N-imidazolidine substituted derivatives of indole, the method of production thereof and pharmaceutical composition

 

(57) Abstract:

Usage: in medicine, because they have activity inhibitor tha2synthase and/or antagonist GH2/Tha2the receptor. The inventive product is N-imidazolidine derivatives substituted indole of the formula

< / BR>
where p = 1,2, A - straight WITH1-C4Allenova a circuit In a simple bond or a straight saturated WITH2-C4hydrocarbon chain, Q is a straight or branched saturated WITH1-C4hydrocarbon chain, R1and R2Is h or halogen, R3and R5- H or C1-C4alkyl, R4means OR6or N(R6R7R6and R7- H or C1-C4alkyl. Reagent 1: compounds of the formula:

< / BR>
Reagent 2: compound of formula

< / BR>
The pharmaceutical composition comprises compound I in an effective amount and a suitable carrier and/or diluent. 3 S. and 4 C.p. f-crystals, 3 tables.

The present invention relates to new N-imidazolinium derivative substituted indole, the method of their preparation, containing pharmaceutical compounds and to their use as therapeutic agents.

By the present invention are new soy which is a straight or branched C1-C4alkylenes chain;

B represents a simple bond, a straight or branched, unsaturated or saturated WITH1-C4hydrocarbon chain;

Q represents a straight or branched, saturated or unsaturated WITH1-C9hydrocarbon chain, or the chain is interrupted by oxygen atom;

each of R1and R2independently represents hydrogen, C1-C4alkyl, C1-C4alkoxy, C1-C4alkylthio,1-C4alkylsulfonyl, halogen, or trihalomethyl;

each of R3and R5independently, represents hydrogen or C1-C4alkyl;

R4-represents-OR6or-N(R6R7) group, in which each of R6and R7independently represents hydrogen, C1-C4alkyl, phenyl or benzyl; and their pharmaceutically acceptable salts.

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

If p is greater than 1, the substituents R1can be either equal or different.

Alcippe.

Group C1-C4alkyl represents, for example, methyl, ethyl, propyl, isopropyl, butyl or tert-butyl, preferably methyl or ethyl.

WITH1-C4alkoxy group represents, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy or tributoxy, preferably methoxy, ethoxy or propoxy group.

Group C1-C4alkylthio represents, for example, methylthio, ethylthio, propylthio or butylthio, preferably methylthio or ethylthio.

C1-C4alkylsulfonyl group represents preferably methylsulphonyl.

Atom of halogen means bromine, chlorine or fluorine, preferably bromine or fluorine.

Straight or branched C1-C4Allenova circuit is, for example, -CH2-, -CH2-CH2-, or-CH(CH3)-CH2-, in particular-CH2-CH2-.

Trigonometria group represents, for example, trichloromethyl or trifluoromethyl, preferably trifluoromethyl.

Straight or branched, saturated or unsaturated C1-C4the hydrocarbon chain is, for example, one of the chains-CH2-, -CH2-CH2- SS="ptx2">

Straight or branched, saturated or unsaturated C1-C9the hydrocarbon chain is, for example, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH(CH(CH3)-CH2, -CH(CH3)-CH(CH3)-, -CH= CH - or-CH=CH-CH2-.

If the hydrocarbon chain is interrupted by oxygen atom, thus formed a chain represents preferably-CH2-O-CH2- or-CH2-CH2-O-CH2-.

Pharmaceutically acceptable salts of the compounds according to the invention include acid additive salts with inorganic acids, for example: nitric, hydrochloric, Hydrobromic, sulphuric, perchloric and phosphoric acids, or with organic acids such as: acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, almond and salicylic acids, and salts with inorganic bases, for example alkali metals, especially sodium or potassium hydroxide, basic or alkaline earth metal, especially calcium or magnesium, or with organic bases, such as bonds alkylamines, preferably the ptx2">

As indicated above, the present invention also includes within its scope pharmaceutically acceptable bioresistance (also known as prodrugs of compounds of formula (I), i.e. compounds that have the formula, different from the above formula (I), but which, nevertheless, with the introduction of man become directly or indirectly in vivo into a compound of formula (I)

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

p represents 1 or 2;

A represents a-CH2- or-CH2-CH2-;

B represents a simple bond or-CH2-;

Q represents-CH2-CH2-, -CH2-CH2-CH2-, -CH2-C(CH3)2-, -CH2-CH2-C(CH3)2-, -CH2-O-CH2-, -CH2-CH2-O-CH2-;

each of R1and R2represents independently hydrogen, C1-C4alkyl, halogen or trifluoromethyl;

R3represents a C1-C4alkyl;

R5represents hydrogen;

R4represents-OR6or other6where R6means hydrogen or C1-C4alkyl, and their pharmaceutical the uly (I), where:

p represents 1 or 2;

A represents-CH2-;

B represents a simple bond or-CH2-;

Q represents-CH2-CH2-, -CH2-CH2-CH2-, -CH2-C(CH3)2-, -CH=CH - or-CH2-O-CH2-;

R2and R5represent hydrogen;

R3represents a C1-C4alkyl;

R1represents halogen or trifluoromethyl;

R4represents-OR6or other6where R6means hydrogen or C1-C4alkyl; and pharmaceutically acceptable their salts.

Examples of preferred compounds of formula (I) below:

1) 5-fluorescent-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] -3-me til-1H-indole-2-propanoic acid;

2) 5,7-Diptera-1-[[(4-(1H-imidazol-1-yl)phenyl] methyl] -3-methyl-1H-indole-2-propanoic acid;

3) 5-fluorescent-1-[[(3-(1H-imidazol-1-yl)phenyl] methyl]-3-methyl-1H-indole-2-propanoic acid;

4) 5-fluorescent-1-[[(4-(1H-imidazol-1-ylmethyl)phenyl] methyl] -3-methyl-1H-indole-2-propanoic acid;

5) Ethyl ester 5-fluorescent-1-[[(4-imidazol-1-yl)phenyl]methyl]-3-methyl-1H-indole-2-propanoic acid;

6) 5-fluorescent-1-[[(4-(1H-imidazol-1-yl)phenyl] methyl]-3-methyl-1H-indole-2-propanamide;


9) 5-fluorescent-1-[[(4-(1H-imidazol-1-yl)phenyl] methyl]-3-methyl-1H-indole-2-butane acid;

10) Ethyl ester 5-fluorescent-1-[[(4-imidazol-1-yl)phenyl]methyl]-3-methyl-1H-indole-2-butane acid;

11) 5-fluorescent-1-[[(4-(1H-imidazol-1-yl)phenyl]methyl]-, , 3-trimethyl-1H-indole-2-butane acid;

12) 5,7-Diptera-1-[[(4-(1H-imidazol-1-yl)phenyl] methyl] -, , 3-trimethyl-1H-indole-2-butane acid; and their pharmaceutically acceptable salts.

Structural formulas of the above compounds, according to their number, shown in the following table 1.

Compounds according to the invention and their salts can be obtained by a method including:

a) interaction of the compounds of formula (II) or its salt

(II)

where p, Q, R1, R3and R4defined above, with a compound of formula (III)

(III)

where a, b, R2and R5defined above and Y is a chip off the group; or

b) interaction of the compounds of formula (IV)

(IV)

in which p, A, B, R1, R2and R5defined above, with a compound of formula (V)

(V)

in which Q, R3and R4defined above; or

c) interaction of the compounds of formula (VI) or its salt

(VI)

in the cat with imidazole, C1-C4alkylimidazole or its salt, and, if necessary, conversion of the compounds of formula (I) into another compound of formula (I) and/or, if necessary, the conversion of the compounds of formula (I) in its salt and/or, if necessary, the conversion of salts of compounds of formula (I) into a free compound and/or, if necessary, the separation of a mixture of isomers of compounds of formula (I) certain isomers.

Useplease group V compound of the formula (III) or formula (VI) means preferably halogen, for example bromine or chlorine, or mesyl or tonilou group.

The reaction of the compound of formula (II) or its salt with the compound of the formula (III) can be made using a strong base such as sodium hydroxide, tert-butyl potassium, potassium hydride, magnesium-bromacil or HEXAMETHYL-disilane potassium in the presence of a suitable organic solvent, such as dimethylformamide, dimethylacetamide, tetrahydrofuran, toluene, acetate, benzene or a mixture thereof, at a temperature in the range from about -20oWith up to about 50oC.

The reaction of the compound of formula (IV) with the compound of the formula (V) can be made using standard conditions indole synthesis, Fischer (well-known reaction described, for example, in "Heterocyclic Compounds", the content of inorganic fillers solvent, for example, alkanol, in particular methanol, ethanol, isopropyl alcohol, benzene or toluene. The reaction can be carried out in the presence of an acid catalyst, such as a strong inorganic acid, in particular sulfuric acid or hydrochloric acid.

The reaction of the compound of formula (VI) or its salt with imidazole or C1-C4alkylimidazole can be carried out in the presence of a base such as triethylamine or preferably using an excess of imidazole or alkylimidazole.

If the compound of formula (VI) or its salt interacts with the salt of imidazole or C1-C4alkylimidazole, then salt the last mentioned compounds are, for example, salt of potassium or sodium, and the reaction does not require the presence of any additional principal reagent.

The reaction is carried out in the presence of a suitable organic solvent, such as ethanol, methanol, dimethylformamide, dimethylacetamide, or even in the absence of a solvent, for example by synthesis with an excess of imidazole or C1-C4alkylimidazole, at a temperature in the range from about 70oWith up to about 170oC. If in the compound of formula (VI) means simple Br2or copper powder.

The compound of formula (I) can be converted, if necessary, into another compound of formula (I).

These optional transformations can be carried out with known methods.

The compound of formula (I) containing esterified carboxyl group can be converted to the compound of formula (I) containing free carbon group, by acid or alkaline hydrolysis is carried out at temperatures in the range from room temperature to a temperature of about 100oC.

The compound of formula (I) containing a free carboxyl group, can be converted to the compound of formula (I) containing esterified carboxyl group by esterification, for example through appropriate galoyanized, for example the chloride, by reaction with an excess of a suitable C1-C4Olkiluoto alcohol, either through direct esterification by acid catalyst in the presence of anhydrous HCl, SOCl2or BF3iterate.

The compound of formula (I) containing a free or esterified carboxyl group, can be converted to the compound of formula (I) containing a-CONR6R7group, where R< is the corresponding amide can be made by direct reaction with ammonia, or with an appropriate amine in a suitable aprotic solvent, for example in a simple ether or benzene, or by using an excess of amine as solvent, at a temperature in the range from room temperature to the temperature of phlegmy.

Conversion of the free carboxyl group to the corresponding amide can be performed through an intermediate reactive derivatives, which can either allocate or not.

Intermediate reactive derivatives may be an active esters, such as NO2-phenyl ester, or N-hydroxysuccinimide esters, galodamadruga, preferably chloride, mixed anhydrides, for example etoxycarbonyl or tert-BUTYLCARBAMATE anhydrides or reactive intermediate compounds formed in situ by the reaction of the acid with dicyclohexylcarbodiimide or carbonyl diimidazol. Reaction of intermediate compounds obtained by known methods, typically used in the synthesis of peptides, in contact with ammonia or with an appropriate amine in a suitable solvent, or with an excess of the amine at temperatures in the range from about -10oWith up to about 50oC.

Optional receiving salt sedimetary can be performed by known methods.

For example, separation of a mixture of geometric isomers, such as CIS - and TRANS - isomers, can be done by fractional crystallization from a suitable solvent or by chromatography or chromatography on a column or using liquid chromatography high pressure.

The compound of formula (II) can be obtained by contacting the compounds of formula (VII)

(VII)

in which R1and p are defined above, with a compound of formula (V) defined above, using standard conditions indole synthesis, Fischer, as described above.

The compound of formula (III) can be obtained by contacting the compounds of formula (VIII)

(VIII)

in which B and Y are defined above, T represents a simple bond or a straight or branched C1-C3alkylenes chain, and R represents a lower, e.g. C1-C4alkyl group, imidazole, C1-C4alkylimidazole or its salt.

The reaction can be done in the presence of a base such as triethylamine or preferably using an excess of imidazole or C1-C2alkylimidazole in a suitable organic solvent, such as ethanol, methanol, dimethylformamide, dim the C4alkylimidazole, at temperatures in the range from about 70oWith up to about 165oC.

If desired the catalyst in the above reaction can optionally be used, for example, CuBr or Cu.

Thus, the obtained ester containing imidazole ring, you can turn an ordinary and well-known methods in the compound of formula (III), for example, restoring LiAlH4and halogenoalkanes thus obtained alcohols, with SOCl2, SOBr2or PCl5.

Alternatively, the compound of formula (III), which represents a simple bond and a represents a-CH2-, can be obtained by contacting the compounds of formula (IX)

(IX)

in which R2and Y are defined above, and where R' and R" are C1-C6alkyl group, or taken together they form a 1,3-dioxolane or 1,3-dioxane ring, imidazole, C1-C4alkylimidazole or preferably their sodium salts or potassium, in the presence of a catalyst, for example C2Br2or copper powder, using a suitable organic solvent, such as dimethylformamide, dimethylacetamide or dimethoxyethane, at temperatures in the tal can be converted to the compound of formula (III) are well-known ways, for example by hydrolysis acetamino group in acidic conditions, the recovery of the aldehyde with NaBH4or c LiAlH4and halogenoalkanes with SOCl>2or SOBr2.

The compound of formula (IV) receive, following the well-known methods N-alkylation of phenylhydrazine using the compounds of formula (III) as the alkylating reagent.

The compound of formula (VI) can be obtained by contacting the compounds of formula (II) with the compound of the formula (X)

(X)

in which E represents a or Y, as defined above, or a chemical precursor In the-Y group, in which b and Y are defined above, thus obtaining, respectively, the compound of formula (VI), which means a direct connection, or after the chemical conversion of the precursor in the-Y group is well known in this field means, get the compound of formula (VI), which means C1-C4hydrocarbon chain.

Chemical predecessor group In the-Y can be, for example, Catalinas or ester group, well known in this field.

The compounds of formula (V), (VII), (VIII), (IX) and (X) are well known compounds, can be obtained by methods well known in the organization the group, which can interfere with the conduct described herein reactions, these groups may be protected prior to the reaction, and then the protection can be removed at the end of the reaction by known methods, for example, by the methods used in the chemistry of peptides.

Pharmacology.

The thromboxane (tha2) is a derivative of the metabolism arachidonoyl acid, which connects the platelets and increases their susceptibility to other a variety of aggregating agents.

In addition, tha2narrows blood vessels, bronchial and tracheal smooth muscle cells and lubochnye mesangial cells.

So tha2participates in a variety of pathologies, such as cardiovascular disease (myocardial infarction and angina), cerebrovascular disease (seizures, transient ischemic stroke and migraine), peripheral vascular disease (microangiopathy), renal disease (glomerulosclerosis, lupus nephritis, diabetic nephropathy), respiratory disease (bronchostenosis and asthma), and, moreover, is usually involved in atherosclerose.

Tha2affects platelets and smooth muscle cells by classes of receptor (or rectomy, having opposite properties for receptors TxA2and/or reagents, innigeria enzymes involved in the synthesis of tha2in particular any abscopal tha2synthase, which catalyses the formation of tha2from cyclic endoperoxide prostaglandin G2and of prostaglandin H2without affecting the synthesis of other prostaglandins.

It can be expected that compounds which inhibit the action of tha2due to antagonism towards tha2and/or slowing the synthesis of tha2-synthase, are of therapeutic value for treatment of these diseases and other pathological conditions involving tha2.

Assume that the compounds of the present invention, which possess these properties, effective in the treatment of painful conditions in which increased synthesis tha2leads to the manifestation of pathogenic effects, such as, for example, as mentioned above.

Methods

Estimated the impact of a representative group of compounds of this invention, compared with the influence of known compounds on the inhibition of the synthesis of tha2in vitro in whole blood of normal rats, and in antagonism to tha2is charity and love, was taken from the abdominal aorta of normal rats, Sprague Dawley (Charles river, Italy) under light anesthesia simple ether. Then, the blood was immediately divided into portions of 0.5 ml and were placed in glass tubes, each of which contain some concentration of test compound or reference compound.

Then the samples were given the opportunity to clotting for 1 hour at a temperature of 37oC, centrifuged at 3000 rpm for 10 min, serum was collected and stored at -20oTo further analyses. Levels THV2was determined by radioimmunoassay according to previously described methods (Thromb. Res. 17, 3/4, 317, 1980), using a highly sensitive antibody.

Substitution of tritium-labeled [3H]-SQ 29548 associated with washed human platelets

The blood of healthy volunteers of both sexes who had not taken any medication within the last 10 days, were placed in one-tenth volume of acid citrate-dextrose containing indomethacin (28 µmol/l). Platelet-rich plasma (PRP) obtained by centrifugation of blood at 200g for 20 minutes, washed twice (1000g for 10 min). Then platelets re-suspended in buffer Tired-HEPES (pH of 7.4) to obtain a final concentration of 5-10 x 10-8cells/ml and incub was added in various concentrations (10-9-10-4mol/l) of competing ligands, and incubated for 30 min at a temperature of 25oC. Nonspecific binding was determined in the presence of 50 μmol/l U46619 and they accounted for approximately 5% of the total number of bindings labeled with tritium [3H]-SQ 29548. After incubation, each tube was added 4 ml ice Tris-Hcl buffer (10 millimoles/l, pH of 7.4), and then the reaction link immediately filtered through prisasyvaniya through the glass disk filter Whatman GF/C, which was washed 2 times with ice Tris-HCl and measured for radioactivity counter Packard.

Data binding was analyzed using a computerized nonlinear curve matching using the program Ligand, and expressing them in units of concentration inhibition IC50.

In table 2, for example compares the results obtained in the tests for binding (washed human platelets with an illustrative compounds of the invention having internal codes FCE and FCE 27005 27093, with the results obtained with the reference standard compounds, BM 13505 and BM 13177 (Naunyn Schmideberg''s Arch. Pharmacol 1986, 332 (Suppl) Abst 144 SR. 36; Cardiovasc. Drug. Rw. 1988, 6:20-34).

These results showed that the compounds FCE and FCE 27005 27093 have bolsita, obtained with the compounds of the invention having internal code FCE 27093, their influence on the synthesis of TxB2in normal rats, with the results obtained with the reference standard dazoxiben and ASA; limit values, if they were calculated are shown in parentheses.

In the above tables 2 and 3 internal code FCE 27005 means 5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl]methyl-3-methyl-1H-indole-2-propanoic acid, internal code FCE 27093 means 5-fluorescent-1-[[4-(1H-imidazol-1-yl)phenyl] methyl-3-methyl-1H-indole-2-butane acid and ASA means of acetylsalicylic acid.

Since the compounds of the present invention are inhibitors of the synthesis tha2and antagonists PGH2/TxA2-platelets, on the basis of knowledge in this area, as reported, for example, in J. Clin.Invest 80, 1435 (1987) and Adv. Prostaglandins, Thromboxanes, Leukotrienes Res. Vol.17 (1987) p.49, these compounds are particularly suitable for the treatment of painful conditions in which increased synthesis tha2exerts its pathogenic action, such as the above.

In particular, in the treatment of renal insufficiency, the compounds of the invention can be used in conjunction with enzyme inhibitor, transforming angiotensin (ACE) as at razmelchite or for treatment, caused by cyclosporine-And nephrosis in mammals.

Compounds of the invention may also be used together with dissolving the clot reagents (e.g., tPA (terephthalic acid), streptokinase, PUK), in order to reduce the required dose of the latter when thrombolytic therapy, and to reduce the possibility of reocclusion and possibly bleeding.

Further use of the compounds of the invention consists in the prevention and/or treatment of restenosis after resconi plastic surgery on the blood vessels.

The toxicity of the compounds of the invention are small, so they can safely be used in therapy. Rats and mice, which previously were not given food for nine hours, were treated orally with single injections with increasing doses of compounds of the invention, and then put it in a cage and normally fed.

Approximate acute toxicity (LD50) was determined on the seventh day after treatment.

In view of their high activity of the compounds of the invention can be used safely in medicine. Treatment for various clinical syndromes must be adjusted to suit the type of pathology, taking into wakie age, the weight and condition of the patient. Oral path is used generally in all cases where such connections. Preference is given intravenous injections or infusions for the treatment of acute pathological connections.

For supportive treatment regimens for oral or parenteral, such as intramuscular method, are preferred.

The magnitude of the dose that is acceptable for oral administration to adult humans of the compounds of the invention, for example 5-fluorescent[[4-(1H-imidazol-1-yl)phenyl] methyl-3-methyl-1H-indole-2-propanoic acid, may be within the range of from about 50 mg to about 500 mg per dose, apply 1 to 3 times a day.

Of course, this pattern of medication can be adjusted to provide the optimum therapeutic response.

The nature of pharmaceutical mixtures containing compounds of this invention together with pharmaceutically acceptable carriers or solvents will depend upon the desired route of administration. The composition can be prepared in a known manner with the usual ingredients. For example, the compounds of the invention can be introduced in the form of aqueous or oily solutions, suspensions, tablets, pills, gelatin capsules, the mixture containing compounds of this invention are preferably tablets, pills or capsules which contain the active substance together with solvents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, such as krasnozem, talc, stearic acid, magnesium stearate or calcium, and/or polyethylene glycols; or they may also contain binders, such as starch, gelatin, methylcellulose, carboxymethylcellulose, gum Arabic, tragakant, polyvinylpyrrolidone; dezintegriruetsja reagents, such as starch, alginic acid, alginates, sodium starch glycolate, foaming the mixture; food colorants; sweeteners; wetting agents, such as lecithin, Polysorbate, laurylsulfate; non-toxic and pharmaceutically inactive substances used in pharmaceutical formulations. These pharmaceutical preparations can be obtained by known methods, for example by mixing, granulating, tabletting, sugar coating or covering film. Liquid dispersions by oral administration can be, for example syrups, emulsions or suspensions.

The syrups may contain as novtel which may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.

The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, etiloleat, glycols, such as propylene glycol, and, if necessary, a suitable number of lidocaineydrocortisone.

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

Suppositories can contain along with the active compound in pharmaceutically acceptable media, such as cocoa butter, polyethylene glycol, surfactant-based polyoxyethylenesorbitan of ester of fatty acid or lecithin.

The following examples illustrate but do not limit the present invention.

Example 1

5-fluorescent-1-[[4-(1H-imidazol-1-yl)phenyl]methyl]-3-methyl-1H-indole-2 - propanoic acid.

A solution of 198 mg of 5-fluorescent-3-methyl-1H-indole-2-propanoic acid in 20 ml of dry N, N-dimethylformamide (at a temperature of 0oWith, then added in several portions 307 mg of 1-[4-(chloro-methyl)phenyl]-1H-imidazole hydrochloride under nitrogen at 0oC. After stirring at room temperature for 16 hours, the mixture is poured into water and washed with methylene chloride. The aqueous solution is neutralized with diluted hydrochloric acid Hcl and extracted by addition of methylene chloride. The organic layer is dried over sodium sulfate and evaporated to dryness. The residue stirred with acetone, filtered and dried, to thereby obtain 35 mg of the above compound (so pl. 222oC).

J. M. R. (DMSO-D6) in ppm: 2,20 (3H, c. CH3), is 2.37 (2H, m-COOH), 2,95 (2H, m-CH2-COOH), vs. 5.47 (2H, c. NCH2), 6,80-the 7.65 (9H, m, benzene, N ), 8,16 (1H, c. ).

Similarly can be prepared the following compounds: 5-fluorescent-1-[[4-(1H-imidazol-1-ylmethyl)phenyl] methyl]-3-methyl-1H-indole-2-propanoic acid, so pl. 192oC.

J. M. R. (DMSO-D6) in ppm: 2,17 (3H, s CH3), of 2.33 (2H, m-COOH), 2,90 (2H, m-CH2-COOH), 5,10 (2H, c. -imidazole) of 5.39 (2H, c. ), 6,75-7,30 (9H, m, benzene, N ), to 7.68 (1H, c. ).

5-fluorescent-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] -3-methyl-1H-indole-2-butane acid, so pl. 192-193oC.

J. M. R. (DMSO-D6) in ppm: 1,7 (2H, m-CH2-COOH), of 2.20 (3H, c. CH3in ), 2.25 (2H, m-COOH), 2,2-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] -3-methyl-1H-indole-2-propanoic acid;

5-fluorescent-1-[[4-(1H-imidazo-1-yl)phenyl] methyl] -3-methyl-1H-indole-2-propanoic acid;

5-bromo-1-[[4-(1H-imidazol-1-yl)phenyl] methyl]-3-methyl-1H-indole-2-propanoic acid;

5-fluorescent-1-[[4-(1H-imidazol-1-yl)phenyl]methyl] , ,, 3-trimethyl-1H-indole-2-propanoic acid;

5-bromo-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] , , 3-trimethyl-1H-indole-2-propanoic acid;

5,7-Diptera-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] , ,, 3-trimethyl-1H-indole-2-propanoic acid;

5-fluorescent-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] , ,, 3-trimethyl-1H-indole-2-butane acid;

5-chloro-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] , ,, 3-trimethyl-1H-indole-2-butane acid;

5,7-Diptera-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] , ,, 3-trimethyl-1H-indole-2-butane acid.

5-fluorescent-3-methyl-1H-indole-2-propanoic acid, used above, can be prepared as follows:

A mixture of isopropyl ether 5-fluorescent-3-methyl-1H-indole-2-propanoic acid (0,42 g), 1H. a solution of sodium hydroxide (6.3 ml) and methanol (20 ml) was stirred at room temperature for 4 hours. The reaction mixture is poured into water, washed with methylene chloride, acidified with 1N. solution of hydrochloric acid Hcl and extracted with methylene chloride. The organic layer is dried and evaporated, to give 0.36 g of 5-fluorescent-3-methyl-1H-indol-y above, can be prepared as follows:

A mixture of 1-(-4-forfinal)hydrazine hydrochloride (1,03 g), ethyl ester of 4-oxo-hexanoic acid (1.0 g), 2-propanol (25 ml) and H2SO4refluxed under nitrogen for 9 hours. After cooling, the mixture is poured into an aqueous solution of NaHCO3, extracted by adding t and evaporated to dryness, thus obtaining 1.45 g of isopropyl ester 5-fluorescent-3-methyl-1H-indole-2-propanoic acid.

1-[4-(chloromethyl)phenyl] -1H-imidazole hydrochloride used above can be prepared as follows.

To a solution of 4-(1-imidazolyl)benzaldehyde (2.5 g) in methanol (20 ml), add 1.5 g of NaBH4.

After stirring at room temperature for 3 hours, the mixture is poured into water and extracted by addition of methylene chloride. The organic phase is dried and evaporated to dryness, thus obtaining 2.0 g of 4-(imidazolyl)-benzyl alcohol.

Alternative 4-(1-imidazolyl)-benzyl alcohol can be obtained by recovering the ethyl 4-(1-imidazolyl) benzoate.

Thus obtained 4-(1-imidazolyl)-benzyl alcohol dissolved in diethyl ether and converted into the corresponding hydrochloride by bubbling getobjectat under reflux for 3 hours. The mixture is evaporated to dryness, stirred with ethyl ether and filtered, obtaining 2.6 g of 1-[4-(chloromethyl)phenyl]-1H-imidazole hydrochloride, T. pl. 176-178oC.

4-(1-imidazolyl)benzaldehyde used above can be prepared as follows: of 7.36 g of p-bromobenzaldehyde treated by boiling under reflux with ethylene glycol in benzene to obtain the corresponding acetal. 8,51 g of the acetal is added to the solution 5,12 g of sodium salt of imidazole in 100 ml of dimethylformamide, then add 3,63 g of copper powder, and the mixture is refluxed for 6 hours, then cooled and poured into dilute hydrochloric acid and crushed ice. The mixture is heated at 50oC for 1 hour, cooled, washed with methylene chloride, neutralized with NaHCO3, extracted by the addition of methylene chloride, dried and evaporated to dryness, obtaining 2.5 g of 4-(1-imidazolyl) benzaldehyde.

Ethyl-4-(1-imidazolyl)-benzoate receive in good yield by the reaction of ethyl 4-bromobenzoate with imidazole, flowing through a radical mechanism, when using CuBr as catalyst.

Example 2

Ethyl ester of 5-fluorescent-1-[[4-(1H-imidazol-1-yl)phenyl]methyl]-3-methyl-1H-indole-2-propanoic acid.

oC for 3 hours and then evaporated under reduced pressure to dryness. The residue stirred with ethyl ether and filtered, giving 0.45 g of the named compound.

Likewise, there may be prepared the following compound: ethyl ester of 5-fluorescent-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] -3-methyl-1H-indole-2 - butane acid.

Example 3

5-fluorescent-1-[[4-(1H-imidazol-1-yl)phenyl] methyl]-3-methyl-1H-indole-2 - propanamide.

A suspension of 5-fluorescent-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] -3-methyl-1H-indole-2 - propanoic acid in dimethylformamide (10 ml) was treated with SOCl2(0.5 g), and after cooling through the reaction mixture for 6 hours, rinsed gaseous ammonia. The ammonium salt is filtered, and to the solution add a simple ether. Thus prepared solution, filtered and dried, resulting in the 0.8 g of the named compound.

Example 4

5-fluorescent-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] -3-methyl-1H-indole-2-propanoic acid.

A mixture of 1-[(4-1H-imidazol-1-yl)benzyl] -1-(4-forfinal) hydrazine hydrochloride (1.7 g), ethyl ester of 4-oxo-hexanoic acid (0.85 grams) and 2-propanol (100 ml) is refluxed under nitrogen for 9 hours. column elyuirovaniya a methylene chloride-methanol (955), while receiving 0.7 g of a mixture of ethyl ester of 5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl] methyl]-3-methyl-1H-indole-2-propanoic acid isopropyl ester-5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl] methyl]-3-methyl-1H-indole-2-propanoic acid.

In a mixture of ethyl and isopropyl esters added methanol (30 ml), water (30 ml) and potassium hydroxide (0.5 g). The resulting mixture is refluxed for 6 hours.

After cooling, the methanol is evaporated under reduced pressure, and the resulting aqueous solution is neutralized with hydrochloric acid and acidified with acetic acid.

The resulting salt is filtered, washed with water and dried, to thereby obtain 0.4 g of the named compound, so pl. 222oC.

1-[(4-1H-imidazol-1-yl)benzyl] -1-(4-forfinal)hydrazine hydrochloride used above is prepared as follows.

A mixture of 1-(4-forfinal)hydrazine hydrochloride (3.3 grams), 1-[4-(chloromethyl)phenyl] -1H-imidazole hydrochloride, triethylamine (6.6 ml) and toluene (200 ml) is refluxed under nitrogen for 13 hours. After cooling, the mixture is filtered and the solution evaporated to dryness. The residue is purified using silicagel henyl)hydrazine hydrochloride, the mass spectrum of the mass/charge 282 (M+), 158157.

Example 5

Tablets each weighing 150 mg and containing 50 mg of active substance, can be produced as follows.

Ingredients (for 10,000 tablets)

5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl]methyl]-3-methyl-1H-indole-2-propanoic acid 500 grams

Lactose 710 g

Corn starch 235,5 g

Powder talc 37,5 g

Magnesium stearate 15 g

Mix 5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl]methyl]-3-methyl-1H-indole-2-propanoic acid, lactose and half the corn starch; the mixture is then sieved through a sieve with openings of 0.5 mm Corn starch (18 ml) suspended in warm water (180 ml). The resulting mixture is used to produce granulated powder. The granules are dried into a powder using a sieve with openings of 1.4 mm, then add the remaining quantity of starch, talc and magnesium stearate, thoroughly mixed and, using hammers, hole diameter 8 mm, made tablets.

1. N-imidazolidine derivatives substituted indole of General formula I

< / BR>
where p is 1 or 2;

A-direct-C1-C4-Allenova chain;

In simple bond or a straight saturated C1-C4hydrocarbon chain and R2independently hydrogen or halogen;

each of R3and R5independently hydrogen or C1-C4-alkyl;

R4-OR6or-N(R6R7)-group, in which each of R6and R7independently hydrogen or C1-C4- alkyl,

and their pharmaceutically acceptable salts.

2. N-imidazolidine derivatives under item 1, in which p is 1 or 2;

A-CH2- or-CH2-CH2-;

In simple bond or-CH2-;

Q-CH2-CH2-, -CH2-CH2-CH2-; -CH2-C(CH3)2-, -CH2-CH2-C(H3)2-;

each of R1and R2independent hydrogen or halogen;

R3C1-C4-alkyl;

R5hydrogen;

R4-OR6or other6where R6hydrogen or C1-C4-alkyl,

and their pharmaceutically acceptable salts.

3. N-imidazolidine derivatives under item 1, in which P is 1 or 2;

A-CH2-;

In simple bond or-CH2-;

Q-CH2-CH2-, -CH2-CH2-CH2- or-CH2-C(CH3)2-;

R2and R5hydrogen;

R3C1-C4-alkyl;

R1- halogen;

R4-OR6or other6where R6water is osvitnye under item 1, selected from the group consisting of the following compounds: 5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl]methyl]-3-methyl-1H-indole-2-propanoic acid; 5,7-debtor-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] -3-methyl-1H-indole-2-propanoic acid; 5-fluoro-1-[[3-(1H-imidazol-1-yl)phenyl]methyl]-3-methyl-1H-indole-2-propanoic acid; 5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl]methyl]-3-methyl-1H-indole-2-propanoic acid; ethyl ester of 5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] -3-methyl-1H-indole-2-propanoic acid; 5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl]methyl]-3-methyl-1H-indole-2-propanamide; 5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl] methyl]-, , 3,3-trimethyl-1H-indole-2- -propanoic acid; 5,7-debtor-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] -, , 3,3-trimethyl-1H-indole-2-propanoic acid; 5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] -3-methyl-1H-indole-2-butane acid; ethyl ester of 5-fluoro-1-[[4-imidazol-1-yl)phenyl] methyl] -3-methyl-1H-indole-2 butane acid; 5-fluoro-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] -, , 3-methyl-1H-indole-2-butane acid; 5,7-debtor-1-[[4-(1H-imidazol-1-yl)phenyl] methyl] -, , 3-trimethyl-1H-indole-2-butane acid, and their pharmaceutically acceptable salts.

5. The method of obtaining N-imidazolidine derivatives substituted indole of the formula I

< / BR>
where R 1 and 2;

And direct C1-C4- Allenova chain;< - Governmental rich C1-C4is a hydrocarbon chain;

each of R1and R2independently is hydrogen or halogen;

each of R3and R5independently hydrogen or C1-C4-alkyl;

R4-OR6- or-N(R6R7)-group, in which each of R6and R7independently hydrogen or C1-C4- alkyl,

or their pharmaceutically acceptable salts, characterized in that the compound of formula II or its salt

< / BR>
where P, Q, R1, R3and R4have the above meanings, is subjected to reaction with the compound of the formula III

< / BR>
where A, B, R2and R5have the specified values;

Y the group to delete, and, if necessary, turn the compound of the formula I into another compound of formula I, and/or, if necessary, turn the compound of formula I into its salt, and/or, if necessary, convert the salt of the compounds of formula I into the free compound, and/or, if necessary, separate the mixture of isomers of compounds of formula I into individual isomers.

6. Pharmaceutical composition having activity inhibitor TxA2- synthase and/or antagonist PCH2/TxA2receptor, comprising a suitable carrier and/or diluent and an active agent, characterized in that the AC is on indole, described in paragraph 1, or its pharmaceutically acceptable salt.

7. N-imidazolidine derivatives under item 1 or their pharmaceutically acceptable salts have activity inhibitor tha2- synthase and/or antagonist PCH2/TxA2- receptor.

 

Same patents:

The invention relates to new imidazole derivative of General formula I

where R1-COOH or the group< / BR>
R2=H-C3H7or n-C4H9;

R3-Cl, CF3C2F5C6H5or COOH;

R4-COOH, CHO, or CH2HE, provided that

a) when R4-CH2OH, R3-C2F5and R2-n-C3H7,

b) when R3-COOH, R4also is COOH,

b) when R2-n-C3H7, R3-C2F5and R4-COOH, R1is the groupwhich inhibit the action of the hormone angiotensin and can be used in medicine

The invention relates to new derivatives of 3-methylene-2-oxindole, method of production thereof, to pharmaceutical compositions containing these compounds and to their use as therapeutic agents

The invention relates to veterinary medicine, in particular to methods for treating visceral mycosis rabbits, caused by a pathogenic fungus of the genus Aspergillus fumigatus

The invention relates to the field of medicines, in particular to the creation of drugs used in medicine and veterinary medicine for the treatment and prevention of diseases and conditions involving intoxication, vomiting, diarrhea, such as gastrointestinal diseases, food poisoning, septic conditions

The invention relates to new amino acid derivatives and their pharmaceutically acceptable salts, specifically to new amino acid derivatives and their pharmaceutically acceptable salts, which have an inhibiting activity against renin, to methods for their preparation, to pharmaceutical compositions containing them and to a method for the treatment of hypertension and heart failure in humans or animals

The invention relates to medicine, namely to drugs acting on the cardiovascular system

The invention relates to new derivatives of 3-aminopyrazole possessing biological activity, and to their use in farbkomposition

The invention relates to new biologically active compounds, namely derivatives of 2-mercaptobenzimidazole General formula

< / BR>
where n 0,2,5; R is allyl, dialkylamino or balance monocyclic saturated amine, which may contain an additional heteroatom R1and R2same or different: H, lower alkali, alkoxy or their pharmaceutically acceptable salts, which have a selective anxiolytic activity

The invention relates to medicine and can be used for the treatment of diabetes and diabetogenic angiopathies

The invention relates to new derivatives of 3-methylene-2-oxindole, method of production thereof, to pharmaceutical compositions containing these compounds and to their use as therapeutic agents

The invention relates to medicine, namely to pharmacology and medicinal, with interferonogenna and immunomodulatory effects

The invention relates to medicine, namely to obstetrics
Up!