N-imidazolidine derivatives substituted alkoksimyetilfosfinov or romanov or their pharmaceutically acceptable salts and pharmaceutical composition active antagonist and thromboxane inhibitor of thromboxane synthetase

 

(57) Abstract:

Usage: in medicine as an antagonist and/or an inhibitor of thromboxane synthetase. The inventive product, imidazole derivatives substituted alkoxyimino-tetrahydronaphthalene or Romanov formula 1:

< / BR>
in which Z represents-CH2- or-O-; m is an integer from 1 to 4; T is a linear or branched, saturated or unsaturated C1-C6hydrocarbon chain; a is a bond or a bivalent group-O-CH2-; R is hydrogen or C1-C4- alkyl, R1and R2which are identical, represent a hydrogen atom or methyl, or one of R1and R2represents a hydrogen atom, and the other is C1-C8-alkyl or C5-C8-cycloalkenyl, thienyl, phenyl-C1-C4is an alkyl group; or phenyl group, which phenyl group or the phenyl fragment is not substituted or is substituted by 1 or 2 substituents, independently selected from a halogen atom, a C1-C4alkyl and C1-C4alkoxy group; R3represents a hydrogen atom or a Deputy selected from a halogen atom, Tagalog-C1-C4- alkyl or C1-C4- alkoxygroup and RMie salt. The pharmaceutical composition active antagonist and thromboxane inhibitor of thromboxane synthetase, which as the active agent contains a compound of formula 1 or its pharmaceutically acceptable salt in an effective amount. 2 S. and 3 C.p. f-crystals, 4 PL.

The invention relates to new imidazolidones alkoxy-imino derivative of tetrahydronaphthalene and chromane, to a method for producing them, to pharmaceutical compositions containing them and to their use as therapeutic agents.

The invention provides new compounds of the following General formula (I):

< / BR>
in which Z is-CH2- or-O-;

m is an integer from 1 to 4;

T is a straight or branched, saturated or unsaturated C1-C6- hydrocarbon chain;

A is a bond or devalentino group-O-CH2-;

R represents hydrogen or C1-C4-alkyl;

R1and R2being identical, are hydrogen or methyl, or one of R1and R2represents hydrogen and the other is C1-C8-alkyl or C5-C8-cycloalkyl, thienyl, phenyl-C1-C4is an alkyl or phenyl group, which is selected by halogen, C1-C4-alkyl and C1-C4-alkoxy-group;

R3represents hydrogen or a Deputy selected from halogen, Tagalog-C1-C4-alkyl and C1-C4-alkoxy;

R4is OR5group, in which R5represents hydrogen or C1-C6-alkyl, and pharmaceutically acceptable salts of them.

The invention also includes within its scope all possible isomers, stereoisomers and their mixtures, and the metabolites and the metabolic precursors or bioresistant compounds of formula (I).

In particular, the compounds of formula (I) are either E-or Z-isomerism about oximes double bond. As a separate E - and Z-isomers of the compounds of formula (I), and a mixture of them also included in the scope of the invention.

When R1or R2is C1-C8is an alkyl group, it may be an alkyl group, branched or straight chain, such as actiom, heptyl, hexyl, Pentium, bootrom, tribution, propylene, ethyl or stands.

When R1or R2is cycloalkyl group, it is preferably cyclopentyl, tsiklogeksilnogo or cycloheptyl group, especially cyclohex cerenomy radical, for example, C1-C5-alkylenes chain, in particular-CH2-, -CH2-CH2- or-CH2-CH2-CH2-, or CH2-CH2= CH2-CH2-, or CH2-C5-alkenylamine chain, in particular-CH=CH-, -CH2-CH=CH - or-CH= CH-CH2-.

When a certain higher the value of m is higher than 1, each substituent R3independently may be the same or different.

When R5is C1-C6is an alkyl group it represents, for example, methyl, ethyl, propyl, isopropyl, butyl or tert-butyl, more preferably methyl or ethyl.

Alkyl and alkoxy groups may be groups with a branched or straight chain.

C1-C4-Alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl or tert-butyl, more preferably methyl or butyl.

C1-C4The alkoxy group is, for example, methoxy, ethoxy-, propoxy-, isopropoxy, butoxy - or tert-butoxy, preferably methoxy, ethoxy - or propoxy group.

The halogen atom is appropriately bromine, chlorine or fluorine, preferably bromine or fluorine.

Pharmaceutically acceptable with the for example nitrogen, hydrochloric, Hydrobromic, sulphuric, perchloric and phosphoric acid; organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, almond and salicylic acid; and salts with inorganic bases, for example salts of alkali metal, especially sodium or potassium, or alkaline earth metal, especially calcium or magnesium, or with organic bases, such as bonds alkylamines, preferably triethylamine.

As mentioned above, the invention also covers its scope pharmaceutically acceptable bis predecessors (commonly known as prodrugs of compounds of formula (I), i.e. compounds that have the formula, different from the above formula (I), but which are nevertheless with the introduction of man become directly or indirectly in vivo into a compound of formula (I).

Preferred compounds of the invention are the compounds of formula (I), in which

Z represents-CH2- or-O-;

m is 1 or 2;

T is C1-C5-alkalinous or C2-C5-alkenylamine chain;

A represents A bond or-O-CH2-;

R is hydrogen;

R1and R24-alkyl, C5-C7-cycloalkyl or phenyl or benzyl group in which the phenyl ring or the phenyl part is unsubstituted or is substituted by one or two substituents, independently selected from halogen, C1-C4-alkyl and C1-C4-alkoxy group; or a thienyl group; R3is hydrogen, halogen, trifluoromethyl, or C1-C4-alkoxy-group;

R3is hydrogen, halogen, trifluoromethyl, or C1-C4-alkoxy-group;

R4is-OR5group, in which R5is hydrogen or C1-C4-alkyl;

and pharmaceutically acceptable salts of them.

Examples of preferred compounds of the invention are the following compounds as either the Z - or E-isomer or Z, E-mixtures of these isomers:

1) 5-[[2,3-dihydro-3-(1H-imidazol-1-yl)- 4H-1-benzopyranyl] -aminooxy]-pentane acid;

2) 5-[[2-methyl-3-(1H-imidazol-1-yl)- 2,3-dihydro-4H-1-benzopyranyl] -aminoxy] pentane acid,

3) Ethyl 5-[[2-methyl-3-(1H - imidazol-1-yl)- 2,3-dihydro-4H-I-benzoperylene]-aminoxy] pentanol acid,

4) 6-[[2-methyl-3-(1H-imidazol-1-yl)- 2,3-dihydro-4H-1-benzopyrane]-hexanoic acid,

6) Ethyl ester 6-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl]-aminooxy]-hexanoic acid,

7) 5-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3 - dihydro-4H-1-benzopyranyl] -aminooxy]-pentane acid,

8) Ethyl ester 5-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl]-aminooxy]- pentanol acid,

9) 4-[[2-(3,4-acid)-3-(1H-imidazol-1-yl)-2,3-dihydro-6-methoxy-4H-1-benzopyranyl]-aminooxy]-butane acid,

10) 5-[[2-phenyl-3-(1H-imidazol-1-yl)- 2,3-dihydro-6-methoxy-4H-1-benzopyranyl]-aminooxy]-pentane acid,

11) 6-[[2-phenyl-3-(1H-imidazol-1-yl) -2,3-dihydro-6-methoxy-4H-1-benzopyranyl]-aminooxy]-hexanoic acid,

12) Methyl ester 6-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-6-methoxy-4H-1-benzopyranyl] -aminoxy] hexanoic acid,

13) 6-[[2-phenyl-3-(1H-imidazol-1-yl)- 2,3-dihydro-6-n-butoxy-4H-1-benzopyranyl]-aminooxy]-hexanoic acid,

14) 5-[[2-(3,4-acid)-3-(1H-imidazol-I-yl) -2,3-dihydro-6-methoxy-4H-1-benzopyranyl]-aminooxy]-pentane acid,

15) 6-[[2-(3,4-acid)-3-(1H - imidazol-1-yl)-2,3-dihydro - 6-methoxy-4H-1-benzopyranyl]-hexanoic acid,

17) 6-[[2-phenyl-3-(1H-imidazol-1-yl)-2,2-dihydro-6-fluoro-4H-1-benzopyranyl] -aminooxy]-hexane sour is>25) 6-[[2-(Tien-2-yl)-3-(1H-imidazol-1-yl) 2,3 - dihydro-4H-1-benzopyranyl]-aminooxy]-hexanoic acid,

26) 5-[[-(Tien-3-yl)-3-(1H-imidazol-1-yl)-2,3 - dihydro-4H-1-benzopyranyl]-aminooxy]-pentane acid,

27) 6-[[2-(Tien-3-yl)-3-(1H-imidazol-1-yl) -2,3-dihydro-4H-1-benzopyranyl]-aminooxy]-hexanoic acid,

28) 3-[[2-(4-forfinal)-3-(1H-imidazol-1-yl)-2,3-dihydro-6-trifluoromethyl-4H-1-benzopyranyl]-aminooxy]-prophylactically acid,

29) 6-[[2-benzyl-3(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl] -aminooxy]-hexanoic acid,

30) 2-[[2-((4-forfinal)-methyl)-3-(1H-imidazol-1-yl)-2,3-dihydro-6-fluoro-4H-1-benzopyranyl]-aminooxy]-atrociously acid,

31) 6-[[2-phenyl-3-((1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl]-aminooxy]-hexanoic acid,

32) 5-[[2-(1H-imidazol-1-yl)-1,2,3,4-tetrahydro-1 - naphthalide]-aminooxy] -pentane acid,

33) 5-[[2-(1H-imidazol-1-yl)-7-methoxy-1,2,3,4-tetrahydro-1-naphthalide] -aminooxy]-pentane acid,

34) ethyl ester 5-[[2-(1H-imidazol-1-yl)-1,2,3,4-tetrahydro-1-naftilan]-aminooxy] -panthanivas acid,

and pharmaceutically acceptable salts of them.

Structural formulas are numbered above compounds are identified by their increasing number, are given in table. 1.

Salt of the compounds of formula (II) is, for example, salt of an alkali metal, particularly sodium or lithium salt.

Salt of the compounds of formula (II) can be obtained by known methods, for example the compound of formula (II) can be subjected to reaction with an alkali metal hydride, preferably NaH, and an inert organic is raised, for example, a halide group, in particular chlorine or bromine group, or the residue of an activated ester group, in particular mesyl (methylsulphonyl or tosyl (toluensulfonyl).

The reaction of the compound of formula (II) or its salt with the compound of the formula (III) can be carried out by known methods, for example in the presence of inert in the reaction of an organic solvent, such as dimethylformamide, dimethyl sulfoxide, tert-butanol or benzene, and by adding the corresponding primary reagent, for example, carbonate of an alkali metal, in particular sodium carbonate, or sodium hydride, or of potassium tert-butylate, at temperatures in the range from approximately 0oC to the boiling point with reverse drains phlegmy.

The reaction of the compound of formula (II) or its salt, which is defined above, with a lactone of the formula (IV) can be carried out by known methods. For example, this reaction can be conducted by following the same reaction conditions described for the reaction of compounds of formula (II) or its salt with the compound of the formula (III).

The reaction of carbonyl compounds of the formula (V) with aminocaproate formula (VI) can be carried out, for example, by dissolving carbonyl, tetrahydrofuran, aromatic hydrocarbons, in particular benzene, toluene or xylene, or mixtures of these solvents, and by adding the corresponding primary reagent, such as hydroxide of alkali metal, in particular sodium hydroxide or potassium, carbonate or bicarbonate of an alkali metal, in particular, carbonate or bicarbonate of sodium and potassium, or organic basic chemicals, such as tertiary amine or pyridine.

When one or both of Q and Q' in the compound of formula (VII) are lower alkyl, they are, for example, C1-C4-alkyl, in particular methyl or ethyl.

In addition, the reaction of the compound of formula (I) with the compound of the formula (VII) can be carried out by known methods. For example, this reaction can be carried out in an inert reaction solvent, for example acetonitrile or acetic acid, and, if desired, in the presence of an inorganic acid, for example sulphuric or hydrochloric acid, at temperatures ranging from room temperature to the boiling temperature with the inverse drains phlegmy.

Salt of the compounds of formula (VII) is, for example, salt of an alkali metal, in particular lithium salt or sodium.

Leaving gruppetto active ester groups, in particular, mesyl or tosyl.

The reaction of the compound of formula (VIII) or its salt with the compound of the formula (IX) can be carried out by following the same reaction conditions as described above for the reaction of compounds of formula (II) or its salt with the compound of the formula (III).

The transformation of compounds of formula (I) into another compound of formula (I) may be conducted according to commonly known methods. For example, the compound of formula (I) containing esterified carboxyl group may be converted into the corresponding free carboxylic acid by known methods. In particular, the compound of formula (I) in which R4is a group OR5where R5has some higher values and is not hydrogen, can be converted by acid or alkaline hydrolysis into the corresponding free carboxylic acid. The reaction preferably is conducted at temperatures in the range from about -5oC to about 50oC.

The compound of formula (I) containing a free carboxyl group, such as the compound of formula (I) in which R4is a hydroxyl group, can be converted into the corresponding esterified carboxy derivative, for example, is achene and is not hydrogen. This esterification reaction can be carried out by known methods, preferably through an intermediate reactive carboxylic acid derivative, which can be selected or no reaction with the appropriate alcohol of formula R5OH, in which R5has some higher values and is not hydrogen. The reaction can be carried out in a conventional solvent such as benzene or toluene, or in the presence of an excess of the alcohol of formula R5OH.

The reaction temperature can vary from approximately 10oC to about 50oC. Intermediate reactive derivative of carboxylic acid can be, for example, galodamadruga acids, for example the acid chloride, mixed anhydrides of the acids, for example etoxycarbonyl - or tert-Butylochka-anhydrides or corresponding reactive intermediate obtained in situ, for example, by reaction with diimide, for example, dicyclohexylcarbodiimide, or carbonyl-diimidazole.

The compound of formula (I) in which R4is a hydroxyl group, i.e., containing a free carboxyl group, can be converted into the corresponding compound of formula (I) in which R4is a group-NR5

Intermediate reactive derivatives can be active esters, such as NO2-phenyl esters, or esters of N-hydroxysuccinimide, galodamadruga acid, preferably the acid chlorides, mixed anhydrides of the acids, for example etoxycarbonyl - or tert-butylcarbamoyl-anhydrides or reactive intermediates obtained in situ by reaction of the acid with dicyclohexylcarbodiimide or carbonyl diimidazol.

For example, the above-defined reactive intermediate, which can be obtained following the standard methods commonly used in the synthesis of peptides is subjected to reaction with ammonia or with an appropriate amine in a conventional solvent or with an excess of the amine at temperatures in the range of about -10oC to about 50oC.

Optional the salt formation of compounds of formula (I), as well as conversion of a salt into a free compound and the separation of the mixture of isomers can be carried out by conventional methods.

For example, separation of a mixture of geometrical isomers, for example, Z - and E-isomers, can be carried out by fractionated crystallization from appropriate is adopted high-pressure.

Optional isomerization oximes double bond in the compound of formula (I), which is an equilibrium reaction can be carried out by known methods, preferably in the presence of an inorganic acid and/or by heating.

The oxime of formula (II), which is due to the presence oximes double bond may be either in the form of a Z - or E-isomer, or mixtures thereof, can be obtained by known methods. For example, a') reaction defined above of compounds of formula (V) with hypoxaemia or its salt accession acid, for example hydrochloric acid hydroxylamine or b') by reaction of the oxime of formula (X)

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in which Y, m, R1, R2, R3and Z are as defined above values, imidazole, C1-C4-alkylimidazole or its salt, for example when following the methodology in the journal Arzneim Forsch. /Drug. Res. 29(II), 1510-13, (1979).

In addition, the oxime of formula (II), if desired, may be subjected to the same isomerization by oximes double bond, as described above for compounds of formula (I), by known methods. Similarly a mixture of Z - and E-isomers of the oxime of formula (II) can be separated into individual isomers by the following conventional methods.

The compounds of formula compounds. In addition, the compounds of formula (VI) are either known compounds or can be obtained from known compounds by the following known methods, for example as described in Tetrahedron (1967), 23, 4441, or in General is described in the book "Getting organic functional groups", Chapter X (Organic Functional Group Preparation, R. S. Sandler and W. Karo, VIII, Chapter X. Academic Press. (1972)).

The compounds of formula (VII) can be obtained by reaction of the known compounds of formula (XI)

,

in which Q and Q' are as defined above, with a compound of formula (VI) defined above, following the same methods reaction, as described above for method b).

Optionally, the compound of formula (VII) can be obtained from compounds of formulas (XI) through the corresponding oxime of formula (XII)

,

in which Q and Q' are as defined above values, the reaction of either a compound of formula (III) or with the compound of the formula (IV), following the same reaction conditions as described above for the methods a) and b).

The compounds of formula (VIII) can be obtained from known compounds by following the procedures similar to that described for methods a), b), C) and d) above.

The compounds of formula (IX) are known compounds is of ineni formula (XIII)

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in which R1, R2, R3, Y and m have the above specified values.

The compounds of formula (XI) and (XIII) are known compounds or can be obtained by the following known methods.

When in the intermediate compounds (intermediates) of the present invention group, which can interfere with the reactions given in the description, these groups may be protected prior to the reaction, and then released (protective groups are removed) at the end of the reaction by known methods, such as techniques used in the chemistry of peptides.

Pharmacology

The thromboxane (TXA2) is a derivative of arachidonic acid metabolism, which causes platelet aggregation and enhances their response (platelets) in a number of other substances that cause aggregation.

In addition, TXA2reduces vascular cells, bronchial and tracheal smooth muscle and glomerular (glomerular) mesangial cells. So TXA2includes a number of pathologies, such as cardiovascular disease (myocardial infarction and angina), cerebrovascular disease (angina ("hit"), the transient disorders of cerebral circulation and the migration is e disease (glomerulosclerosis, lupus nephritis (lupus nephritis), diabetic nephropathy) and respiratory diseases (bronchostenosis) (narrowing of the lumen of the bronchus and asthma) and in more General terms, includes atherosclerose.

TXA2exerts its effect on trombotsitnoy cells and smooth muscle cells by blocking (capture) receptor(s), TXA2. The effects of TXA2can be neutralized by means of having antagonistic properties of receptors TXA2and/or means, inhibiting enzymes involved in the synthesis of TXA2in particular (enzyme) TXA2synthase, which catalyses the formation of THA2from cyclic endoperoxide prostaglandin G2and prostaglandin H2without affecting the synthesis of other prostaglandins.

Tools that inhibit the effect of TXA2either by antagonization (rivalry) TXA2and/or by inhibition of TXA2-synthase, as you might expect, may have therapeutic value in the treatment of the aforementioned diseases and other pathological conditions, which involved TXA2.

Compounds of the invention that possess these activities are considered to be effective in the treatment of painful with who you are.

Ways

Effects characteristic group of compounds of the invention are estimated by comparison with known compounds on in vitro-inhibition of synthesis TXB2in whole blood normal rats and antagonisms TXA2in the analysis of binding in washed human platelets.

Inhibition of the synthesis TXB2< / BR>
Blood is withdrawn from the abdominal aorta normal rats species Sprague Dawley (Charles River, Italy) under anesthesia with a volatile ester. Blood immediately share in parts of 0.5 ml and distributed in glass vials, each of which contains a concentration of the test compounds or test compounds.

Then the samples allow clotting for 1 h at 37oC, centrifuged with a speed of 3000 rpm for 10 min, collect the serum and stored at -20oC until analyzed. Levels TXB2determined by radioimmunoassay (RIA) according to previously described methods (Thromb. Res. 17, 3/4, 317, 1980), using a highly sensitive antibody.

Bias binding (3H)-SO 29,548 to washed platelets man

Blood from healthy volunteers of both sexes who had not taken any drugs for at least 10 days. collect one-tenth), obtained by centrifugation of blood at 200 x g for 20 min, washed twice (1000 g for 10 min). Then the platelets are subjected to repeated suspendirovanie buffer Tyrod-Hepia (Tyrode-Hepes buffer (pH of 7.4) to a final concentration of 5 1010-8cells/ml and incubated for 0 to 60 min at 25otogether with (3H)-SQ 29.548 (5 nm). For experiments with mixing add different concentrations (10-910-4M) competing ligands and incubated for 30 min at 25oC. Nonspecific binding determined in the presence of 50 Ám U 46619 approximately 5% of the total binding (3H)-SQ 29.548. After incubation in each tube add 4 ml ice TRIS-HCl buffer (10 mm, pH 7,4) and the reaction mixture was immediately filtered by suction through a circle of glass filter Paper (Whatman G/C), washed twice with ice TRIS-HCl buffer (4 ml) and count the radioactivity by using the-counter Packard.

Data binding analyzed by computerized nonlinear selection formulas using the program Ligand, and is expressed as the value IC50(concentration to inhibit activity by 50%).

In table. 2 in the form of premuim designation FCE 27016, when tested for binding (washed human platelets) are compared with the results obtained using reference compounds, BM 13505 and BM 13177 (Nounyn Schmideberg''s Arch. Pharmacol. 1986, 332 (Annex Sppl), Abst. 144S. P 36, Cardiovasc. Drug. Rev. 1988, 6 20-34). These results show that the compound FCE 27016 has an affinity to the receptor more than connections BM 13505 and BM 13177, and is patentable antagonist TxA2.

In the following table BM 13505 is 4-[2-(4-chlorobenzenesulfonamide)-ethyl]benzooxazol acid, and BM 13177 - 4[2-(benzosulfimide)-ethyl]Phenoxyethanol acid.

In table. 3 as an example of the results obtained using the characteristic connection with the internal code designation FCE 26365, synthesis DV2in normal rats, compared with the results obtained with the control standards: dazoxiben and ASA, limits, when they are evaluated, are reported in parentheses. The comparative data presented in the table. 2, show that FCE 26365 potent inhibitor THA2-synthase in platelets.

In the above table. 2 and 3 internal code FCE 26365 denotes the (+-)-(Z)-5-[2-methyl-3-(1H - imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl]-aminolevulinate; and ASA indicates acetylsalicylic acid.

In table. 4, in an additional example, the results obtained using the characteristic compounds of the invention, (+-)-(Z)-5- [[2-(3,4-acid)-3-(1H-imidazol-1-yl)-2,3-dihydro-6 - methoxy-4H-1-benzopyranyl] -aminooxy] -pentanol acid (internal code FCE 26603), inhibition of synthesis DV2in whole blood of rats and the mixture bind3HSQ 29548 in washed human platelets compared with the results obtained with the control standard connections dazoxiben, BM 13177 and BM 13505.

Because compounds of the invention are inhibitors THA2-synthase and antagonists PGH2/THA2in platelets, on the basis of modern science, which reported, for example in J. Clin. Invest. 80,1435 (1987) and Adv. Prostaglndins, Thromboxanes, Leukotrienes Res. Vol. 17 (1987), page 49, these compounds are particularly suitable for the treatment of painful conditions in which the acceleration of the synthesis THA2develops pathogenic effect, for example, in patients and animals mentioned above.

In particular, in the treatment of renal diseases, the compounds of the invention can be used in combination with the inhibitor angiotensinase. Compounds of the invention can also be used for prevention or treatment of nephrosis in mammals induced by cyclosporine A.

Compounds of the invention can also be used in combination with thrombolytics (e.g., tPA, streptokinase, PUK) in order to lower the dose of thrombolytics required to thrombolytic therapy, and to reduce the incidence of reocclusion and bleeding.

The use of additional compounds of the invention is the prevention and/or treatment of restenosis after conducted through the skin transluminal plastic surgery on the blood vessels.

The toxicity of the compounds of the invention is small, so they can be reliably used in therapy. Mice and rats that were deprived of feed for 9 h, treated with single oral glands increasing doses of the compounds of the invention, after which they are placed and properly fed. Due to their high activity of the compounds of the invention can be reliably used in therapy. Therapeutic mode for different clinical syndromes should be adapted to the type of pathology, whereas, as usual, and the method of application, and the form of the aircraft. Oral method is used in General in all States that require the use of such compounds. Preference is given an intravenous injection or infusion (injection) in the treatment of acute pathological conditions. To maintain preferred is oral or parenteral, such as intramuscular, fashion..

The dose level, suitable for oral administration adults, the compounds of the invention, for example, Z-6-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-benzoperylene] -aminooxy] -hexanoic acid can vary from about 50 mg to about 500 mg per dose 1 to 3 times per day.

Of course, these dosing regimens can be adjusted for optimal therapeutic effect.

The nature of the pharmaceutical compositions containing compounds of the invention in combination with pharmaceutically acceptable carriers or diluents, of course, depends on the desired method of application.

The composition can be prepared by a common way of conventional ingredients. For example, the compounds of the invention can be approximately in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatin capsules, soderjashie compounds of the invention, are preferably tablets, pills or capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, for example silica, talc, stearic acid, magnesium stearate or calcium, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatin, methylcellulose, carboxy/methylcellulose, summerby, tragakant, polyvinylpyrrolidone; means causing raspadaemost aggregation, such as starches, alginic acid, alginates, sodium starch glycolate; effervescent mixtures; dyestuffs; sweeteners; wetting agents such as lecithin, Polysorbate, laurilsulfate and generally non-toxic and pharmacologically inactive substances used in pharmaceutical dosage forms. These pharmaceutical preparations can be manufactured by a known method, for example by mixing, granulating: tabletting, sugar coating or coating film. Liquid dispersions for oral administration can be, for example, syrups, emulsions and suspensions.

The syrups may contain as carrier,'t contain as carrier, for example, a natural gum (resin), agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain the active compound together with a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl ester of oleic acid, glycols, such as propylene glycol, and, if desirable, the appropriate amount of hydrochloric acid lidocaine.

The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of a sterile aqueous isotonic saline solutions.

Suppositories can contain the active compound together with a pharmaceutically acceptable carrier such as cocoa butter, polyethylene glycol, surface-active substance on the basis of ester of fatty organic acids and polyoxyethylenesorbitan or lecithin.

Example 1. Ethyl ester of (+-)-(Z)-5-[[2-methyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl] -aminooxy]-pentanol acid (compound 3).

The oxime (+-)-(Z)-2-methyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-besplat in portions under stirring at room temperature, sodium hydride (80%, 0,250 g 0,015 mol). The resulting slurry is stirred for another 3 h at room temperature and added dropwise ethyl ester 5-bromopentanoate acid (1,33 ml of 8.4 mol). The reaction mixture is stirred for further 3 h at room temperature, the solvent is evaporated and the residue is cautiously treated with water, ice (20 ml). The resulting mixture was extracted with ethyl acetate (3 x 30 ml) and the collected organic phases are washed with brine, dried over Na2SO4and evaporated in vacuum. The resulting oily substance chromatographic over silica gel, using as eluent a mixture of ethyl acetate (hexane) of triethylamine (30:20:7). Clean the above-named compound obtained as a light yellow oil (1,15 g).

Microanalysis:

Found: C 64,40, H 57,53, N 8,27

Calculated for C20H25N3O4: C 64,91, H 7,46, N TO 8.41.

1H-NMR (200 MHz) (CDCL3) memorial plaques

of 2.23 (6H, multiplet, -OCHCH3+ -COOCH2CH3)

1,5-1,8 (4h, multiplet, -OCH2CH-2CH2)

of 2.27 (2H, multiplet, CH2COO)

4,0-4,2 (4H, multiplet, -COOCH2- + -OCH-2CH2-)

4,34 (1H, two quartets, H2)

5,49 (1H, doublet, H3)

6,8-7,5 (6H, multiplet, H6+ H7
(+-)-2-Methyl-3-(1H-imidazol-1-yl)-2,3 dihydro-4H-1-benzopyran-4-one (J. Het. Chem. 21,311(1984)) (of 3.78 g, to 0.016 mole) is dissolved in 95% ethanol (160 ml), the resulting solution was added anhydrous Na2CO3(3,99 g to 0.032 mole) and hydrochloric acid hydroxylamine (2,22 g to 0.032 mol) and the reaction mixture is refluxed for 24 hours

The solvent is evaporated and the resulting oily substance was dissolved in CHCl3(150 ml). The organic layer was washed with water (I ml), dried over CaCl2and evaporated in vacuo to obtain the crude substance that chromatographic over silica gel.

Elution with a mixture of CH2Cl2/MeOH/AcOH(90:10:0,4) gives the net reaction product as a white solid (3,24 g), melting at 226-228oC.

1H-NMR (200MHz, Me2SO-d6) memorial plaques

a 1.08 (3H, doublet, -O-CH-CH3)

4,43 (1H, two quartets, H2)

5,80 (1H, doublet, H3)

6,75-of 7.60 (6H, multiplet, H6+ H5+ H7+ imidazole cycle)

to 7.84 (1H, two doublet, H5)

Example 2. (+-)-(Z)-5-][[2-Methyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl] -aminooxy]-pentane acid (compound 2).

Microanalysis:

Found: C 62,61, 6,12 H, N 12,08

Calculated for C18H21H3O4: C 62,96, H 6,16, N 12,24

1H-NMR (200 MHz, CDCl3) memorial plaques

to 1.21 (3H, doublet, -O-CH-CH2)

1,5 1,8 (4H, multiplet, -CH2CH2CH2)

to 2.29 (2H, Multiplan, -CH2COOH)

4,18 (2H, multiplet, -OCH2CH2)

of 4.35 (1H, two quartets, H2)

to 5.57 (1H, doublet, H3)

6,70 7,80 (6H, multiplet, H6+ H7+ H5+ imidazole cycle)

to $ 7.91 (1H, two doublet, H5)

InterAmerican]-aminooxy]-pontenova acid (compound 1), so pl. 125 - 128oC.

Microanalysis:

Found: C 61,26, H of 5.83, N 12,42

Calculated for C17H19N3O4: C 61,99, H OF 5.81, N 12,76

1H-NMR (C17H19N3O4HCl, 200 MHz, CDCl3) memorial plaques

the 1.6-to 1.9 (4H, multiplet, -OCH2CH2CH2)

of 2.35 (2H, multiplet, -CH2COOH)

4,24 (2H, multiplet, -OCH2CH2-)

4,37 (1H, two doublet, H2a)

of 4.66 (1H, two doublet, H2b)

the 6.06 (1H, broadened singlet, -OCH2CH-C=N-)

of 7.0 to 7.4 (5H, multiplet, H6+ H7+ H5+ H4,5imidazole cycle)

a 7.92 (1H, two doublet, H5)

8,82 (1H, broadened singlet, H2imidazole cycle)

(+-)-(D-6-[[2-Methyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H/1-benzopyrylium] -aminooxy]-hexanoic acid (compound 4). So pl. 133 135oC

Microanalysis:

Found: C 63,51, H to 6.58, N 11,54

Calculated for C19H23N3O4: C 63,85, H OF 6.49, N 11,76

1H-NMR (200 MHz, Me2SO-d6) memorial plaques

a 1.08 (3H, doublet, -OCHCH3)

1,05 1,65 (6H, multiplet, -OCH2CH2CH2CH2-)

of 2.15 (2H, multiplet, -CH2COOH)

4,10 (2H, multiplet, -OCH2CH2-)

4,47 (1H, two quartets, H2)

of 5.75 (1H, doublet, H3)

6,75 (6H, imidazol-1-yl)-1,2,3,4-tetrahydro-1-naphthalide] -aminooxy]-pentane acid (compound 32), so pl. 81 - 83oC

Microanalysis:

found: C 64,04, H 6,87, N BR11.01

Calculated for C18H21N3O3: C 66,04, H 6,46, N 12,83

1H-NMR (200 MHz, CDCl3) memorial plaques

of 1.75 (4H, multiplet, -OCH2CH2CH2-)

of 2.2 (4H, multiplet, -CB2COOH + H3)

2,7 (2H, multiplet, H4)

to 4.15 (2H, multiplet, -OCH2CH2CH2)

5,80 (1H, triplet, H2)

6,8-to 7.35 (6H, multiplet, H5+ H6+ H7+ H4,5imidazole cycle)

and 7.7 (1H, broadened singlet, H2imidazole cycle)

8,01 (1H, two doublet, H5)

(+-)-(Z)-5-[[2)(1H-imidazol-1-yl)-7-methoxy-1,2,3,4-tetrahydro-1-naphthalide] -aminooxy]-pentane acid (compound 33) So pl. 97 99oC

Microanalysis:

Found: C, 63, 70, H 6, 59, No. 11, 54

Calculated for C19H23N3O4: C 63, 85, H, 6, 49, NO. 11, 76

1H-NMR (200 MHz, CDCl3) memorial plaques

1,4 1,8 (4H, multiplet, -OCH2CH2CH2)

2 (3H, multiplet, -CH2COOH + H3)

2,7 (2H, multiplet, H4)

of 3.84 (3H, singlet, -OCH3)

to 4.15 (2H, multiplet, -OCH2CH2CH2)

5,79 (1H, triplet, H2)

6,8 7,1 (4 H, multiplet, H5+ H6+ H4,5imidazole cycle)

rate of 7.54 (1H, duplicates the 2-('1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphthalen]-Amin - oxy] -pentanol acid (compound 34).

The oxime (+-)-(E)-2-(1H-imidazol-1-yl)-1,2,3,4-tetrahydronaphthalen-1-she (500 mg, 2.2 mmole), dissolved in dry DMF (27 mm), add in dry nitrogen atmosphere to a suspension washed with pentane sodium hydride (160 mg NaH 55%, 3.6 mmole) in dry DMF (10 ml). The resulting reaction mixture was stirred at room temperature for 2 hours Then at room temperature add ethyl ester 5-bromopentanoate acid (0,530 ml, 3.3 mmole) and the reaction mixture was stirred at room temperature for 3 h, the solvent is evaporated in vacuum and the residue is cautiously treated with ice water and extracted with ethyl acetate. The combined organic phases are dried over Na2SO4and evaporated to obtain an oily crude substance that chromatographic over silicagel. Lilloana a mixture of CH2Cl2/MeOH(95: 5) receive a net above entitled compound as a pale yellow oil (250 mg).

1H-NMR (200 MHz, CDCl3) memorial plaques

of 1.23 (3H, triplet, -COOCH3)

a 1.75- (4H, multiplet, -OCH2CH2CH2-)

2,3-3,0 (6H, multiplet,-CH2COO- +H3+H4)

4,0-of 4.25 (4H, multiplet, -COOCH2CH3- + -OC2CH2-)

5,07 (1H, two doublet, H2
8,53 (1H, multiplet, H5).

Example 4. (+-)-(E)-5-[[2,3-Dihydro-3-(1H-imidazol-1-yl)-4H-1-benzopyranyl] -aminooxy]-pentane acid (compound 1).

The oxime (E)-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyran-4-it (1.5 g, 6.5 mmole) is subjected to reaction with ethyl ester of 5-bromopentanoate acid (2 ml, 13.9 mmole), by using the same method as that described in example 1 to obtain the ethyl ester of (+-)-(E)-5-[[2,3-dihydro-3-(1H-imidazol-1-yl)-4H-1-benzopyranyl] -aminoxy/-pentanol acid (1.18 g) as a colourless oil.

This is followed by hydrolysis of the above-described complex ester, following the same technique as described in example 11, leading to compound 1 as a colorless solid, melting at 125-127oC.

Microanalysis:

Found: C 61,26, H 65,88; N 12,08

Calculated for C17H19N3O4: C 61,99, H OF 5.81, N 12,76

1H-NMR (200 MHz, CDCl3) memorial plaques

1,6-2,0 (4H, multiplet, -OCH2CH2CH2-)

2,4 (2H, multiplet, -CH2COOH)

of 4.25 (2H, multiplet, -OCH2CH2-)

to 4.52 (IH, two doublet, H2a)

4,84 (IH, two doublet, H2b)

5,07 (IH, triplet, -OCH2CH-C=N-)

of 6.8 to 7.4 (5H, multiplet, H6+ H7+ H5+ HTA, H5)

As an example, the oxime intermediate is used as starting substances can be obtained in the following way:

3-Bromo-2,3-dihydro-4H-1-benzopyran-4-one (37.6 g, to 0.17 mole) is suspended in methanol at room temperature and stirring, hydrochloric acid hydroxylamine (35.5 g, of 0.51 mol) and the reaction mixture is refluxed for 6 hours From the resulting solution a white precipitate is formed by storage at room temperature over night. Thus obtained solid is filtered and washed with ethyl ether to obtain 30.1 g of the oxime of 3-bromo-2,3-dihydro-4H-1-benzopyran-4-it. This compound (29.5 g, 0,122 mole) is dissolved in CHCl3(150 ml) and the solution added dropwise to a cooled with ice to a solution of imidazole (25 g, and 0.37 mol) in CHCl3(200 ml) at energy stirring. The resulting solution was stirred at 0oC for one hour, then add water and soon when mixing the formed white solid. It then collected, washed with ethyl ether and dried to obtain the target oxime (15 g) as a white solid, melting at 248 249oC.

Microanalysis:

Found: C 59,44, H 4,76, N 18,31

Vychisl">

4,50 (1H, two doublet, H2a)

is 4.85 (1H, two doublet, H2b)

of 5.24 (1H, triplet, H3)

6,85 of 7.6 (6H, multiplet, H6+ H7+ H5+ imidazole cycle)

8,67 (1H, two doublet, H5)

12,10 (1H, singlet,N-OH)

This same technique can be obtained from the following link:

(+-)-(E)-5-[2-(1H-imidazol-1-yl)-1,2,3,4-tetrahydro-1-naphthalide]-aminooxy]-pentane acid (compound 32).

Microanalysis:

Found: C 64,04, H 6,86, N BR11.01

Calculated for C18H21N3O3: C 66,04, H 6,46, N 12,83

1H-NMR (200 MHz, CDCl3) memorial plaques

of 1.75 (4H, multiplet, -OCH2CH2CH2-)

2,15 was 3.05 (4H, multiplet, -CH2COON + H3+ H4)

to 4.15 (2H, multiplet, -CCH2CH2-)

5,07 (1H, two doublet, H2)

6,8 7,7 (6H, multiplet, H5+ H6+ H7+ imidazole cycle)

8,55 (1H, multiplet, H5)

Example 5. Ethyl ester of (+-)-(Z)-6-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-benzoperylene] -aminooxy]-hexanoic acid (compound 6)

Suspension is washed with pentane sodium hydride 55% (166 mg, 3.8 mmole) in dry DMF (10 ml) is added dropwise and stirred in a dry nitrogen atmosphere at -78oC oxime (+-)-(Z)-2-phenyl-3-(1H-imidazolyl-1)-2,3-dig the new acid (1,16 ml, 6.5 mmole) and the resulting solution was left to reach room temperature. The reaction mixture was poured into ice-cold water (3 g), neutralized with acetic acid and extracted with ethyl acetate (3 x 20 ml). The combined organic phases are washed with water (3 x 10 ml), dried over Na2SO4and evaporated in vacuum. The resulting oily residue chromatographic through silicagel column. By elution with a mixture of CH2Cl2/EtOH (98:2) to obtain the pure ester as a pale yellow oil, which crystallizes the processing of hexane to obtain 0,864 g of white solid, melting at 65 66oC.

Microanalysis:

Found: C at 69,39, H 6,56, N 9,13

Calculated for C26H29N3O4: C 69,78, H 6,53, N 9,39

1H-NMR (200 MHz, CDCl3) memorial plaques

to 1.22 (3H, triplet, -COOH2CH3)

1,1 1,7 (6P, multiplet, OCH2CH2CH2CH2-)

of 2.23 (2H, triplet, -CH2COO-)

4,0 4,2 (4H, multiplet, -OCH2CH2CH2CH2-)

5,28 (1H, doublet, H2)

of 5.68 (1H, doublet, H3)

of 6.6 to 7.4 (11H, multiplet, H5+ H7+ H6+ imidazole cycle + phenyl ring)

8,0 (1H, multiplet, H5)

As example, the reaction of intermeidate-1-yl)-2,3-dihydro-4H-benzopyran-4-one [J. Het. Chem. 21, 311 (1984)] (4 g of 0.014 mole) is dissolved in pyridine and to the solution at room temperature add hydrochloric acid hydroxylamine (2.4 g, 0,034 mol) dissolved in ethanol (20 ml).

The resulting solution is stirred overnight and the solvent is evaporated to obtain a pale yellow residue, which is crystallized by treatment with water. The resulting solid is recrystallized from ethanol to obtain 3,116 grams of pure oxime, melting at 224 225oC.

1H-NMR (80 MHz, Me2SO-d6) memorial plaques

to 5.58 (1H, doublet, H2)

5,98 (1H, doublet, H3)

of 6.6 to 7.6 (11H, multiplet, H6+ H7+ H5+ imidazole cycle + phenyl ring)

of 7.9 (1H, multiplet, H5)

By the same method can be obtained the following compounds:

Ethyl ester of (+-)-(Z)-5-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl] -aminooxy]-pentanol acid (compound 8), T. p. 86 88oC.

1H-NMR (80 MHz, CDCl3), M. D.

to 1.22 (3H, triplet, -COOCH2CH3)

of 1.45 to 1.7 (4H, multiplet, -OCHCH2CH2-)

of 2.25 (2H, multiplet, -CH2COO-)

4,0-4,2 (4H, multiplet, -OCH2CH2-, + -COOCH2CH3)

5,3 (1H, doublet, H2)

TSO)

8,0 (1H, multiplet, H5)

Methyl ester of (+-)-(Z)-6-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-6-methoxy-4H-1-benzopyranyl] -aminooxy]-hexanoic acid (compound 12)

1H-NMR (80 MHz, CDCl3): (Conn. 12) M. D.

of 1.1 to 1.9 (6H, multiplet, -OCH2(CH2)3-)

of 2.28 (2H, broadened signal, -CH2COO-)

3,68 (3H, singlet, -COOCH3)

of 3.85 (3H, singlet, -OCH3)

4,18 (2H, triplet, -OCH2-)

5,23 (1H, doublet, H2)

5,70 (1H, doublet, H3)

6,60 (1H, broadened singlet, imidazole H)

6,85 (1H, broadened singlet, imidazole H)

7,0-7,50 (9H, multiplet, H5H7H6, imidazole H, phenyl ring).

Similarly get:

3-[[2-(4-forfinal)-3-(1H-imidazol-1-yl)-2,3-dihydro-6-fluoro-4H-1-benzopyranyl]-aminooxy]-propylacetamide (compound 19).

Example 6. (+-)= (Z)-6-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-benzoperylene]-aminoxy] hexanoic acid (compound 5).

Ethyl ester of (+-)-(Z)-6-[[2-phenyl-3-(1H-imidazol-1-yl) -2,3-dihydro-4H-benzoperylene] -aminooxy] -hexanoic acid (300 mg, 0.67 mmole) dissolved in water-methanol mixture (2:5,7 ml) and to this solution was added in portions at 0oC methylate sodium (90 mg, 1.61 of malaut at 0oC and neutralized with acetic acid. So produced precipitate is collected and recrystallized from ethyl acetate to obtain a white solid (190 mg), melting at 176-178oC.

Microanalysis:

Found: C 68,54, H 6,06, N TO 9.91

Calculated for C24H25N3O4: C 68,72, H 6,01, N 10,02

1H-NMR (200 MHz, CDCl3) memorial plaques

the 0.9 to 1.7 (6H, multiplet, -OCH2CH2CH2CH2-)

of 2.15 (2H, multiplet, -CH2COOH)

to 4.15 (2H, multiplet, -OCH2CH2CH2-)

to 2.57 (1H, doublet, H2)

5,69 (1H, doublet, H3)

6,6 was 7.45 (11H, multiplet, H6+ H7+H5+ imidazole cycle + phenyl ring)

8,0 (1H, multiplet, H5)

This same method can be obtained the following compounds:

(+-)-(Z)-5-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl]-aminooxy]-pentane acid (compound 7). So pl. 163-164oC

Microanalysis:

Found: C 68,22, H 5,71, N 10,16

Calculated for C23H23N3O4: C 68,13, H 5,74, N 10,36

1H-NMR (200 MHz, CDCl3) memorial plaques

of 1.4 to 1.7 (4H, multiplet, -OCH2CH2CH2-)

of 2.2 (2H, multiplet, -CH2COOH)

to 4.15 (2H, multiplet, -OCH2CH2-)

5,28 (1H, Dubcek + phenyl ring)

8,0 (1H, multiplet, H5)

4-[[2-(3,4-Acid)-3-(1H-imidazol-1-yl)-2,3-dihydro-6-methoxy-4H-1-enteralite] -aminooxy] -butane acid (compound 9). So PL 220-221oC

Microanalysis:

Found: C 62,44, H of 5.84, N compared to 8.26

Calculated for C25H27N3O7: C62,36, H 5,65, N 8,73

1H-NMR (200 MHz, Me2SO-d6) memorial plaques

of 1.75 (2H, multiplet, -OCH2CH2-)

to 2.13 (2H, multiplet, -CH2COOH)

3,55 (3H, singlet, -OCH3)

of 3.69 (3H, singlet, -OCH3)

3,76 (3H, singlet, -OCH3)

of 4.12 (2H, multiplet, -OCH, CH2-)

of 5.40 (1H, doublet, H2)

5,80 (1H, doublet, H3)

of 7.5 to 7.2 (8H, multiplet, H7+H6+ imidazole cycle + phenyl ring)

7,33 (1H, doublet, H5)

(+-)-(Z)-5-[[2-Phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-6-methoxy-4H-1-benzopyranyl] -aminooxy] -pentane acid (compound 10). T. pl. 152-155oC

Microanalysis:

Found: C, 65.22 per, H 5,71, N 9,49

Calculated for C24H25N3O5: C 66,19, H 5,78, N 9,65

1H-NMR (200 MHz, CDCl3) memorial plaques

of 1.4 to 1.7 (4H, multiplet, -OCH2CH2CH2-)

of 2.15 (2H, multiplet, -CH2COOH)

a 3.83 (3H, singlet, -OCH3)

to 4.17 (2H, multiplet, -OCH2CH2-)

5,23 ( + phenolic ring)

7,42 (1H, doublet, H5)

(+-)-(Z)-6-[[2-Phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-6-methoxy-4H-I-benzoperylene] -aminooxy] -hexanoic acid (compound II). T. pl. 159-161oC

Microanalysis:

Found: C 66,54, of 6.02 H, N 9,31

Calculated for C25H27N3O5: C 66,80, H 6,06, N 9,35

1H-NMR (200 MHz, CDCl3) memorial plaques

0,9 1,7 (6N, multiplet, -OCH2CH2CH2CH2-)

of 2.15 (2H, multiplet, -CH2COOH)

a 3.83 (3H, singlet, -OCH3)

to 4.15 (2H, multiplet, -OCH2CH2-)

with 5.22 (1H, doublet, H2)

the 5.65 (1H, doublet, H3)

of 6.6 to 7.3 (10H, multiplet, H7+ H6+ imidazole cycle + phenyl ring)

7,42 (1H, doublet, H5)

(+-)-(Z)-65-[[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-6-n-butoxy-4H-1-benzopyranyl] -aminooxy] -hexanoic acid (compound 13). So pl. 130 134oC

Microanalysis:

Found: C 67,66, H 6,76, N AT 8.36

Calculated for C28H33N3O5: C 69,41, H 6,77, N 8,55

1H-NMR (200 MHz, CDCl3) memorial plaques

to 0.97 (3H, triplet, -OCH2CH2CH2CH3)

0,95 of 1.85 (10H, multiplet, -OCH2CH2CH2CH3+ -OCH2CH2CH2CH2-)

of 2.15 (2H, multiplet, -CH2COOH)

of 3.97 (2H, triplet, -OBR>
5,64 (1H, doublet, H3)

of 6.6 to 7.3 (10H, multiplet, H7+ H6+ imidazole cycle + phenyl ring)

7,41 (1H, doublet, H5)

(+-)-(Z)-5-[[3,4-acid)-3-(1H-imidazol-1-yl) -2,3-dihydro-6-methoxy-4H-1-benzopyranyl]-aminooxy]-pentane acid (compound 14). So pl. 201 205oC

Microanalysis:

Found: C 61,56, H 5,91, N 8,25

Calculated for C26H29N3O7: C 63,02, H OF 5.89, N 8,48

1H-NMR (200 MHz, Me2SO-d6) memorial plaques

1,35 1,65 (4H, multiplet, -OCH2CH2CH2-)

of 2.15 (2H, multiplet, -CH2COOH)

3,55 (3H, singlet, -OCH3)

3,70 (3H, singlet, -OCH3)

3,76 (3H, singlet, -OCH3)

4,10 (2H, multiplet, -OCH2CH2-)

5,41 (1H, doublet, H2)

5,78 (1H, doublet, H3)

of 6.5 to 7.2 (8H, multiplet, H7+ H6+ imidazole cycle + phenyl ring)

7,33 (1H, doublet, H5)

(+-)-(Z)-6-[[2-(3,4-Acid)-3-(1H-imidazol-1-yl)-2,3-dihydro-6-methoxy-4H-1-benzopyranyl] -aminooxy] -hexanoic acid (compound 15). So pl. 203 206oC

Microanalysis:

Found: C 62,7, H 6,28, N 8,02

Calculated for C27H31N2O7: C 63,64, H 6,13, N 8,25

1H-NMR (200 MHz, Me2SO-d6) memorial plaques

1,0 1,6-OCH3)

of 3.69 (3H, singlet, -OCH3)

3,76 (3H, singlet, -OCH3)

4,08 (2H, multiplet, -OCH2CH2-)

5,41 (1H, doublet, H2)

5,78 (1H, doublet, H3)

6,5 to 7.15 (8H, multiplet, H7+ H5+ imidazole cycle + phenyl ring)

7,33 (1H, doublet, H5)

(+-)-(Z)-6-[[2-Phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-6-fluoro-4H-1-benzopyranyl] -aminooxy] -hexanoic acid (compound 17). So pl. 179 181oC

Microanalysis:

Found: C 65,47, H 5.56mm, N 9,59

Calculated for C24H25N3FO4: C 65,89, H OF 5.53, N 9,60

1H-NMR (200 MHz, CDCl3) memorial plaques

0,9 1,7 (6N, multiplet, -OCH2CH2CH2CH2-)

of 2.15 (2H, multiplet, -CH2COOH)

to 4.15 (2H, multiplet, -OCH2CH2-)

of 5.24 (1H, doublet, H2)

the 5.65 (1H, doublet, H3)

6,6 to 7.35 (10H, multiplet, H7+ H5+ imidazole cycle + phenyl ring)

the 7.65 (1H, multiplet, H5) (+-)-(Z)-6-[[2-Benzyl-3-(IH - imidazol-I-yl)-2,3-dihydro-4H-I-benzoperylene/-aminoxy/-hexanoic acid (compound 29). So pl. 74-76oC.

Microanalysis:

Found: C 68,76, H 6,28, N 9,50

Calculated for C25H27N3O4C 69,26, H 6,28, N RS 9.69

1H-NMR 8200 MHz, CDCl3) memorial plaques

1,4-1,8 (4H, multiplet, -CH2-(CH2)2-CH2-)

of 2.25 (2H, multiplet, -CH2COO)

to 4.15 (2H, triplet, -OCH2)

of 5.55 (1H, doublet, H2)

5,78 (1H, doublet, H3)

's 6.75 to 7.50 (9H, multiplet, aromatic H)

of 7.96 (1H, doublet, H5)

(+-)-(Z)-5-[[2-(Tien-3-yl)-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl/-aminoxy/-pentane acid (compound 26). So pl. 150-151oC

Microanalysis:

Found C 61,61, H of 5.34, N 9,96

Calculated for C21H21N3O4S: C 61,30, H 5,15, N OF 10.21

1H-NMR (80 MHz, CDCl3) memorial plaques

1,4-1,8 (4H, multiplet, -CH2(SH2)2-CH2-)

of 2.1-2.4 (2H, triplet, -CH2
8,01 (1H, two doublet, H5)

(+2)-(Z)-6-[[2-(Tien-3-yl)-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl]-aminoxy]hexanoic acid (compound 27). So pl. 149-150oC

Microanalysis:

Found C 62,09, H of 5.45, N 9,88

Calculated for C22H23N3O4S: C 62,45, H OF 5.53, N 9,81

1H-NMR (80 MHz, CDCl3) memorial plaques

1,0-1,8 (6H, multiplet, (CH2)3)

of 2.21 (2H, triplet, -CH2COO)

4,18 (2H, triplet, -CH2O)

of 5.40 (1H, doublet, H2)

5,72 (1H, doublet, H3)

6,74 is 7.50 (9H, multiplet, Aromatic H)

8,02 (1H, two doublet, H5)

And in a similar way:

6-[[2-(Tien-2-yl)-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl]-aminooxy]-hexanoic acid (compound 25)

3-[[2-(4-Forfinal)-3-(1H-imidazol-1-yl)2,3-dihydro-6-trifluoromethyl-4H-1-benzopyranyl]-aminooxy]-prophylactically acid (compound 28)

2-[[2-((4-Forfinal)-methyl)-3-(1H-imidazol-1-yl) -2,3-dihydro-6-fluoro-4H-1-benzopyranyl]-aminooxy]-atrociously acid (compound 30)

6-[[2-Phenyl-3-((1H-imidazol-1-yl)-methyl)-2,3-dihydro-4H-1-benzopyranyl]-aminooxy]-hexanoic acid (compound 31)

5-[[2-Phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl] -aminooxy]-2-pentane
5-[[2-Phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl] -aminooxy]-3,3-dimethylpentane acid.

Example 7. (+-)-(Z)-5-[[2-Phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl]-aminooxy]-pentane acid (compound 7).

(+-)-2-Phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-benzopyran-4-one (580 mg, 2 mmole) was dissolved in dry pyridine (30 ml), to this solution was added in portions at 0oC hydrochloride 5-aminoacetanilide acid (510 mg, 3 mmole).

Then the temperature of the resulting solution is brought to room temperature and the mixture is stirred over night.

Then the solvent is evaporated in vacuum and the oily residue is mixed with water, add glacial acetic acid to pH 5 and the aqueous phase extracted with ethyl acetate (3 x 40 ml), the resulting organic layer is washed with water, dried over Na2SO4and evaporated in vacuo.

Chromatography through silicagel column by elution with a mixture of CH2Cl2/MeOH (95:5) of pure titled above compound (700 mg, 86%) as a colourless solid, melting at 166 167oC (ethyl ether/hexane).

Microanalysis:

Found: C 68,18, H 5,65, N 10,28

Calculated for C23H23N3O

Sodium salt of N-hydroxyphthalimide (6.6 g, 36 mmol) dissolved in dry DMF (120 ml) to the resulting dark red solution was added at room temperature and stirring ethyl ester 5-bromopentanoate acid (7.3 ml, 43 mmole).

The reaction mixture was stirred at 50oC for 6 hours in a dry nitrogen atmosphere and then poured onto 500 g of crushed ice. The resulting aqueous phase is extracted with ethyl acetate (4 x 100 ml), the combined organic layers washed with water, dried over Na2SO4and evaporated in vacuum to obtain an oily substance, which was crystallized by treatment with hexane to obtain ethyl ester of N-5-phtalimidospiroaziridines acid (9.2 grams, 86% ), so pl. 57 58oC.

1H-NMR (80 MHz, CDCl3) memorial plaques

of 1.25 (3H, triplet, CH3)

of 1.88 (2H, multiplet, CH2CH2)

of 2.45 (2H, multiplet, CH2COO)

4,10 (2H, triplet, CH2CH3)

4,32 (2H, multiplet, N-O-CH2)

7,80 (4H, multiplet, phenyl ring)

The above ethyl ester of N-5-phthalimidomethyl acid (9 g, 30 mmol) dissolved in 95% ethanol (100 ml), to this solution is added dropwise at 0 2 h, the solution is concentrated to half volume and add a 15% NaOH solution (50 ml). The resulting reaction mixture was stirred at room temperature overnight, the ethanol is evaporated under vacuum, then cooling at 0oC add 37% HCl to pH 1, the thus obtained aqueous solution washed with ethyl acetate to remove phthalic acid, and evaporated to dryness and vacuum. The resulting residue is mixed with cold ethanol, the insoluble part is filtered, and the filtrate was concentrated in vacuo. Pure hydrochloride 5-aminoacetanilide acid (4.6 g) precipitates upon standing, so pl. 127 129oC.

Similarly can be obtained the following compounds:

6-[[2-Phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl]-aminooxy]-hexanoic acid (compound 5),

5-[[2-Phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl]-aminooxy]-2-pontenova acid (compound 38) and

6-[[2-Phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-ventolinonline] -2-hexenoic acid (compound 39).

Example 8

(Z)-5-[[2,3-Dihydro-3-(1H-imidazol-1-yl)-4H-1-benzopyranyl]-aminooxy]-pentane acid 500 grams

Lactose 710 g

Corn starch 237,5 g

Powdered talc 37,5 g

Stearate half the corn starch are mixed, the mixture is then sieved through a sieve with openings of 0.5 mm Corn starch (18 mg) is suspended in warm water (180 ml). The resulting paste is used for granulation of powder. The granules are dried, sieved through a sieve with openings of 1.4 mm, then the remaining quantity of starch, talc and magnesium added, thoroughly mixed and pressed into tablets using punches with a diameter of 8 mm

Example 9

Prepare capsules, each of which is dosed at 0.5 g and containing 50 mg of active substance.

Composition for 200 capsules:

(A)-(E)-ethyl-5-{ [2-(1H-imidazol-1-yl)-1,2,3,4-tetrahydro-1-naphthalide] aminoxy}pentanoate: 10 g

Lactose 80 g

Corn starch 5 grams

Magnesium stearate 5 g

This drug is encapsulated in hard gelatin capsules consisting of 2 parts, and dosed at 0.5 g each.

Example 10

Using conventional techniques adopted in the pharmaceutical industry, prepare medical candles or suppositories of the following composition.

(Z)-5-{[2,3-dihydro-3-(1H-imidazol-1-yl)-4H-1-benzopyranyl]aminoxy} pentane acid 50 mg

Lactose 298 mg

Corn starch 50 mg

Magnesium stearate 2 mg

Example 11

Using conventional techniques of pharmaceutical industry is-naphthalide] -aminooxy}pentanoate 0.05 g

lecithin 0.07 g

cocoa butter 0,088 g

Example 12

Intravenous injectable 50 mg/ml

Injectable pharmaceutical preparation obtained by dissolving 50 g of sodium salt of ()-(Z)-6-{ [2-phenyl-3-(1H-imidazol-1-yl) -2,3-dihydro-4H-benzoperylene] aminoxy} acid in water for injection (1000 ml) and sealed in ampoules of 1 to 10 ml.

Sodium salt for preparative formula of example 12 was obtained according to the following example 13.

Example 13

Sodium salt of ()-(Z)-6-{[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-benzoperylene]aminoxy}-acid

()-(Z)-ethyl-6-{ [2-phenyl-3-(1H-imidazol-1-yl) -2,3-dihydro-4H-benzoperylene] -aminooxy} hexanoate (300 mg, 0.67 mmole) was dissolved in a mixture of methanol-water (5:2,7 ml) and to this solution is added a stoichiometric amount of 0.1 norms. NaOH. After the usual processing of the obtained target compound with so pl. > 250oC.

1. N-Imidazolidine substituted derivatives of alkoxyimino-tetrahydronaphthalene or Romanov General formula I

< / BR>
where Z is CH2- or-O-;

m 1 4 integer;

T linear or branched saturated or unsaturated WITH1- C6is a hydrocarbon chain;

A bond or the divalent group-O-CH2-;

R fogoros them hydrogen, and the other WITH1WITH8-alkyl or C5- C8-cycloalkyl, thienyl, phenyl-C1WITH4is an alkyl group or phenyl group, which phenyl group or the phenyl fragment is not substituted or is substituted by 1 or 2 substituents, independently selected from halogen, C1WITH4-alkyl and C1- C4-alkoxygroup;

R3hydrogen or a Deputy selected from halogen, Tagalog-C1WITH4-alkyl or C1WITH4-alkoxygroup;

R4group OR5where R5hydrogen or C1- C6-alkyl,

or their pharmaceutically acceptable salts.

2. The compounds of formula I on p. 1, wherein Z is CH2- or-O-,

m is 1 or 2,

T1WITH5-Allenova or2- C5-Alcanena chain,

R is hydrogen, A bond or-O-CH2-, R1and R2both hydrogen, or one of them is hydrogen and the other WITH1WITH4-alkyl, C5WITH7-cycloalkyl, or phenyl or benzyl group, where the phenyl ring or the phenyl fragment is not substituted or substituted by one or two substituents, independently selected from halogen, C1- C4-alkyl and C1WITH4-alkoxygroup the4group-OR5where R5is hydrogen or C1WITH4-alkyl, or their pharmaceutically acceptable salts.

3. Connection on p. 1, selected from the following compounds or in the form of a Z-or E-isomer or Z, E-mixtures of these isomers: 5-{ [2,3-dihydro-3-(1H-imidazol-1-yl)-4H-1-benzopyranyl] -aminooxy} pentane acid, 5-{ [2-methyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl]-aminooxy} -pentane acid, ethyl ester 5-{ [2-methyl-3-(1H-imidazol-1-yl)-2,3 - dihydro-4H-1-benzopyranyl] -aminooxy} -pentanol acid, 6-{ [2-methyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl] -aminooxy} -hexanoic acid, 6-{ [2-phenyl-3-(1H-imidazol-1-yl)- 2,3-dihydro-4H-1-benzopyranyl)-aminooxy} -hexanoic acid, ethyl ester 6-{ [2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl]-aminooxy}-hexanoic acid, 5-{ [2-phenyl-3- (1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl] -aminooxy} pentane acid, ethyl ester 5-{ [2-phenyl-3-(1H-imidazol-1-yl)- 2,3-dihydro-4H-1-benzopyranyl] -aminooxy} -pentanol acid, 4-{ [2-(3,4-acid)-3-(1H-imidazol-1-yl)- 2,3-dihydro-6-methoxy-4H-1-benzopyranyl] -aminooxy}-butane acid, 5-{[2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-6 - methoxy-4H-1-benzopyranyl] -aminox the Wai acid, methyl ester of 6-{ [2-phenyl-3-(1H-imidazol-1-yl)- 2,3-dihydro-6-methoxy-4H-1-benzopyranyl] -aminooxy} -hexanoic acid, 6-{[2-phenyl-3-(1H-imidazol-1-yl)-2,3 - dihydro-6-n-butoxy-4H-1-benzopyranyl]-aminooxy}-hexanoic acid, 5-{ [2-(3,4-acid)-3-(1H-imidazol-1-yl)- 2,3-dihydro-6-methoxy-4H-1-benzopyranyl] -aminooxy} -pentane acid, 6-{ [2-(3,4-acid)-3-(1H-imidazol-1-yl)-2,3 - dihydro-6-methoxy-4H-1-benzopyranyl] -aminooxy} -hexanoic acid, 6-{ [2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-6-fluoro-4H-1-benzopyranyl] -aminooxy} -hexanoic acid, 5-{ [2-(Tien-2-yl)-3-(1H-imidazol-1-yl)- 2,3-dihydro-4H-1-benzopyranyl] -aminooxy} -pentane acid, 6-{ [2-Tien-2-yl)-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1 - benzopyranyl] -aminooxy}-hexanoic acid, 5-{ [2-(Tien-3-yl)-3-(1H-imidazol-1-yl)-2,3 - dihydro-4H-1-benzopyranyl] -aminooxy}-pentane acid, 6-{[2-(Tien-3-yl)-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl - den] -aminooxy}-hexanoic acid, 3-{ [2-(4-forfinal)-3-(1H-imidazol-1-yl)- 2,3-dihydro-6-trifluoromethyl-4H-1-benzopyranyl] -aminooxy} - prophylactically acid, 6-{ [2-benzyl-3-(1H-imidazol-1-yl)-2,3 - dihydro-4H-1-benzopyranyl] -aminooxy} -hexanoic acid, 2-{ [2((4-forfinal)-methyl)-3-(1H-imidazol-1-yl)- 2,3-dihydro-6-fluoro-4H-1-banter the den]-aminooxy}-hexanoic acid, 5-{ [2-(1H-imidazol-1-yl)-1,2,3,4-tetrahydro-1-naphthalide] aminoxy}-pentane acid, 5-{ [2-(1H-imidazol-1-yl)- 7-methoxy-1,2,3,4 tetrahydro-1-naphthalide] -aminooxy} -pentane acid, ethyl ester 5-{ [2-(1H-imidazol-1-yl)-1,2,3,4 - tetrahydro-1-naphthalide] -aminooxy} -pentanol acid, 5-{ [2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl] aminoxy} -2-pentane acid, 6-{ [2-phenyl-3-(1H-imidazol-1-yl)- 2,3-dihydro-4H-1-benzopyranyl] -aminooxy}-2-hexanoic acid, 5-{ [2-phenyl-3-(1H-imidazol-1-yl)-2,3-dihydro-4H-1-benzopyranyl] - aminooxy}-3,3-dimethylpentane acid and its pharmaceutically acceptable salts.

4. The pharmaceutical composition active antagonist and thromboxane inhibitor of thromboxane synthetase, contains an active ingredient and a pharmaceutically acceptable carrier and/or diluent, wherein the active substance contains a compound of formula I or its pharmaceutically acceptable salt p. 1 in an effective amount.

5. The compounds of formula I or their pharmaceutically acceptable salt p. 1 active antagonist and thromboxane inhibitor of thromboxane synthetase.

 

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