Compounds selectively inhibiting aromatase, the method of preparation and pharmaceutical composition

 

(57) Abstract:

Describes new compounds of formula I, where R1represents H or fluorine; R2represents a heterocyclic radical selected from 1-imidazolyl, triazolyl, tetrazolyl, thiazolyl; R3represents H or OH; R4represents H; R5represents H or OH, or R4is H, and R3and R5together form a bond, or R3is H, and R4and R5together form =O; R6represents a methylene, ethylene, -CHOH-, -CHOH-CH2-, -CH=CH - or-C(=O)-, or R4is H, and R5and R6together are =CH-, or their stereoisomers or their non-toxic pharmaceutically acceptable acid salt additive, provided that R6can not be-C(= O)-, when is also Described a method of obtaining such compounds, pharmaceutical compositions on their basis, inhibiting aromatase, and a method of inhibiting aromatase. 4 C. and 17 C.p. f-crystals, 2 tab.

The present invention relates to new heterocyclic diarylethylenes, their stereoisomers and their non-toxic pharmaceutically suitable salts with acids and their receipt, to pharmaceutical preparations containing them, and their PR is represents H, R2represents a heterocyclic radical selected from 1-imidazolyl, triazolyl, in particular 1-(1,2,4-triazolyl), tetrazolyl, thiazolyl, R3represents H or OH, R4represents H, R5represents H or OH, or R4represents H, and R3and R5together form a bond, or R3represents H, and R4and R5together form =O; R6represents a methylene, ethylene, -CHOH-, -CHOH-CH2-, -CH= CH-, or-C(= O)-, or R4represents H, and R5and R6together form =CH - stereoisomers and their non-toxic pharmaceutically suitable salts with acids.

The compounds of formula (I) and their stereoisomers form salts connection with organic and inorganic acids. They can, therefore, form a lot pharmaceutically suitable salts with acids, such as chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formate, tartratami, maleates, citrates, benzoate, salicylates, ascorbate and similar salts.

The invention includes within its scope pharmaceutical preparations containing at least one compound of formula (I), its stereoisomers or non-toxic pharmaceutically suitable sovershaetsya 4(5)-imidazolidinone, which, as described, are aromatase inhibitors. In U.S. patent US 4 978 672 describes diphenylsilane 1-(1,2,4-)- 1-(1,3,4-triazolyl)compounds in which the carbon chain between the phenyl groups is preferably stands, for example 2-[ - (4-chlorophenyl)-1-(1,2,4-triazolyl)methyl]benzonitrile. In U.S. patent US 4 937 250 describes diphenylsilane 1-imidazolidinone. In U.S. patent US 5 071 861 describes diphenylsilane 3-pyridylamine and in U.S. patent US 5073574 describes diphenylsilane 1 - and 2-tetrachloroethane. As stated in these U.S. patents, these compounds are inhibitors of aromatase.

Compounds of the present invention possess any abscopal selective aromatase properties compared with any abscopal desmolase properties. They are therefore suitable for the treatment of estrogenzawisimy diseases, such as breast cancer or benign prostatic hyperplasia (national Department of standardization).

The most preferred compounds of formula I, selected from the group:

where R3and R4is H, and R5is OH, or R3is OH, and R4and R5is H, and R6is methylene or ethylene; or R3
where R3and R4are H, and R5represents OH, R6represents methylene or ethylene, or R3, R4and R5represent H; R6is a-CHOH-or-CHOH-CH2-, and R1and R2have the meanings defined above;

where R4= H, and R3and R5together form a bond, or R3= H, and R4and R5together form = O, and R6represents methylene or ethylene; or R3and R4are H, and R5and R6together form =CH-; or R3, R4and R5together represent H, and R6= -CH=CH - or-C(=O)-; and R1and R2have the meanings given above. Among them, preferably a compound which is 1-[1-(4-cyanophenyl)-4-(4-forfinal)butyl] -1H-imidazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid, which is 1-[1-(4-cyanophenyl)-4-(4-forfinal)-2-hydroxybutyl] -1H-imidazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid;

which is 1-[1-(4-cyanophenyl)-4-(4-forfinal)-1-butenyl]-1,2,4-triazole, its stereoisomer or a non-toxic farmatsevticheskii suitable salt with an acid;

the cat is Oh farmatsevticheskii suitable salt with an acid;

which is 1-[1-(4-cyanophenyl)-4-(4-forfinal)-2 - hydroxybutyl] -1,2,4-triazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid;

which is 1-[1-(4-cyanophenyl)-3-(4-forfinal)-3 - hydroxypropyl] -1,2,4-triazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid;

which is 1-[1-(4-cyanophenyl)-4-(4-forfinal)-3 - oxobutyl] -1,2,3-triazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid;

which is 1-[1-(4-cyanophenyl)-3-(4-forfinal)-1 - propenyl] -1,2,4-triazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid;

which is 5-[1-(4-cyanophenyl)-3-(4-forfinal)-1 - hydroxypropyl] thiazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid;

which is 1-[1-(4-cyanophenyl)-3-(4-forfinal)propyl] tetrazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid;

which is 2-[1-(4-cyanophenyl)-3-(4-forfinal)propyl] tetrazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid.

The selectivity of compounds of the formula I is regulated stereochemical predelena. It usually corresponds to the designation of stereoisomers as "a", "b", etc. without additional information on the absolute stereochemical configuration.

Stereoisomer the compounds of formula (I) course included in the scope of the present invention.

The compound can be obtained in different ways.

Thus, the compounds of formula (I) can be obtained by reaction of a halide of the formula (II)

< / BR>
in which Hal denotes halogen, preferably bromine or chlorine, n represents 1 or 2, R1has the above significance, and R7represents CN or another functional group that can be converted into a cyano techniques that are typically used in preparative organic chemistry, with teyracycline compound which is a 1-imidazolyl, 1-(1,2,4-, 4-(1,2,4-, 1-(1,2,3- or 2-(1,2,3-triazolyl) or 1 - or 2-tetrazolyl, in a suitable solvent to form compounds of the formula (III)

< / BR>
Heterocyclic compound is used preferably in the form of its salts, preferably sodium. Starting compound (II) can be obtained by conventional methods from possibly substituted benzaldehyde and a suitable derivative of benzene.

Appropriate soedinenii above, in the presence of a strong base, for example alkylate when the source heterocyclic compound is N-protected with a suitable protecting group.

The compounds of formula (I) can also be obtained by reaction of compounds of formula (IV)

< / BR>
in which R2and R7have the above significance, and R2possibly protected by ordinary methods, with the appropriate halide of formula (V)

< / BR>
in which Hal represents halogen, preferably bromine or chlorine, n represents the number 1 or 2, and R1has the above meanings, in the presence of a strong base, for example alkylate, preferably n-utility, for the formation of compounds of the formula (III), which has values of R2.

Another way of obtaining consists in the reaction of compounds of formula (IV) with a suitable aldehyde of formula (VI)

< / BR>
in which n and R1have the above values in the presence of a strong base, for example alkylate, preferably n-utility, to form compounds of the formula (VII)

< / BR>
which can be further degidratiruth conventional methods, for example by boiling with SOCl2, POCl3or PCl5possibly in a suitable solvent, for example acetonitrile, to receive what genitalia be converted into the corresponding saturated compounds.

According to the present invention proposes a method of producing compounds of the formula (I) which consists in the reaction of compounds of formula (IV) in which R2has the above meaning, R7-CN with a suitable complex ester of the formula (IX)

< / BR>
in which R' represents lower alkyl, preferably methyl or ethyl, in the presence of a strong base, for example alkylate, preferably n-utility, to form compounds of formula (X)

< / BR>
which can then recover the usual methods, for example using NaBH4to obtain the corresponding alcohols of the formula (VII), where R7- CN.

The compounds of formula (I) can also be obtained by reaction of heterocyclic compounds which have the above values, with a ketone of formula (XI)

< / BR>
in the presence of chloride tiomila with the formation of unsaturated compounds of the formula (VIII) in which R2matter of starting compound of the formula (XI) can be obtained by ordinary methods of possibly substituted benzaldehyde and a suitable derivative of benzene.

The compounds of formula (I) can also be obtained by reaction of a ketone of formula (XII)

< / BR>
in which R1and R7have the above e values, in the manner specified in J. Am. Chem. Soc. Vol. 77 (1955) p. 2572 and Vol. 76 (1954) p. 4933, with the formation of ketones of formula (XIII)

< / BR>
which has the above values, which will then restore the compounds of formula (XIV)

< / BR>
which can dehydration be turned into unsaturated compounds of the formula (I).

Another method of preparing compounds of formula (I) consists in the reaction of compounds of formula (IV) with formamide in the presence of a strong base, for example n-utility, to form compounds of the formula (XV)

< / BR>
Alderney condensation of the compounds of formula (XV) with a suitable acetophenon receive unsaturated ketones, which can then be restored in the alcohols included in the formula (I).

The compounds of formula (VIII) can also be obtained by reaction of a ketone of formula (XVI)

< / BR>
in which R2and R7have the above significance, and R2maybe protected with compounds of the formula (XVII) or (XVIII)

< / BR>
in which R' represents a lower alkyl, n is 1 or 2, and R1has the above meanings, in an inert solvent, for example tetrahydrofuran, according to the method described in WO 92/10482.

The compounds of formula (I) in which R3represents OH, you peasall, 2-, 4 - or 5-thiazolyl,

Y represents H or a protective group, with a ketone of formula (XI) in the presence of a strong base, such as alkylate, for example n-utility, to form compounds of formula (XX)

< / BR>
which you can then optionally degidratiruth and gidrirovanii.

The compounds of formula (XX) can also be obtained by reaction of a ketone of formula (XVI) with a halide of formula (V). The reaction is carried out in a suitable solvent, for example tetrahydrofuran, in the presence of alkylate, for example n-utility, or magnesium.

The compounds of formula (XIV), which has values of R2you can get a reaction-derived epoxy compounds of formula (XXI)

< / BR>
in which R1has the above values, and n' is 0 or 1, with compounds of the formula (IV) in the presence of a strong base.

R7that can be converted into cyano, represents, for example, the nitro-group, amino group, halogen, preferably bromine, formyl or aminogroup carboxylic acid.

Compounds of formula (II), (VII), (VIII), (XIII), (XIV), (XV) and (XX), in which R7is a nitro-group, can be converted into compounds of formula (I) by hydrogenation and subsequent diazotization Aminogen, can be converted into compounds of formula (I) using, for example, cyanide salts, in particular sodium cyanide or potassium.

Compounds of formula (II), (VII), (VIII), (XIII), (XIV), (XV) and (XX), in which R7represents formyl, can be converted into compounds of formula (I) by the methods described in the literature.

Compounds of formula (II), (VII), (VIII), (XIII), (XIV), (XV) and (XX), in which R7is aminogroup carboxylic acid, can be converted into compounds of formula (I) by reacting them while boiling, for example, with SOCl2or PCl5.

In the original compounds and intermediate products, which convert into compounds of the invention, the above reactions, functional groups present, such as NH2CN and NH, in the nucleus possibly protected by conventional methods, which are usually used in preparative organic chemistry for the protection of functional groups against undesirable reactions.

Protective groups for the nitrogen atom in the heterocyclic radicals are preferably three(lower alkyl)silly, such as trimethylsilyl.

The stereoisomers of the compounds of formula (I) can be obtained by known separation methods such as selective crystallization and chromate.

The compounds of formula (I), their non-toxic pharmaceutically suitable salts with acids or their mixtures can be entered parenterally, intravenously or orally. Typically, an effective amount of the compound is combined with a suitable pharmaceutical carrier. Used in the description, the term "effective amount" means such amount, which provide the desired activity, but do not cause harmful side effects. The exact amount used in a particular case depends on various factors, such as method of administration, the type of mammal, the condition for the improvement of which impose this connection, and of course the link structure.

Pharmaceutical carriers, which are usually used with the compounds of the present invention may be solid or liquid, they are usually selected in accordance with the intended method of administration. So, for example, solid carriers include lactose, sucrose, gelatin and agar, liquid carriers include water, syrup, peanut butter and olive oil. Combinations of connections and media can be shaped in various suitable forms, such as tablets, capsules, suppository, solution, emulsions and powders.

Compounds of the invention, in chastnostej diseases, for example breast cancer or benign prostatic hyperplasia (national Department of standardization).

Estrogens are the main steroid physiology and function of the normal development of the mammary gland and genital organs of the female. On the other hand, estrogens are known to stimulate the growth estrogenzawisimy cancer tumors, particularly cancer of the breast and uterus. They can increase the risk of developing breast cancer if they enter in pharmacological doses over an extended period of time. Excessive production of estradiol may also cause other benign diseases in gormonzavisimykh bodies. The importance of estrogen as promoters and/or growth regulators of cancer clearly underlined by the fact that antiestrogens are of key importance in the treatment of cancer of the breast, enriched with estrogen receptors. Antiestrogens act by binding to the estrogen receptor, resulting in inhibition of the biological actions of estrogens. This is achieved clinically by aminoglutethimide, which is a nonspecific inhibitor of steroid synthesis. Synthesis of estrogenos you can block specially estrogen. Inhibition of aromatase is important because some types of breast tumors synthesize estradiol and estrone in situ and therefore there is a continuous stimulation of tumor growth (Alan Lipton et al., Cancer 59 : 770 - 782, 1987).

The ability of compounds of the invention inhibit the enzyme aromatase showed by way of the in vitro tests described M. Pasanen (Biological Research in pregnance period, vol. 6, No. 2, 1965, pp. 94 - 99). Used aromatase person. The enzyme was obtained from human placenta, which is rich in this enzyme. Microsome fraction (1000000 x g sediment) was obtained by centrifugation. The enzyme preparation was used without further purification. The test compounds listed in table. 1, was added together with 1.2/3H/-androsten-3,17-dione (100,000 disintegrations per minute) and the system generating NADPH (nicotine-imidazenil-dinucleotides restored). The concentration of the test compounds were of 0.001, 0.01 and 1.0 mm. Incubation was carried out at 37oC for 40 minutes Aromatization 1,2/3H/-androsten-3,17-dione leads to the formation of 3H2O. Tsitirovaniyu water and tretirovanie substrate easily share on minicrane Sep-PakRthat absorbs steroid and allows water to freely buyouts. Radioactivity was counted liquid STI processed inhibitors of samples with the control samples, not containing the inhibitor. IC-50 values were calculated as the concentration that inhibited enzyme activity by 50%. These concentrations are presented in table. 2.

Activity by cleavage of the side chain of cholesterol (SCC) desmolase was measured by the method Panasen and Pelkonen (Steroids 43 : 517 - 527, 1984). Incubation was performed in plastic Eppendorf tubes 1.5 ml was Used shaker (Eppendorf, centrifuge and incubator in the form of a single block. In the incubation vessel 300 ál of substrate (5 μm) was obtained by the method Hanukoglu and Jefcoate (J. Chromatogr. 190 : 256 - 262, 1980) and added radioactive3H-4-cholesterol with the number of decays 100000 min (frequency connection was controlled by TLC) in 0.5% tween-20, 10 mm MgCl25 µm atenolola and 2 mm NADPH. A control sample contained all of the above substances, but the preparation of the enzyme was inactivated prior to incubation by adding 900 μl of methanol. As the source of enzyme was used fraction of mitochondria (1 mg protein) from human placenta or bovine adrenal glands. After 30 min incubation at 37oC the reaction was stopped by adding 900 μl of methanol, in every incubat added token14C-4-pregnenolone (1500 disintegrations per minute) and the tube was intensively shaken. After 10 min of equilibrium osujdenni syringes of 1 ml and transferred into a pre-equilibrated (75% methanol) minicolor. The column was washed with 1 ml 75% methanol and then 3 ml of 80% methanol. The eluate obtained using 80% methanol was transferred into a scintillation vial and add 10 ml scintillation fluid. Radioactivity was counted using dual label on a liquid scintillation counter (Rack 1 KV-Beta). Typical activity for preparation of the enzyme from the placenta and bovine adrenal was 0.5 - 3 and 50 - 100 pmol formed pregnenolone /mg protein/ min, respectively.

In experiments on the inhibition of the substance (final concentration of 1 to 1000 μm) was added to the incubation mixture of 10 - 20 ál, usually in the form of a solution in methanol or ethanol. The same amount of solute was added in the control incubation tube. IC-50 values (concentration causing 50% inhibition) was determined graphically, they are presented in the table. 2.

The daily dose for the patient should be from about 10 to about 200 mg by oral administration.

Acute toxicity, LD50, diastereomer a+d 1-[1-(4 - cyanophenyl)-3-(4-forfinal)-2-hydroxypropyl] -1,2,4-triazole was determined on a young Mature female mouse strain NVRI. The test compound is administered orally. Higher and the s.

The invention is illustrated by the following examples.

The NMR spectra of nuclei1H was filmed on the instrument Bruker AC-300 P. as a standard substance tetramethylsilane was used. In the spectra quintet denotes quintet, m is multiplet, t denotes the triplet, d means doublet, s denotes the sextet, q denotes the quintet.

Example 1

1-[1-(4-Cyanophenyl)-4-(4-forfinal)-butyl]-1H-imidazol

1-(4-Cyanobenzyl)imidazole (1 g, 0,0054 mol) and dissolved in dry tetrahydrofuran (30 ml) and cooled to -70oC. the reaction mixture was added dropwise n-BuLi in hexane (0,0054 mol). After stirring additionally for 30 min at -70oC the mixture was added methyl 3-(4-forfinal)propyl (1.5 g, 0,0069 mol) in THF (10 ml) and stirring is continued for 2 hours. Then, the mixture is left to warm to room temperature. The mixture was added saturated aqueous solution of ammonium chloride, the mixture is shaken and the layers separated. The THF phase is dried and evaporated to dryness. The residue is crystallized from isopropanol as a salt with hydrogen chloride. The filtrate cleanse flush-chromatography.

1H NMR spectrum (HCl-salt, MeOH-d4):

1.5 - 1.63 (quintet 2 H), 2.3 - 2.5 (m, 2H), 2.7 (t, 2H), 5.75 (t, 1H), 6.94 - 7.00 (m, 2H), 7.14 - 7.19 (m, 2H), 7.62 (d, 2H), 7.63">

This connection is produced by a method described in example 1 from 1-(4-cyanobenzyl)1,2,4-triazole (6.0 g, 0,0272 mol) of n-BuLi (0,0272 mol) and 3-(4-forfinal)propyl bromide (7.6 g, 0.035 mol). The product was then purified first by suspendirovanie balance in 2M aqueous hydrogen chloride and petroleum ether. Phase petroleum ether was separated and the water layer and the separated oil is extracted with diethyl ether. Phase diethyl ether is evaporated and the residue purified flash-chromatography.

1H NMR spectrum (HCl-salt; CDCl3):

1.4 - 1.65 (m, 2H), 2.2 - 2.4 (m, 1H), 2.45 - 2.6 (m, 1H), 2.67 (t, 2H), 6.12 (t, 1H), 6.94 (t, 2H), 7.06 - 7.10 (m, 2H), 7.67 (d, 2H), 7.73 (d, 2H), 8.43 (s, 1H), 11.31 (s, 1H).

Example 3

1-[1-(4-Cyanophenyl)-4-phenyl)-1-butenyl]-1,2,4-triazole

a) 1-[1-(4-Cyanophenyl)-2-hydroxy-4-phenylbutyl]-1,2,4 - triazole

1-[1-(4-Cyanophenyl)-2-hydroxy-4-phenylbutyl] -1,2,4-triazole is obtained from 1-(4-cyanobenzyl)-1,2,4-triazole (2.0 g, 0,0108 mol), n-BuLi (0,0108 mol) and 3-phenylpropenoic aldehyde (1,74 g of 0.013 mol). The product was then purified flash-chromatography.

1H NMR spectrum (base, CDCl3):

1.5 - 1.75 (m, 2H), 2.6 - 2.75 (m, 1H), 2.8 - 2.95 (m, 1H), 4.3 - 4.5 (m, 1H), 5.25 - 5.27 (m, 1H), 7.0 - 7.35 (m, 5H), 7.39 and 7.51 (d, 2H), 7.60 (d, 2H), 7.89 and 7.91 (s, 1H), 8.08 and 8.13 (s, 1H).

This way there were obtained the following compounds included in the present description the Tr (base, CDCl3):

diastereomer a+d:

1.5 - 1.7 (m, 2H), 2.6 - 2.73 (m, 1H), 2.8 - 2.9 (m, 1H), 4.4 - 4.5 (m, 1H), 5.23 (d, 1H), 6.96 (t, 2H), 7.11 (dd, 2H), 7.48 (d, 2H), 7.66 (d, 2H), 8.05 (s, 1H), 8.08 (s, 1H)

diastereomer b+c:

1.5 - 1.7 (m, 2H), 2.63 - 2.73 (m, 1H), 2.8 - 2.9 (m, 1H), 4.3 - 4.4 (m, 1H), 5.26 (d, 1H), 6.95 (t, 2H), 7.05 (dd, 2H), 7.38 (d, 2H), 7.65 (d, 2H), 8.07 (s, 1H), 8.12 (s, 1H).

1-[1-(4-cyanophenyl)-4-(4-forfinal)-2-hydroxybutyl] -1H-imidazole, diastereomers a+d+b+c

diastereomer a+d:

1H NMR spectrum (base, CDCl3):

1.6 - 1.8 (m, 2H), 2.6 - 2.75 (m, 1H), 2.81 - 2.9 (m, 1H), 4.24 - 4.3 (m, 1H), 5.04 (d, 1H), 6.9 - 7.0 (m, 4H), 7.08 - 7.12 (m, 2H), 7.49 (d, 2H), 7.57 (s, 1H), 7.67 (d, 2H),

diastereomer b+c

1H NMR spectrum (base, CDCl3+MeOH-d4):

1.6 - 1.8 (m, 2H), 2.6 - 2.73 (m, 1H), 2.8 - 2.89 (m, 1H), 4.21 - 4.27 (m, 1H), 5.09 (d, 1H), 6.93 - 7.11 (m, 6H), 7.3 (d, 2H), 7.64 (d, 2H), 7.69 (s, 1H).

b) 1-[1-(4-cyanophenyl)-4-phenyl-1-butenyl]-1,2,4-triazole

1-[1-(4-Cyanophenyl)-2-hydroxy-4-phenylbutyl] -1,2,4 - triazole (0,42 g, 0,00132 mol) is dissolved in acetonitrile. To the solution add Piatigorsky phosphorus (0.27 g, 0,0013 mol) and the mixture refluxed for 2 hours. The acetonitrile is evaporated and the residue is dissolved in 2 M aqueous sodium hydroxide solution and the solution is extracted with methylene chloride. The extract is dried and the product is crystallized from ethyl acetate in the form of a salt with hydrogen chloride (isomer a).

Thus were obtained the following compounds included in the invention:

1-[1-(4-cyanophenyl)-4-(4-forfinal)-1-butenyl]1,2,4-triazole, isomers a and

1H NMR spectrum (HCl-salt, MeOH-d4):

isomer a:

2.42 (q, 2H), 2.85 (t, 2H), 6.85 (t, 1H), 7.0 (t, 2H), 7.16 - 7.21 (m, 2H), 7.37 (d, 2H), 7.74 (d, 2H), 8.82 (s, 1H), 9.38 (s, 1H)

isomer b;

2.53 (q, 2H), 2.83 (t, 2H), 6.63 (t, 1H), 6.98 (t, 2H), 7.12 - 7.17 (m, 2H), 7.33 (d, 2H), 7.80 (d, 2H), at 8.62 (s, 1H), 9.33 (s, 1H).

1-[1-(4-cyanophenyl)-4-forfinal)-1-butenyl]-1H-imidazole,

isomers a and b

isomer a:

1H NMR spectrum (base, CDCl3):

2.4 (q, 2H), 2.77 (t, 2H), 6.33 (t, 1H), 6.69 (s, 1H), 7.0 (t, 2H), 7.05 - 7.1 (m, 2H), 7.15 (d, 2H), 7.19 (s, 1H), 7.3 (s, 1H), 7.6 (d, 2H).

isomer b:

1H NMR spectrum (HCl-salt, CDCl3):

2.56 (q, 2H), 2.87 (t, 2H), 6.55 (t, 1H), 6.89 (s, 1H), 7.0 (t, 2H), 7.11 (dd, 2H), 7.19 (d, 2H), 7.44 (s, 1H), 7.72 (d, 2H), 9.64 (s, 1H).

Example 4

1-[1-(4-Cyanophenyl)-3-(4-forfinal)propyl]-1,2,4-triazole

a) 1-(4-cyanophenyl)-3-(4-forfinal)prop-2-EN-1-he

4-Acetylbenzoate (14.5 g, 0.1 mol) and 4-forbindelse (12.1 g, 0.1 mol) is dissolved in methanol (150 ml) and alkalizing solution add sodium hydroxide. The mixture is stirred at room temperature for 6 hours. The product is separated by filtration and washed with methanol.

1H NMR-spectrum (the

1-(4-Cyanophenyl)-3-(4-forfinal)prop-2-EN-1-he hydronaut in ethanol using as catalyst 5% Pd on coal

1H NMR spectrum (CDCl3):

3.05 (t, 2H), 3.29 (t, 2H), 6,98 (t, 2H), 7.20 (dd, 2H), 7.76 (d, 2H), 8.02 (d, 2H),

c) 1-(4-cyanophenyl)-3-(4-forfinal)-1-propanol

1-(4-Cyanophenyl)-3-(4-forfinal)-1-propanone (6,35 g, 25 mmol) dissolved in methanol (50 ml). Add in a solution of borohydride sodium (0,48 g, 12.6 mmol) and the mixture was stirred at 30oC for 1 hour. The mixture was acidified with 2M hydrochloric acid and the solvent is evaporated. The residue is dissolved in ethyl acetate. The solution is washed with diluted sodium hydroxide solution and water, dried and the solvent is evaporated. The product used for the next stage without further purification.

1H NMR spectrum (CDCl3):

1.94-2.10 (m, 2H), of 2.66-2.74 (m, 2H), 4.74 (dd, 1H), 6.97 (t, 2H), 7.13 (dd, 2H), 7.45 (d, 2H), 7.64 (d, 2H).

d) 1-chloro-1-(4-cyanophenyl)-3-(4-forfinal)propane

1-(4-Cyanophenyl)-3-(4-forfinal)-1-propanol (3,43 g, 13 mmol) dissolved in dichloromethane (20 ml). The cooled solution is added dropwise chloride thionyl (1.2 ml, 16 mmol) and the mixture is stirred for 2 hours at room temperature. The mixture is washed with water, dried and the solvent is evaporated. The remainder is used for the next stage without further purification.

e) 1-[1-(4-cyanophenyl)-3-(4-forfinal)propyl]-1,2,4-triazole

A mixture of 1-chloro-1-(4-cyanophenyl)-3-(4-forfinal)propane (4,18 g, 15 mmol) and sodium derivative of 1,2,4-triazole (1,37 g, 15 mmol) in DMF (30 ml) is heated gently for 4 hours. DMF is distilled off. The residue is dissolved in ethyl acetate and washed with water. The organic layer is dried and the solvent is evaporated. The product was then purified flash-chromatography (silica gel 60 mesh. 230-400 mesh, eluent: a mixture of methylene chloride-methanol, 99:1).

1H NMR (HCl-salt, MeOH-d4):

2.55-2.65 (m, 3H), 2.78-2.84 (m, 1H), 5.83 (dd, 1H), 7.00 (t, 2H), 1.17 (dd, 2H), 7.68 (d, 2H), 6.78 (d, 2H), 8.75 (s, 1H), RS 9.69 (s, 1H).

1-[1-(4-Cyanophenyl)-3-(4-forfinal)propyl] -1H-imidazole receive the same method, using as starting compounds 1-chloro-1-(4-cyanophenyl)-3-(4-forfinal)propane and sodium derivative 1H-imidazole.

1H NMR spectrum (HCl-salt, MeOH-d4):

2.59-2.80 (m, 4H), 5.72 (m, 1H), 7.00 (t, 2H), 7.19 (dd, 2H), 7.63 (d, 2H), to 7.67 (s, 1H), 7.81 (d, 2H), 7.84 (s, 1H), 9.23 (s, 1H).

Example 5

1-[1-(4-Cyanophenyl)-3-(4-forfinal)propyl]-1H-imidazol

1-[1-(4-Cyanophenyl)-3-(4-forfinal)propyl] -1H-imidazole is obtained by a method described in example 1 using methyl 4-florfenicol as alkylating funds. The product was then purified flash-chromatography.

1-[1-(4-Cyanophenyl)-3-(4-forfinal)propyl]-1,2,4-triazole receive the same manner, using 1-(4-cyanophenyl)-1,2,4-triazole and methyl 4-florfenicol as starting compounds. The product was then purified flash-chromatography.

Example 6

1-[1-(4-Cyanophenyl)-3-(4-forfinal)-1-propenyl]-1H-imidazol

a) 1-[1-(4-Cyanophenyl)-3-(4-forfinal)-2-hydroxypropyl]-1H - imidazol

1-[(4-Cyanophenyl)-3-(4-forfinal)-2-hydroxypropyl]-1H-imidazole is obtained by the method of example 1 using as starting compounds 1-(4-cyanobenzyl)imidazole and 4-perforatewelded. The product was then purified flash-chromatography.

1H NMR spectrum (HCl-salt, MeOH-d4):

2.57-2.70 (m, 1H), 2.75-2.82 (m, 1H), 4.62-4.68 (m, 1H), 5.64-5.66 (m, 1H), 6.97-7.05 (m, 2H), 7.17-7.24 (m, 2H), 7.54-7.85 (m, 6H), 9.16 and 9.21 (2s, together 1H).

b) 1-[(4-cyanophenyl)-3-(4-forfinal)-1-propenyl]-1H-imidazol

1-[1-(4-Cyanophenyl)-3-(4-forfinal)-2-hydroxypropyl] -1H - imidazole dehydration by way of example 3b. The product is a mixture of E - and Z-isomers (1:1). The product was then purified flash-chromatography.

1H NMR spectrum (base, CDCl3):

3.42 and 3.52 (2D, together 2H), 6.16 and 6.50 (2 d, together 1H), 6.91-7.12 (m, 6H), 7.26 and 7.42 (2D, together 2H), 7.55 and 7.59 (2c, together 1H), 7.62 and 7.55 (2D, together 2H).

Example 7

1-[1-(4-Ana. The solution is cooled in an ice bath and to the cooled solution is added dropwise SOCl2(0.16 ml, 2 mmol). The mixture is stirred for 10 minutes Add 1-(4-cyanophenyl)-3-(4-forfinal)-1-propane (0.34 g, 1.3 mmol) and the mixture is stirred for 4 days at room temperature. Add methylene chloride and the mixture is washed with water. The organic layer is dried and the solvent is evaporated. The residue contains 35% of the product (1H NMR) as a mixture (9:1) isomers. The product was then purified flash-chromatography (eluent a mixture of CH2Cl2-MeOH, 99:1).

Isomer b:

1H NMR spectrum (HCl-salt, MeOH-d4):

3.62 (d, 2H), 6.65 (t, 1H), 7.05 (t, 2H), 7.26 (dd, 2H), 7.63 (d, 2H), 7.66 (s, 1H), 7.69 (s, 1H), 7.91 (d, 2H), 9.16 (s, 1H).

Example 8

1-[1-(4-Cyanophenyl)-3-(4-forfinal)-2-propenyl]-1,2,4-triazole

a) 3-(4-cyanophenyl)-1-(4-forfinal)prop-2-EN-1-he

3-(4-Cyanophenyl)-1-(4-forfinal)prop-2-EN-1-it is produced by a method described in example 4a, using 4-cyanobenzaldehyde and 4-fortetienne as starting compounds.

1H NMR spectrum (CDCl3):

7.21 (t, 2H), 7.59 (d, 1H), 7.73 (s, 4H), 7.79 (d, 1H), 8.8 (dd, 2H),

b) 3-(4-cyanophenyl)-1-(4-forfinal)-3-(1-triazolyl)propanone

3-(4-Cyanophenyl)-1-(4-forfinal)prop-2-EN-1-he (2.5 g 10 mmol), 1,2,4-triazole (0.7 g, 10 mmol) and one drop of Triton B TPC is used for the next stage without further purification.

1H NMR spectrum (CDCl3):

3.61 (dd, 1H), 4.37 (dd, 1H), 6.25 (dd, 1H), 7.15 (t, 2H), 7.55 (d, 2H), 7.68 (d, 2H), 7.95 (s, 1H), 7.99 (m, 2H), 8.23 (m, 1H)

c) 1-[1-(4-cyanophenyl)-3-(4-forfinal)-3-hydroxypropyl]-1,2,4 - triazole

1-[1-(4-Cyanophenyl)-3-(4-forfinal)-3-hydroxypropyl]-1,2,4 - triazole is obtained from 3-(4-cyanophenyl)-1-(4-forfinal)-3-(1-triazolyl) propanone by way of example 4c. The product was then purified flash-chromatography as a mixture of diastereoisomers (a+d : b + c, 2:1).

1H NMR spectrum (base, CDCl3):

2.27 - 2.37 and 2.54 - 2.63 (2m, together 1H), 2.76 - 2.88 (m, 1H), 4.26 and 4.41 (DD, together 1H), 5.62 and 5.91 (DD, together 1H), 7.03 and 7.04 (2T, together 2H), 7.22 - 7.31 (m, 2H), 7.50 and 7.55 (2D, together 2H), 7.65 and 7.69 (2D, together 2H), 7.94 8.04 and (2 s, together 1H), 8.05 and 8.22 (2C, together 1H).

The mixture of diastereomers triturated with diethyl ether and filtered. The diastereoisomer a + b is accumulated in the insoluble part (the content above 90%) and the diastereoisomer b + c is accumulated in the filtrate (the content above 80%). Both diastereoisomer purified by recrystallization from toluene.

1H NMR spectrum (HCl-salt, MeOH-d4):

the diastereoisomer a + d:

2.67 (ddd, 1H), 2.84 (dd, 1H), 4.54 (dd, 1H), 6.13 (dd, 1H), 7.04 (t, 2H), 7.33 (dd, 2H), 7.77 (d, 2H), 7.81 (d, 2H), 8.79 (s, 1H), 9.86 (s, 1H).

the diastereoisomer b + c:

2.43 (ddd, 1H), 2.94 (ddd, 1H), 4.33 (dd, 1H), 6.14 (dd, 1H), 7.05 (t, 2H), 7.34 (dd, 2H), 7.66 (d, 2H), 7.75 ((4-forfinal)-3-hydroxypropyl] -1,2,4 - triazole (100 mg) is heated with potassium bisulfate (400 mg) on an oil bath at 140oC for 2 hours. Add methanol and inorganic material is separated by filtration. The methanol is evaporated, receiving the product as a mixture of CIS - and TRANS-isomers.

1H NMR spectrum (base, CDCl3):

6.22 (m, 1H), 6.56 (m) vinyl protons of the CIS isomer 6.47 (d) and 6.81 (DD) vinyl protons of the TRANS-isomer 6.09 and 7.12 (2 g, together 2H), 7.29 - 7.34 (m, 2H), 7.36 and 7.49 (2D, together 2H), 7.69 and 8.02 (2D, together 2H), 8.03 and 8.02 (2 s, together 1H), 8.26 and 8.12 (2 s, together 1H).

Example 9

1-[1-(4-Cyanophenyl)-3-(4-forfinal)-1-propenyl]-1,2,4-triazole

a) 1-[1-(4-Cyanophenyl)-3-(4-forfinal)-2-hydroxypropyl]- 1,2,4-triazole

1-[1-(4-cyanophenyl)-3-(4-forfinal)-2-hydroxypropyl]- 1,2,4-triazole receive according to the method of example 2 using 1-(4-cyanophenyl)-1,2,4-triazole and 4-perforatewelded as starting compounds. The diastereomers of the product share flash-chromatography (eluent: a mixture of ethyl acetate/methanol, 95:5).

1H NMR spectrum (HCl-salt, MeOH-d4):

The diastereoisomer a + d:

2.62 (dd, 1H), 2.72 (dd, 1H), 4.73 (ddd, 1H), 5.73 (d, 1H), 7.00 (t, 2H), 7.19 (dd, 2H), 7.80 (s, 4H), 8.75 (s, 1H), 9.67 (s, 1H).

The diastereoisomer b + c:

2.66 - 2.70 (m, 2H), 4.67 (dt, 1H), 5.70 (d, 1H), 6.98 (t, 2H), 7.15 (dd, 2H), 7.80 (m, 4H), 8.78 (s, 1H), 9.78 (s, 1H).

b) 1-[1-(4-Cyanophenyl)-3-(4-forfinal)-1-propenyl]- 1,2,4-triazole

1-[1-(4-Ciani-(4-forfinal)-2-hydroxypropyl] - 1,2,4-triazole. This method basically get isomer a. The product was then purified flash-chromatography.

1H NMR spectrum (HCl-salt of isomer a, MeOH-d4):

3.47 (d, 2H), 6.97 (t, 1H), 7.04 (t, 2H), 7.26 (dd, 2H), 7.43 (d, 2H), 7.75 (d, 2H), 8.86 (s, 1H), 9.71 (s, 1H)

1H NMR spectrum (HCl-salt of isomer b, MeOH-d4):

3.58 (d, 2H), 6.79 (t, 1H), 7.04 (t, 2H), 7.23 (dd, 2H), 7.62 (d, 2H), 7.90 (d, 2H), at 8.62 (s, 1H), 9.39 (s, 1H).

Example 10

1-[1-(4-Cyanophenyl)-3-(4-forfinal)-2-oxobutyl]-1,2,4-triazole

1-[1-(4-Cyanophenyl)-3-(4-forfinal)-2-oxobutyl] -1,2,4-triazole is obtained by the method described in example 1, using 1-(4-cyanobenzyl)-1,2,4-triazole (1.7 g, 0,0092 mol) of n-Buli EA 0108 mol) and ethyl-3-(4-forfinal)propionate (2.3 g, to 0.0117 mol) was obtained from 4-tortorice acid esterification and hydrogenation. The product was then purified flash-chromatography using a mixture of methylene chloride-methanol (95:5) as eluent.

1H NMR spectrum (base, CDCl3):

2.65 - 2.95 (m, 4H), 6.15 (s, 1H), 6.93 (t, 2H), 7.04 (dd, 2H), 7.37 (d, 2H), 7.67 (d, 2H), 7.97 (s, 1H), 8.18 (s, 1H).

Example 11

2-[1-(4-Cyanophenyl)-3-(4-forfinal)propyl] tetrasil and 1-[1-(4-cyanophenyl)-3-(4-forfinal)propyl]tetrazole

NaH (0.45 g of a 55% suspension in mineral oil) is added to anhydrous DMF under nitrogen atmosphere. Add tetrazol (1.1 g) and the mixture gently arrogant)propane (1,53 g). The reaction mixture was then heated for 6 hours. Add water and the products extracted with ethyl acetate. After drying and evaporation of the solvent the products cleanse flush-chromatography. The elution starting with pure methylene chloride and increase the content of methanol, there are the first 2-[1-(4-cyanophenyl)-3-(4-forfinal)propyl]tetrazole, which has the following1H NMR spectrum:

1H NMR spectrum (base, CDCl3):

2.47 - 5.62 (m, 3H), 2.88 - 3.01 (m, 1H), 5.93 (dd, 1H), 6.96 - 7.10 (m, 4H), 7.51 (d, 2H), 7.67 (d, 2H), 8.57 (s, 1H).

Further elution allocated 1-[1-(4-cyanophenyl)-3-(4-forfinal)propyl]tetrazole, which has the following1H NMR spectrum:

1H NMR spectrum (base, CDCl3):

2.50 - 2.65 (m, 3H), 2.86 - 2.93 (m, 1H), 5.54 (dd, 1H), 6.98 - 7.26 (m, 4H), 7.44 (d, 2H), 7.71 (d, 2H), 8.54 (s, 1H).

Example 12

5-[1-(4-Cyanophenyl)-3-(4-forfinal)propenyl]thiazole

a) 5-[1-(4-cyanophenyl)-3-(4-forfinal)hydroxypropyl]thiazole

5-Bromothiazole (1.66 g, 10 mmol) dissolved in diethyl ether. In nitrogen atmosphere at -60oC very slowly add n-utility (4,85 ml, 2.5 M). After stirring 20 min at -60oC added at the same temperature (4-cyanophenyl)-2-(4-forfinal)ethylketone (2.5 g, 10 mmol) in diethyl ether and peremeshaem it is decomposed with a saturated solution of ammonium chloride. A layer of diethyl ether is separated and the solvent is evaporated. Add water and the product extracted with ethyl acetate. After drying and evaporation of the solvent the residue is mixed with ethanol and the black precipitate was separated by filtration. The ethanol is evaporated and the product purified flash-chromatography (eluent: a mixture of dichloromethane/methanol, 46:1).

1H NMR spectrum (base, CDCl3):

2.33 - 2.40 (m, 1H), 2.52 - 2.67 (m, 2H), 2.68 - 2.83 (m, 1H), 6.96 (t, 2H), 7.061 (dd, 2H), 7.65 (ABquart, 4H), 7.73 (s, 1H), 8.73 (s, 1H).

b) 5-[1-(4-Cyanophenyl)-3-(4-forfinal)-1-propenyl]thiazole

b) 5-[1-(4-Cyanophenyl)-3-(4-forfinal)-1-propenyl] thiazole is obtained by way of example 3b from 5-[1-(4-cyanophenyl)-3-(4-forfinal)-1-hydroxypropyl] thiazole. The product contains mainly isomer a. Isomers share the flash-chromatography (eluent: a mixture of ethyl acetate/methanol, 99:1).

1H Yarm-range (base, CDCl3):

isomer a:

3.35 (d, 2H), 6.67 (t, 1H), 6.70 (t, 2H), 7.03 (dd, 2H), 7.33 (s, 1H), 7.43 (d, 2H), 7.77 (d, 2H), 8.67 (s, 1H)

isomer b:

3.60 (d, 2H), 6.41 (t, 1H), 7.01 (t, 2H), 7.14 (dd, 2H), 7.39 (d, 2H), 7.60 (d, 2H), 7.79 (s, 1H), 8.92 (s, 1H).

1. The compound of formula (I)

< / BR>
where R1represents H or fluorine;

R2represents a heterocyclic radical selected from 1-imidazolyl, triazolyl, tetrazolyl, R4is H, and R3and R5together form a bond; or R3is H, and R4and R5together form = O; R6represents a methylene, ethylene, -CHOH-, -CHOH-CH2-, -CH= CH - or-C(=O)-; or R4is H, and R5and R6together are = CH-,

or their stereoisomers or their non-toxic pharmaceutically acceptable acid salt additive, provided that R6can not be-C(=O)-, when is .

2. Connection on p. 1, in which R3and R4are H, and R5is OH, or R3is OH, and R4and R5is H, and R6is methylene or ethylene; or R3, R4and R5are H and R6is - CHOH - or-CHOH-CH2-; and R1and R2have the meanings given in paragraph 1.

3. Connection on p. 1, where R3and R4are H, and R5represents OH, R6represents methylene or ethylene, or R3, R4and R5represent H; R6is a-CHOH - or-CHOH-CH2-, and R1and R2have the meanings given in paragraph 1.

4. Connection on p. 1, where R4Is H and R3and R5together form a bond and R4are H and R5and R6together form =CH-; or R3, R4and R5together represent H and R6- -CH=CH - or-C(=O)-; R1and R2have the meanings given in paragraph 1.

5. The compound according to any one of paragraphs.1 to 4, where R2chosen from 1 imidazolyl, triazolyl, tetrazolyl and thiazolyl.

6. Connection on p. 5, where R2chosen from 1 imidazolyl, 1-(1,2,4-triazolyl), 1 - or 2-tetrazolyl and 5-thiazolyl.

7. Connection on p. 1, which is 1-[1-(4-cyanophenyl)-4-(4-forfinal)butyl] -1H-imidazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid.

8. Connection on p. 1, which is 1-[1-(4-cyanophenyl)-4-(4-forfinal)-2-hydroxybutyl] -1H-imidazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid.

9. Connection on p. 1, which is 1-[1-(4-cyanophenyl)-4-(4-forfinal)-1-butenyl] -1,2,4-triazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid.

10. Connection on p. 1, which is 1-[1-(4-cyanophenyl)-3-(4-forfinal)-2-hydroxypropyl]-1,2,4-triazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid.

11. With the leader or a non-toxic pharmaceutically suitable salt with an acid.

12. Connection on p. 1, which is 1-[1-(4-cyanophenyl)-3-(4-forfinal)-3-hydroxypropyl]-1,2,4-triazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid.

13. Connection on p. 1, which is 1-[1-(4-cyanophenyl)-4-(4-forfinal)-2-oxobutyl] -1,2,3-triazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid.

14. Connection on p. 1, which is 1-[1-(4-cyanophenyl)-3-(4-forfinal)-1-propenyl] -1,2,4-triazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid.

15. Connection on p. 1 which is 5-[1-(4-cyanophenyl)-3-(4-forfinal)-1-hydroxypropyl] thiazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid.

16. Connection on p. 1, which is 1-[1-(4-cyanophenyl)-3-(4-forfinal)propyl] tetrazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid.

17. Connection on p. 1, which is 2-[1-(4-cyanophenyl)-3-(4-forfinal)propyl] tetrazole, its stereoisomer or a non-toxic pharmaceutically suitable salt with an acid.

18. Compounds according to any one of paragraphs.1 - 17 to obtain a pharmaceutical composition, ingibirujut is in the medium characterized in that as an active means it contains a compound according to any one of paragraphs.1 - 17 in an effective amount.

20. Method of inhibiting aromatase by introducing the subject of active means, characterized in that as an active means of introducing the compound according to any one of paragraphs.1 - 17 in an effective amount.

21. The method of obtaining the compounds of formula

< / BR>
where R1represents H or fluorine;

R2represents a heterocyclic radical selected from 1-imidazolyl, triazolyl, tetrazolyl, thiazolyl;

n = 1 or 2

or its stereoisomer or a non-toxic pharmaceutically acceptable acid salt additive, characterized in that it includes the interaction of the compounds of formula

< / BR>
where R2defined above,

complex ester

< / BR>
where R' represents lower alkyl,

in the presence of a strong base to obtain compound

< / BR>
where R1, R2defined above;

n = 1 or 2

subsequent reduction of the obtained compound and obtaining the compounds of formula

< / BR>
where R1, R2and n are defined above.

 

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The invention relates to the synthesis of heterocyclic compounds, and in particular to an improved process for the preparation of substituted 1(2)-benzyl-5-R-tetrazoles General formula I

Rwhere(A)< / BR>
R = phenyl, R1= A, R = 4-OCH3-phenyl, R1= A;

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R = 4-pyridyl, R1= A; R = 4-Cl-phenyl, R1= A;

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