pharmacological effects of the compounds of the present invention as molecular targets. The arachidonic acid metabolites produced by the lipoxygenase enzyme are known to be involved in the production of inflammatory and allergic processes (see E. J. Goetzl, Immunology, 40, 709 (1980); Ford-Hutchinson et al., J. Pharm. Pharmacol, 32, 517 (1980), B. Samuelsson: Trends in Pharmacol. Sci. May 1980, 227; and Borgeat et al., J. Med. Chem. 24, 121 (1981).

Inhibition of the lipoxygenase enzyme has been conclusively demonstrated on a suitable animal lipoxygenase, as described by Rapoport et al., Eur. J. Biochem. 96, 545 (1979)] were isolated from rabbit reticulocytes. The compounds of the present invention exhibit a predominant inhibition of 90% or greater at a final concentration of 1 mmol (see Example 20). This potent inhibitory effect was detectable for some of the compounds of the invention even at a final concentration of 0.1 mmol. By varying the concentration of the substance, the titration curves of the inhibition were constructed and the I ₅₀ values (i.e., the concentration at which the active substance inhibits lipoxygenase enzyme activity by 50%) were calculated. This value of ₅₀ was 7 micromolar for 2-hydroxy-5-methyl-laurophenone oxime with anti-asthma activity. Because of the low water solubility of this substance, and many other compounds of the invention, at this concentration in the in vitro assay system, which was noticeable due to the significant turbidity of the solution, it is believed that the true I ₅₀ values are significantly lower. The fact that the lipoxygenase enzyme derived from rabbit reticulocytes is a negative model for the molecular pharmacological activity of the compounds of the invention has been demonstrated by the use of other lipoxygenase inhibitors known in the art, such as 3-amino-1- (3-trifluoromethyl). -phenyl) -pyrazoline, 5,8,11,14-eicosacetraic acid, 5,8,11-eicosacrylic acid, nor-dihydroguric acid, propyl gallate, 4-nitropyrocatechin and 3- (tert-butyl) -4-hydroxy -anisole - this enzyme is also very effectively inhibited. However, the known lipoxygenase inhibitors do not achieve the anti-asthma efficacy of the compounds of the invention. The compounds of the present invention also inhibit all lipoxygenase enzymes isolated from plant sources, including soybean lipoxygenase-1 (cf. Example 20) and pea-derived lipoxygenase. From these studies, as well as from further research, it has been concluded that the compounds of the invention inhibit lipoxygenase enzymes universally, regardless of their origin and position specificity. This gives rise to a number of valuable pharmacological properties.

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Of particular interest is the observation that the other important enzyme of the arachidonic acid cascade, cyclooxygenase, isolated from the bovine seminal vesicle by the method of FJG van der Ouderan et al. degree. In this regard, the compounds of the present invention also outperform many known anti-inflammatory drugs which either inhibit only cyclooxygenase (e.g., acetylsalicylic acid, indomethacin) or inhibit both lipoxygenase and cyclooxygenase (e.g., fenidone) and by their properties undesirable pharmacological side effects of these known compounds (e.g., ulcer-forming, gastric toxicity, and pro-asthmatic effect with acetylsalicylic acid).

Since the compounds of the invention have been identified as a molecular target for inhibition of lipoxygenase, their effect on platelet aggregation (platelet aggregation) was further investigated. The irreversible pathway of platelet aggregation via lipoxygenase is now known [C. E. Dutilh et al., Prostaglandins ad Medicine 6, 111 (1981)]. Irreversible platelet aggregation is considered to play a key role in the development of thrombotic diseases. Therefore, it is extremely important to recognize that the compounds of the invention either completely inhibit platelet aggregation or render it reversible (cf.

Example 21). In the experiments, platelet aggregation was induced with either arachidopsic acid or platelet activating factor (PAF-Acether).

These experiments demonstrate appropriate anti-asthma, antiallergic, antithrombotic and anti-inflammatory effects in appropriate biological models.

In the field of human and veterinary medicine, for example, the following indication areas may be mentioned:

1. All forms of bronchial asthma including intrinsic asthma of infectious origin, exogenous asthma types 1, 11 and IV] R. R. A. Coombs and P.G.H. Gell, "The classification of allergic reactions responsible for clinical hypersensitivity and disease" in Clinical Aspects of Immunology, edited by P.G.H.Gell and R.R. A. Coombs, 575. side; Blackwell Scientific Publications, Oxford, 1968]: Aspirin-induced asthma, exercise-induced bronchial asthma, cold-induced asthma, irritable bronchial asthma. and psychogenic bronchial asthma.

2. Asthma bronchitis and obstructive pulmonary emphysema, as well as all bronchoconstrictor states, which occur as complications of other diseases or as a side effect of medical activity, such as anesthesia complications or the use of beta-adrenergic blocking agents.

3. Allergic diseases in the long term, in particular - atopic dermatitis;

- allergic rhinitis (for example, periodic rhinitis, recurrent rhinitis for several years and rhinitis due to dilation of the blood vessels in the nasal mucosa);

- hives;

- angioedema;

- contact dermatitis (contact eczema);

- allergic diseases of the gastrointestinal tract; and allergic conjunctivitis.

4. All forms of thrombosis and treatment of pre-existing thrombosis (thrombophlebitis) and prevention of thrombosis in the following cases:

- during chronic heart failure;

- post-treatment of myocardial infarction;

- during recurrent chronic thrombosis; and - chronic thrombophlebitis.

5. Non-steroidal anti-inflammatory drugs, in which the compounds of the formula I are primarily indicated in inflammatory processes where conventional anti-inflammatory drugs (eg acetylsalicylic acid, salicylates), which are active beyond the inhibition of the lipoxygenase enzyme, do not provide sufficient therapeutic especially in cases of purulent inflammation and rheumatic and joint diseases.

6. All forms of hypertension, especially hypertension in the pulmonary circulation.

7. Smooth muscle spasms of various origins, in particular in the case of smooth muscle spasms in different sections of the digestive tract and urogenital tract, and in the smooth muscle of the blood vessels.

Other known pharmacological effects of lipoxygenase inhibitors known in the art indicate that the compounds of the present invention also have gastroprofective (gastric wall protection) and antimetastatic action against atherosclerosis.

The compounds of formula (I) are useful as agents for the treatment of oral, sublingual, rectal, parenteral, intravenous or transdermal routes and for the treatment of bronchial asthma and thrombosis, as well as rheumatic, arthritic and other inflammatory diseases.

The following compounds are exemplified for their particularly favorable pharmacological properties:

2-H-hydroxy-5-methyl-laurophenone oxime;

2-H-hydroxy-4-methylcaprofenone oxime;

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2-Hydroxy-5-methyl-oxime carprofen;

4- (decyloxy) -2-hydroxyacetophenone oxime;

4- (decyloxy) -2-hydroxypropiophenone oxime;

4- (Benzyloxy) -2-hydroxyacetophenone oxime;

4- (decyloxy) -2-hydroxycaprofenone oxime;

4- (Hexyloxy) -2-hydroxyacetophenone oxime; 2-Hydroxy-4-pentyloxy-oxime; 2-Hydroxy-4-pentyloxy-carprofen oxime; 4-Butoxy-5- (n-hexyl) -2-hydroxyacetophenone oxime; and the

2-Hydroxy-5-methyl-caprofenone-N- (phenylcarbamoyl) -oxime.

The present invention also provides pharmaceutical compositions comprising one or more active ingredients of the invention in admixture with an inert, non-toxic pharmaceutically acceptable carrier or compositions comprising one or more active ingredients of the invention.

Non-toxic, inert, pharmaceutically acceptable carriers include all types of solid, semi-solid, or liquid diluents, fillers, and formulation auxiliaries.

Examples of preferred pharmaceutical compositions include tablets, dragees, capsules, pills, granules, syrups, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

The tablets, dragees, capsules, pills and granules may contain, in addition to the active ingredient (s) and the usual excipients, the following excipients: (a) fillers and propagating agents, such as starch, lactose, cane sugar, glucose, mannitol and silica; b) binders such as carboxymethylcellulose, alginates, gelatins and polyvinylpyrrolidone; (c) humectants, such as glycerol; d) tablet disintegrating agents such as agar, calcium carbonate and sodium bicarbonate; e) dissolution retardants such as paraffin; and f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents such as acetyl alcohol and glycerol monostearate; (h) adsorption promoters such as coalin and bentonite; and i) lubricants such as talc, calcium and magnesium stearate, sodium lauryl sulfate, and solid polyethylene glycols; or mixtures of the substances listed in points (a) to (i).

The tablets, dragees, capsules, pills and granules may be coated with the usual opacifying agents and may be formulated so as to release the active ingredient (s) exclusively or predominantly over a selected period of the gastrointestinal tract, optionally in a delayed manner. In this case, the embedding compound is made of polymeric materials or waxes.

The active ingredient (s) may be in microencapsulated form with one or more excipients.

Suppositories may contain, in addition to the active ingredient, conventional water-soluble or water-insoluble carriers, such as polyethylene glycols, fats such as cocoa fat, and longer chain esters (e.g.

Ointments, pastes, creams and gels, in addition to the active ingredient, may contain, in addition to the active ingredient, common carriers such as vegetable and animal fats, waxes, paraffins such as petroleum fractions, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, or mixtures of these substances.

Sprays and powders may contain, in addition to the active ingredient, customary carriers such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders, or mixtures thereof. In addition, the sprays may contain conventional propellants such as chlorofluorocarbons.

Solutions and emulsions may contain, in addition to the active ingredient, customary carriers such as non-toxic organic solvents, solubilizers, and emulsifiers such as water, dimethylsulfoxide, ethyl alcohol, isopropyl alcohol, methyl glycol, ethyl carbonate, ethyl acetate. , benzyl alcohol, benzo benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils - especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil - glycerol, glycerol fur, tetrahydro , polyethylene glycols, and fatty acid esters of sorbitan; or they may contain mixtures of these substances.

For parenteral administration, solutions and emulsions may be in sterile form and may be isotonic with blood. The suspensions may contain, in addition to the active ingredient, customary carriers such as liquid diluents such as water, dimethylsulfoxide, ethyl alcohol, propylene glycol; suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth; or they may contain mixtures of these substances.

Dispersing agents such as lignin, sulphite bases, methylcellulose, starch and polyvinylpyrrophidone may also be used in the formulation.

The above dosage forms may further comprise coloring agents, preservatives, and odor and taste.

-7194816 improving additives such as peppermint oil and eucalyptus oil, and sweeteners such as saccharin.

The pharmaceutically active compounds should preferably be present in the pharmaceutical compositions listed above in a concentration of from 0.1 to 99.5% by weight, more preferably from about 0.5% to 90% by weight (based on the total weight of the particular pharmaceutical composition). The active ingredient must be present in the pharmaceutical composition in an amount sufficient to reach a given dosage range.

In addition to the active compounds of the present invention, the above-mentioned pharmaceutical compositions may also contain other therapeutic agents, such as antihistamines and cyclooxygenase inhibitors.

The above-mentioned pharmaceutical compositions are prepared by conventional methods known in the art, for example, by mixing the active ingredients with the excipients.

The invention also encompasses the use of the active compounds of the invention and pharmaceutical compositions for the prevention, amelioration and / or cure of the diseases listed above in human and veterinary medicine.

The active compounds or pharmaceutical compositions may be applied topically, orally, parenterally, intraperitoneally and / or rectally, but preferably orally, particularly in aerosol form.

In general, it has been found to be advantageous to administer the active compound (or agents) of the invention in an amount of from about 0.05 mg / kg body weight to about 100 mg / kg body weight every 24 hours, preferably from 0.1 to 50 mg / kg body weight. in amounts, optionally in several portions, to achieve the desired results.

However, it may be desirable to deviate from the aforementioned dosage, depending on the type and weight of the individual in need of treatment, the type and severity of the disease, the type of drug formulation and the drug application and the interval at which the dosage is administered. In some cases it may be sufficient to administer less than the aforementioned amount of the active ingredient of the invention; in other cases the above quantities should be exceeded.

The following examples illustrate the process of the invention. These examples are not intended to limit the scope of the invention.

Example 1

Preparation of 2-Hydroxy-4-methyl-caprophenone oxime The m-cresol is converted to the ester by a known method and converted to 2-hydroxy-4-methyl-caprofenone by the Fries rearrangement [J. Chem. Soc. 63, 3164 (1941)]. A solution of this ketone (20 g, 0.1 mol) in a solution of 10.6 g of 8 (0.15 mol) hydroxylamine hydrochloride in 35 ml of ethanol and 2 ml of water with 19.5 g (0.5 mol) of sodium hydroxide was shaken mixed. The reaction mixture was refluxed for 5 minutes, then allowed to cool and the mixture was concentrated to 55 ml. is poured into a mixture of hydrochloric acid and 350 ml of water. The resulting oxime was taken up in ether and dried over anhydrous sodium sulfate. After distillation of the ether, 21 g of crude product are obtained, m.p. 45 ° C after recrystallization from petroleum ether.

Example 2

Preparation of 2-Hydroxy-5-methyl-ca- profenone oxime (known) From p-Cresol, a known ester is prepared from caproyl chloride and this ester is converted by Fries rearrangement to 2-hydroxy-5-methyl-caprofenone, b.p. // 8.666 kPa [J. Am. Chem. Se. 63, 3164 (1941)], 20 g (0.1 mol) of ketone are dissolved in 45 ml of ethanol, 7.5 g of a concentrated aqueous solution of hydroxylamine hydrochloride and 15 g of crystalline sodium acetate are added. reflux for a minute. The mixture was diluted with water and the precipitated oxime was recrystallized from a mixture of ethanol and water, m.p. 83-85 ° C.

Example 3

Preparation of 2-Hydroxy-5-methylcaprofenone (N-phenylcarbamoyl) oxime

2.2 g (0.01 mol) of 2-hydroxy-5-methylcaprofenoxime are dissolved in 25 ml of toluene, with slight heating, and 1.2 g (0.01 mol) of phenyl isocyanate are added slowly with shaking. added. After standing for one hour, the solvent was evaporated in vacuo. The crystalline residue was recrystallized from ethanol or aqueous ethanol to give the title compound as colorless crystals, m.p. 117-120 ° C.

Example 4

Preparation of 2-hydroxy-5-methyl-laurophenone oxime

The ester of p-cresol with lauroyl chloride (m.p. 28 ° C) is converted to the ketone by m.p. Fries rearrangement (m.p. 42-43 ° C). This ketone (29 g, 0.1 mol) was dissolved in ethanol to give a clear solution of 7 g of an aqueous solution of hydroxylamine hydrochloride and 15 g of crystalline sodium acetate, and the resulting solution was refluxed for 20 minutes. After cooling or addition of water, the reaction mixture precipitated the title oxime, which was recrystallized from ethanol to give colorless crystals, m.p. 93 ° C.

Example 5

Preparation of 2-H.hydroxy-5-chlorocaprofenone oxime

2-Chlorophenol is esterified with caproyl chloride in a known manner, and the resulting ester is converted to 2-hydroxy-3-chlorocaprofenone by Fries rearrangement 8194816 (heating for 1 hour at 120 ° C). : 78-80 ° C after recrystallization from water-containing ethanol and n-heptane. 22.6 g (0.1 mol) of this ketone with 15.2 g (0.22 mol) of hydroxylamine hydrochloride in 150 ml of abs. of ethanol and 25 ml of pyridine are refluxed for 3 hours. The solvent was removed in vacuo and the oily residue was treated with aqueous ethanol and then recrystallized from n-heptane. The title oxime is obtained, m.p. 102-103 ° C.

In a similar manner, the following compounds were prepared:

2-Hydroxy-5-chlorocaprofenone oxime, m.p. 100 ° C (after recrystallization from n-heptane); 2-Hydroxy-3-chloro-laurophenone oxime, m.p. 96 ° C (after recrystallization from ethanol); and 2-Hydroxy-5-chloro-laurophenone oxime, m.p. 97 ° C (after recrystallization from ethanol).

Example 6

Preparation of 2-hydroxy-4-pentoxyacetophenone oxime

A solution of 2,4-dihydroxyacetophenone (30.4 g, 0.2 mole) in n-pentyl bromide (45 g, 0.3 mole) and dry acetone (28 g) in dry acetone (300 ml) was heated at reflux for 24 hours. . The acetone is then evaporated in vacuo, the residue is stirred with a little water and extracted with ether. The ether layer was dried over anhydrous sodium sulfate and the ether was evaporated to give 2-hydroxy-4-pentoxyacetophenone, m.p. 33 ° C. This ketone (11.1 g, 0.01 mol) was heated at reflux for 3 hours with 7.5 g of potassium acetate and 4.5 g of hydroxylamine hydrochloride, and then the reaction mixture was hot filtered and filtered to separate the oxime. water. Recrystallization from n-heptane gave the title oxime (9 g), m.p. 66-67 ° C.

In a similar manner, the following compounds were prepared:

4-Butoxy-2-hydroxyacetophenone oxime, m.p. 87 DEG C. (after treatment with aqueous ethanol and recrystallization from n-heptane);

4- (Dodecyloxy) -2-hydroxypropiophenone oxime, m.p. 63 DEG C. (after recrystallization from n-heptane);

4- (Hexadecyloxy) -2-hydroxyacetophenone oxime, m.p. 86-87 ° C (after recrystallization from n-heptane); and

2-Hydroxy-4- (octadecyloxy) acetophenone oxime, m.p. 90 DEG C. (after recrystallization from ethanol).

Example 7

Preparation of 4- (n-decyloxy) -2-hydroxyacetophenone oxime

30.4 g (0.2 mol) of 2,4-dihydroxyacetophenone,

A mixture of 66.3 g (0.3 mol) of n-decyl bromide, 28 g of anhydrous potassium carbonate and 300 ml of dry acetone is refluxed in a water bath for 22 hours and then evaporated under ace14 tonne vacuum. The residue is taken up in a little water, extracted with ether and the organic phase is dried over anhydrous sodium sulfate. After distilling off the ether, the residue is recrystallized from ethanol to give 4- (decyloxy) -2-hydroxyacetophenone, m.p. 35 ° C. This ketone was 14.6 g (0.05 mol)

7.6 g (0.11 mol) of hydroxylamine hydrochloride in 90 ml of abs. in ethanol in the presence of 30 ml of pyridine under reflux for 3 hours and then evaporate the solvent in vacuo. The residue was first treated with water-containing ethanol and then recrystallized from n-heptane. The title oxime is obtained in the form of colorless crystals, m.p. 69-70 ° C.

Example 8

Preparation of 4- (decyloxy) -2-hydroxypropiophenone oxime

16.6 g (0.1 mol) of 2,4-dihydroxypropiophenone,

A mixture of 33.1 g (0.15 mol) of decyl bromide, 14 g of anhydrous potassium carbonate and 150 ml of dry acetone is refluxed for 20 hours and then the acetone is distilled off in vacuo. The residue is taken up in water, extracted with ether and the organic phase is dried over anhydrous sodium sulfate. Distillation of the ether gave 4- (decyloxy) -2-hydroxypropiophenone, m.p. 30 ° C. E ketone

9.2 g (0.03 mol) in 15 ml of pyridine and 25 ml of abs. in ethanol solution

4.5 g (0.066 mol) of hydroxylamine hydrochloride are heated under reflux for 3 hours. The solvent was distilled off in vacuo, the residue was washed with water and then recrystallized from ethanol. The title oxime is obtained as colorless crystals, m.p. 58-59 ° C.

Example 9

Preparation of 4- (Benzyloxy) -2-hydroxyacetophenone oxime: To a mixture of g (0.2 mol) of 2,4-dihydroxyacetophenone and 300 ml of dry acetone was added 28 g of anhydrous potassium carbonate followed by 38 g (0.3 g). mole) of benzyl chloride was added and the mixture was refluxed for about 20 hours. After the acetone was distilled off, 2N sulfuric acid solution was added to the residue, the solid product was filtered off with suction, treated with 2N potassium hydroxide solution and then washed with water until neutral. The crude product is recrystallized from ethanol to give 22 g of 4- (benzyloxy) -2-hydroxyacetophenone as colorless crystals, m.p. 103-105 ° C. The latter product was heated under reflux for 3 hours in a mixture of 1.28 g of hydroxylamine hydrochloride and 18.8 g of potassium acetate in 110 ml of ethanol. The reaction mixture was then filtered and water was added to the filtrate. This gives the title oxime, which, after recrystallization from water-containing ethanol, melts at 143 ° C.

Example 10

Preparation of 4- (n-butoxy) -5- (n-hexyl) -2-hydroxy-aaethophenone oxime

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7.1 g (0.03 mol) of 2,4-dihydroxy-5- (n-hexyl) acetophenone, 6.1 g (0.045 mol) of n-butyl bromide,

A mixture of 4.2 g of anhydrous potassium carbonate and 50 ml of dry acetone is refluxed in a water bath for 20 hours and then the solvent is distilled off. The residue is taken up in water, extracted with ether and the organic phase is dried over anhydrous sodium sulfate. Distillation of the ether gave 4- (n-butoxy-5- (n-hexyl) -2-hydroxyacetophenone, m.p. 37 ° C (after recrystallization from n-heptane) 2.8 g (0.01 mol). ketone, 30 ml of absolute ethanol, 6 ml of pyridine and 1.52 g (0.022 mol) of hydroxylamine hydrochloride are refluxed for 3 hours, then the solvent is distilled off and the residue is washed with water and then with n-heptane. Recrystallization gave the title oxime, m.p. 62 ° C.

Example 11

Preparation of 2-Hydroxy-4- (n-pentoxy) caprofenone oxime

A mixture of 20.8 g (0.1 mol) of 2,4-dihydroxycaprofenone, 22 g (0.145 mol) of n-pentyl bromide, 14 g of anhydrous potassium carbonate and 150 ml of dry acetone is refluxed for 30 hours in a water bath. Store at -70 ° C. The acetone was evaporated in vacuo and the residue was stirred with water. After extraction with ether, the organic phase is dried over sodium sulfate and the ether is distilled off. The residue evaporates when it cools down. Recrystallization from ethanol gave 2-hydroxy-4- (n-pentoxy) caprofenone, m.p. 4142 ° C. 14 g (0.05 mol) of ketone, 7.6 g (0.11 mol) of hydroxylamine hydrochloride A mixture of 15 g of potassium acetate and 200 ml of ethanol is refluxed for 3 hours, then the ethanol is distilled off and 100 ml of warm water are added to the residue. The oxime obtained as an insoluble residue was recrystallized from aqueous ethanol to give the title compound as colorless crystals, m.p. 80 ° C.

Example 12

Preparation of 4- (n-decyloxy) -2-hydroxycaprofenone oxime

A mixture of 20.8 g (0.1 mole) of 2,4-dihydroxycaprofenone, 32 g (0.145 mole) of n-decyl bromide, 14 g of anhydrous potassium carbonate and 150 ml of dry acetone was prepared as described in Example 11. (n-decyloxy) -2-hydroxycaprofenone (m.p. 45-47 ° C). The latter compound can be converted to the oxime in ethanol solution in the presence of potassium acetate, m.p. 57 DEG C. (after recrystallization from aqueous ethanol).

Example 13

Preparation of 2-Hydroxy-4- (n-octyloxy) laurophenone oxime

A mixture of 29.2 g (0.1 mol) of 2,4-dihydroxyl laurophenone, 28 g (0.145 mol) of n-octyl bromide, 14 g of anhydrous potassium carbonate and 150 ml of dry acetone is obtained. Reaction as described in Example 1c gives 2-hydroxy-4- (n-octyloxy) laurophenone, which is recrystallized from ethanol, m.p. 56-57 ° C. This ketone is reacted with hydroxylamine hydrochloride in ethanol solution in the presence of potassium acetate to give the title oxime, m.p. 60-63 ° C (after recrystallization from ethanol and n-heptane).

In a similar manner, 4- (n-decyloxy) -2-hydroxy-laurophenone oxime, m.p. 64-69 ° C (after recrystallization from n-heptane and ethanol) can be prepared.

Example 14

Preparation of 4- (cyclohexyl-1-oxy) -2-hydroxypropiophenone oxime

A mixture of 8.3 g (0.05 mole) of 2,4-dihydroxypropiophenone, 12 g (0.07 mole) of cyclohexyl bromide, 7 g of anhydrous potassium carbonate and 50 ml of ethyl glycol was refluxed for 8 hours. The reaction mixture was filtered, and after cooling, 250 ml of water were added to the filtrate. Precipitates 4- (cyclohexyloxy) -2-hydroxy-p rop iofenon, mp 80- 81 C. ^c Recrystallisation from ethanol. This ketone in ethanolic solution, in the presence of potassium acetate, reacts with hydroxylamine hydrochloride to give the title oxime, which is recrystallized first from ethanol and then from n-hepate at 65-69 ° C.

Example 15

Effect of 2-Hydroxy-5-methyl-laurophenone oxime on carbachol-induced contraction of isolated guinea pig trachea The activity of this compound against asthma was investigated in a tracheal preparation isolated from terger guinea pig using a modifier known in the literature (see page 7). Measurements were made in an isotonic thermostat in an organ bath, with contraction measuring apparatus equipped with a raised indicator, a measuring spindle and a measuring amplifier (inductive measurement using a high-vibration oscillation circuit). The passage through the gas was carried out with air. The composition of the suspension was 39.46 g of sodium chloride.

2.2 g of potassium chloride, 6.07 g of Tris, 1.0 g of calcium chloride, 9.9 g of glucose, 1.0 ml of saturated magnesium chloride solution and 43 ml of 1 N hydrochloric acid in 5 liters of pH 7, 4).

Convulsions were induced with 3.9 micromoles of carbachol. After the addition of the test drug, a strong dilatation was observed, which was already detectable at a concentration of 50 µM.

Example 16

Effect of 2-Hydroxy-5-methyl-laurophenone oxime on exogenous arachidonic acid-induced contraction of lung strip isolated from guinea pig

Similarly to the assay system described in Example 15, this experiment was organized. The studies were performed on lung strips isolated from guinea pigs. Contraction was induced with increasing concentrations of arachidonic acid 10194816 and measured cumulatively. (The arachidonic acid was stored in a concentrated ethanolic solution under a nitrogen atmosphere).

The 10 micromolar amount of the above compound of the invention reduced the arachidonic acid-induced contraction response by 70% ("metactoid inhibition") in the range of 0.1-100 micromolar, according to FG van den Brink, General General of Drug-Receptor-Interactions in Kinetics of Drug Action, edited by JM van Rossum, Springer Berlin, Heidelberg, New York, 1977, Chapter 4, pp. 169-254. p.

Example 17

Effect of 2-hydroxy-5-methyl-laurophenone oxime on allergen-induced bronchoconstriction in in vivo sensitized guinea pigs ('allergic guinea pig asthma')

This assay was performed on male guinea pigs 30-35 days after the animals were sensitized with 330 mg Al (OH) ₃ and 33 pg ovalbumin (freshly prepared in physiological saline). [P. Anderson: Brit. J. Pharmacol. 77, 301 (1982). The animals were anesthetized with 1.3 g / kg body weight (hereinafter g / kg or mg / kg) for intraperitoneal administration of urethane and induced muscle relaxation with 2 mg / kg intravenous Pavulon ^R. The allergen-induced bronchoconstriction, which evolved into a complete anaphylactic shock within a few seconds in all control animals, was induced by the administration of 40 pg of intravenous ovalbumin. Tracheostomized and venous catheterized animals were ventilated under reduced pressure in a ventilator cabinet (16 times per minute, inhalation / exhalation ratio 1: 1). Gas flow (V) and respiratory volume (Vt) were monitored by penumotachography and the animals were monitored for electrocardiogram (ECG). The animals were pretreated twice with finely powdered 2-hydroxy-5-methyl-laurophenone oxime by agar- was suspended in agar and injected intraperitoneally at 10 mg / kg 90 minutes and 60 minutes prior to the experiment.

The active substance completely inhibited the ovalbumin-induced asthma reaction in all the tested animals. In contrast, after a single intravenous administration of 40 pg of ovalbumin, all control animals died after a persistent, extremely severe asthma reaction (silence chest syndrome).

The pretreated animals also survived two subsequent injections of 40 pg / kg ovalbumin without reaction. Comparable anti-asthma, anti-18 allergic or anti-anaphylactic effects in a full animal model are not known even for modern anti-asthma drugs such as ketotifen and disodium chromoglycate. [C. Armor and D. M. Temple, Agents and Actions 12, 285 (1982)].

Example 18

Effect of 2-Hydroxy-5-methyl-laurophenone oxime on the contraction of exogenous arachidonic acid in lung arteries isolated from rabbit

The experimental setup of this assay system corresponds to that described in Example 15.

The test was performed on lung artery strips isolated from saliva.

The contraction was induced by increasing concentrations of arachidonic acid in the presence of 10 micromoles of indomethacin (thereby inhibiting the cyclooxygenase pathway of arachindonic acid) and was measured in a cumulative form.

micromolar 2-hydroxy-5-methyl-laurophenone oxime reduced the arachidonic acid-induced contraction response by 60-80% in the range of 0.1 to 100 micromoles ("metactoid inhibition") according to FG van den Brink: "The General Theory of Drug-Receptor-Interactors" in Kinetics of Drug Action, edited by JM van Rossum, Springer Berlin, Heidelberg, New York, 1977,

Chapter 4, pp. 169-254 p.

Example 19

Inhibitory effect of 2-hydroxy-5-methyl-laurophenone oxime on rat carrageenin-induced edema

According to international literature, carrageenan edema is capable of modeling inflammatory (proflogistic) processes and provides an opportunity to investigate in vivo the anti-inflammatory (anti-inflammatory) action of compounds. This assay was performed according to the general method [C. A. Winter et al., Poc. Soc Exp Bioi. Med., 111, 544 (1962)]. 2-Hydroxy-5-methyl-laurophenone oxime was administered intraperitoneally to 10 rats at 50 mg / kg and 0.1 ml of 0.1% carrageenin solution was administered to each animal at the same time. The size of the soles of the soles was measured hourly after dosing and compared with the control group. The results are summarized in the table below.

Table 2

Gstlo effect of 2-hydroxy-5-methyl-laurophenone oxime on carrageenan edema

Ico / hour / Inhibition /% /

0.5 43+

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Table 2 (cont'd)

TIME ΙοτάΙ Inhibition /% / 3 1 -i> + 4 31 5 29

+: P is significant at 0.05

Example 20

Inhibitory Effect of Compounds of the Invention on Lipoxygenase Activity from Rabbit Reticulocytes Lipoxygenase derived from rabbit reticulocytes was prepared in the electrophoretic and immunologically pure form according to the procedure described in SM Rapoport et al., Eur. J. Biochem. 96, 545 (1979)] The lipoxygenase activity was determined at 25 ° C by amperometric measurement of O ₂ consumption using the Clarck electrode in the following system: 0.1 molar potassium phosphate, pH 7.4; 2% sodium 20-chromate and 0.53 mmol of linoleic acid. The concentration of the enzyme in the measuring system was 25 nanomolar. The test substances were needles dissolved in freshly distilled methylglycol in vacuo and preincubated with the enzyme at the measuring temperature for 10 minutes in the absence of sodium cholate and lfolic acid. Dilutions of compounds were chosen so that the final concentration of methyl glycol in the preincubation mixture was

Not exceeding 2%; under these conditions no significant inhibition was observed in the control mixtures. The enzyme reaction was initiated by the addition of sodium cholate and linoleic acid. The active compound concentration varies, the inhibition titration curve plotted adjusted with _15, and this calculated concentration required for 50% inhibition was to compare the inhibitory effects of the compounds tested also available from commercial sources from soybean lipoxygenase-1 enzyme.

Unlike the compounds of the invention, ketotifen and disodium chromoglycate, which are modern anti-asthma drugs, do not inhibit the lipoxygenase enzyme derived from reticulocytes, even at a final concentration of 1 mM.

Table 3

Inhibitory effect of compounds of the present invention on the lipoxygenase enzyme of salivary reticulocytes and soybeans

The compound Chemical concentration in mmole From reticulocytes from soybeans t t ff derivative derivative lipoxygenase inhibitory activity / £ / / I _{50 in} brackets /

2-Hydroxy-5-methyl-

laurophenone oxime 2-hydroxy-5-chloro- 1, p 100 / 0.007 / 67 caprofenone oxime 4-Hexyloxy-2-hydr 1.0 90 / 0,3 / 24 oxy oxime 4- / yloxy Hexadecyl ~ / ~ -2-hydroxy-aceto- 1.0 100 / 0.26 / 68 butoxide oxime 0.5 75 / 0,5 / 38

Example 21

Inhibitory effect of compounds of the invention on platelet aggregation induced by arachidonic acid or platelet activating factor

The antithrombotic and thrombolytic activity of the compounds of the invention was tested in vitro on an authentic human cell system. Plasma-rich plasma from healthy donors was prepared by centrifugation at 1000 x g in trom12 bocytes. The aggregation of platelets was measured by diffuse light scattering or light absorption of the formed cell sets. Platelet-rich plasma was preincubated with the active compounds at 37 ° C for 3 minutes, and platelet aggregation was then induced by the addition of either 0.8 mmol of ⁶⁵ arachidonic acid or 1 micromole of thrombin-12194816 cytosolic activator. The mixture was then stirred at 800 rpm. Depending on the drug concentration used, platelet aggregation was either delayed significantly or completely inhibited.

During aggregation with platelet activating factor (PAF-Acether), all test compounds dissolved the first-formed cell clusters at a concentration of 40 micromoles. A similar effect was observed when aggregation was induced with 16 micromoles of arachidonic acid in the washed platelet suspension. It follows that the lipoxygenase inhibitors tested inhibit platelet aggregation in its irreversible phase and thus have a platelet effect.

For example, 4- (hexyloxy) -2-hydroxyacetophenone oxime delayed aggregation at 44 micromoles for 2 minutes while completely inhibiting aggregation at 60 micromoles. Similar results were obtained with other compounds of the invention as well as with known lipoxygenase inhibitors, such as 4-nitropyrocatechin.

Claims (5)

PATENT CLAIMS 1. A process for the preparation of a new I- ( For the preparation of 2-hydroxyaryl) -1-alkanone oximes - in the formula (I), R ^{1 represents a} hydrogen or chlorine atom or a C 1-9 alkyl group, R is R 7 -C 14 alkyl for R ² -R ³ = Z = H with the proviso that for R = C 11 alkyl R ¹ is other than methyl or R is C 1 -C 14 alkyl and R ^{2 is} hydrogen or -OR ⁴ where R ⁴ is C 1 -C 18 alkyl but different from hexadecyl or C 4 -C 8 cycloalkyl or phenyl alkyl or naphthylalkyl containing 1 to 4 carbon atoms in the alkyl moiety. and R ^{3 is} hydrogen or halo, while Z is hydrogen or -CONHR ⁵ wherein R ^{5 is} phenyl or naphthyl, characterized in that C ₁ H 2 H _{+ 1} COOH (where n is the number of carbon atoms of R) or a reactive derivative thereof, preferably the acid chloride , By reacting a phenol derivative of formula (II) under acylating conditions, And then, if desired, alkylating the intermediate compound formed by the Fries conversion, where R ^{2 is} hydroxy, followed by a base, preferably potassium acetate or pyridine. The reaction is carried out in the presence of 10 hydroxylamine salts and, if desired, the resulting oxime group is substituted by treatment with phenyl and naphthyl isocyanate. 2. A process for the preparation of a medicament for inhibiting lipoxygenase, asthma, allergy, thrombosis and arteriosclerosis, having anti-inflammatory and gastroprotective properties, and for lowering arterial hypertension and solubilizing smooth muscle, characterized in that one (or more) A compound of formula (I) according to claim 1 wherein R, R ', R ² , R ³ and Z are 25 as defined in claim 1, mixed with excipients, carriers or other excipients customary in the manufacture of a pharmaceutical composition to form a pharmaceutical composition. 3Q 3. A process for the manufacture of a medicament for the treatment of lipoxygenase inhibitor, asthma, allergy, thrombosis and arteriosclerosis, anti-inflammatory and gastroprotective, as well as for lowering arterial hypertension and smooth muscle spasmodically, and the corresponding aliphatic carboxylic acid as active ingredient. the substituted phenol derivative reacts under acylating conditions 1- (2-hydroxyaryl) -alkan-1-one oximes of formula (I) prepared by reaction of the obtained ketone with the resulting ketone and a hydroxylamine salt. R is methyl or undecyl, 45 R ^{1 of} hydrogen or methyl, R ^{2 is} hydrogen or hexadecyloxy, while R ³ and Z are hydrogen - 5Q, characterized in that the active ingredient of the formula I is formulated into a pharmaceutical composition in admixture with carriers and other excipients customary in the pharmaceutical industry.