New phenol derivatives and their pharmaceutical or cosmetic application

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula (I), which can be used for treating diseases mediated by an androgen receptor. In formula (I), R1 means (C2-6)alkyl, (C1-6)alkyloxy, -S(O)m-(C1-6)alkyl, (C1-6)fluoroalkyl, CN or halogen, R2 and R3 are identical or different and mean a hydrogen atom or (C1-9)alkyl, R4, R5, R6, R7 are identical or different and mean a hydrogen or halogen, X means CH or N, Y means either a nitrogen atom, or a carbon atom substituted by (C1-6)alkyl, (C1-6)alkyloxy, (C1-6)fluoroalkyl, a hydrogen atom or halogen; m is equal to 0, 1 or 2.

EFFECT: invention refers to using the compounds for preparing a therapeutic agent for preventing and/or treating hirsutism, androgenetic alopecia, hypertrichosis, atopic dermatitis, disordered sebaceous gland, such as hyperseborrhea, acne, greasy skin or seborrheic dermatitis.

8 cl, 2 tbl, 26 ex

 

The object of the present invention are new compounds of General formula:

and their cosmetic or pharmaceutical application.

The present invention offers a new phenolic derivatives, which are potent modulators of the androgen receptor.

From the documents of the prior art describing molecules, modulating the activity of androgen receptor can be, for example, to call phenylimidazoline described in patent application EP 580459 or in the application WO 200542464.

The object of the invention are new phenolic derivatives, which correspond to the following General formula (I):

in which:

- R1means (C2-6)alkyl, (C3-7)cycloalkyl, (C1-6)alkyloxy, -S(O)m-(C1-6)alkyl, (C1-6)foralkyl, (C1-6)peralkaline, -(CH2)n-(C3-9)cycloalkyl, -(CH2)n-(C3-9)cycloalkyl, (C2-6)alkyl-OH, -(CH2)n-(C1-6)alkyloxy, -(CH2)n-(C1-6)foralkyl, -(CH2)p-O-(C1-6)foralkyl, CORa, CN, NO2, NR8R9, halogen, phenyl or heteroaryl group containing either a) from 1 to 4 nitrogen atoms, or (b) an atom of oxygen or sulfur and 1 or 2 nitrogen atom. These phenyl and heteroaryl groups can be substituted one-Proc. of the two groups R bthe same or different,

- R2and R3are identical or different and denote a hydrogen atom or (C1-9)alkyl, (C3-9)cycloalkyl, (C1-6)foralkyl, -(CH2)r-(C3-9)cycloalkyl, (C2-6)alkyl-OH, -(CH2)r-(C1-6)alkyloxy, -(CH2)r-(C3-7)cycloalkyl, -(CH2)r-(C1-6)foralkyl, -(CH2)q-O-(C1-6)foralkyl.

Perhaps the group R2and R3may form with the carbon atom to which they relate, (C3-9)cycloalkyl or a heterocycle, such as tetrahydrofuran, tetrahydropyran, tetrahydrothiopyran, tetrahydro-1-existieren or tetrahydro-1,1-dioxythiophene.

- R4, R5, R6, R7are the same or different and represent either a hydrogen atom, or (C1-6)alkyl, (C3-7)cycloalkyl, (C1-6)alkyloxy, -S(O)s-(C1-6)alkyl, (C1-6)foralkyl, (C1-6)peralkaline, -(CH2)t-(C3-9)cycloalkyl, -(CH2)t-(C3-9)cycloalkyl, (C1-6)alkyl-OH, -(CH2)t-(C1-6)alkyloxy, -(CH2)t-(C1-6)foralkyl, -(CH2)u-O-(C1-6)foralkyl, CORd, CN, NR8'R9'or halogen, or phenyl or heteroaryl group containing either a) from 1 to 4 nitrogen atoms, or (b) the oxygen atom ilitary and 1 or 2 nitrogen atom. These phenyl and heteroaryl groups can be substituted one to three groups Rcthe same or different,

X denotes CH or N,

- Y represents either a nitrogen atom or a carbon atom substituted (C1-6)alkyl, (C3-7)cycloalkyl, (C1-6)alkyloxy, -S(O)v-(C1-6)alkyl, (C1-6)perakyla, (C1-6)peralkaline, -(CH2)l-(C3-9)cycloalkyl, -(CH2)l-(C3-9)cycloalkyl, (C1-66)alkyl-OH, -(CH2)l-(C1-6)alkyloxy, -(CH2)l-(C1-6)perakyla, -(CH2)w-O-(C1-6)perakyla, CORe, CN, NR10R11, NO2the atom of hydrogen or halogen, or phenyl or heteroaryl group containing either a) from 1 to 4 nitrogen atoms, or (b) an atom of oxygen or sulfur and 1 or 2 nitrogen atom. These phenyl and heteroaryl groups can be substituted one to three groups Rbthe same or different,

- Ra, Rdand Reare identical or different and denote (C1-6)alkyl, (C1-6)alkyloxy or NR12R13,

- Rband Rcare identical or different and denote halogen, (C1-6)alkyl, (C3-7)cycloalkyl, (C1-6)alkyloxy, -S(O)j-(C1-6)alkyl, (C1-6)foralkyl, (C1-6)peralkaline, -(CH2)i-(C3-7)the CEC shall alkyl, OH, -(CH2)i-(C3-7)cycloalkyl, (C1-6)alkyl-OH, -(CH2)i-(C1-6)alkyloxy, -(CH2)i-(C1-6)foralkyl, -(CH2)z-O-(C1-6)foralkyl, CORaCN or NR14R15,

- R8and R8'are identical or different and denote (C1-6)alkyl, (C3-7)cycloalkyl, -(CH2)f-(C3-7)cycloalkyl or -(CH2)f-(C1-6)foralkyl.

- R9, R9', R10, R11, R12, R13, R14and R15are identical or different and denote a hydrogen atom, (C1-6)alkyl, (C3-7)cycloalkyl, -(CH2)g-(C3-7)cycloalkyl or -(CH2)g-(C1-6)foralkyl.

Perhaps the group R8and R9can form with the nitrogen atom to which they are bound, a heterocycle, such as azetidin, pyrolidine, piperidine, ASEAN, morpholine or piperazine. Perhaps the group R8'and R9'can form with the nitrogen atom to which they are bound, a heterocycle, such as azetidin, pyrolidine, piperidine, ASEAN, morpholine or piperazine. Perhaps the group R10and R11can form with the nitrogen atom to which they are bound, a heterocycle, such as azetidin, pyrolidine, piperidine, ASEAN, morpholine or piperazine. Perhaps the group R12and R13can form with the nitrogen atom to which they relate, a heterocycle, such as azetidin, pyrolidine, piperidine, ASEAN, morpholine or piperazine. Perhaps the group R14and R15can form with the nitrogen atom to which they are bound, a heterocycle, such as: azetidin, pyrolidine, piperidine, ASEAN, morpholine or piperazine.

- f, g, i, l, n, r and t are the same or different and is 1, 2 or 3,

- j, m, s and v are the same or different and is 0, 1 or 2,

- p, q, u, w and z are the same or different and equal to 2, 3 or 4,

as well as their pharmaceutically acceptable salt, solvate or hydrate and their conformers or rotamer.

The compounds of formula (I) may contain one or more asymmetric carbon atoms. Therefore, they can be in the form of mixtures of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as mixtures thereof, including racemic mixtures, belong to the invention.

The compounds of formula (I) can be in the form of bases or of salts of joining with acids. Such salts are joining to the invention. These salts are mainly obtained using pharmaceutically acceptable acids but the salts of other acids that are suitable, for example, for the purification or separation of compounds of formula (I), also belong to the invention. These acids can for example be a picric acid, axalingua acid or optically active CIS the GTC, for example, tartaric acid, dibenzoyltartaric acid, almond acid or campuslevel acid and such, which form physiologically acceptable salts such as hydrochloride, Bromhead, sulfate, hydrogensulfate, dihydrogenphosphate, maleate, fumarate, 2-naphthalenesulfonate, paratoluenesulfonyl. For an overview fiziologicheskii acceptable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use de Stahl et Wermuth (Wiley-VCH, 2002).

A solvate or hydrate can be obtained directly at the output of the synthesis method, the compound (I) is isolated in the form of a hydrate, for example, mono-or hemihydrate or MES solvent reaction or purification.

In the framework of the invention understand:

- Cb-cwhere b and C can take values from 1 to 9, carbon chain containing from b to C carbon atoms, for example With1-6-carbon chain that may contain from 1 to 6 carbon atoms,

- alkyl - aliphatic group, saturated linear or branched, for example (C1-6)alkyl means a carbon chain containing from 1 to 6 carbon atoms, linear or branched, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, hexyl,

- cycloalkyl - carbon chain, saturated cyclic, possibly branched, containing from 3 to 7 carbon atoms. As example (C3-7)cyclol the l means a carbon chain, containing from 3 to 7 carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl,

- heterocycle - hydrocarbon chain, cyclic or bicyclic, saturated or unsaturated, containing one or more heteroatoms selected from O, S and N,

- heteroaryl - aromatic heterocycle, preferably, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, pyrazolyl, isooxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, triazolyl or imidazolyl,

the halogen atom is fluorine, chlorine or bromine,

- alkyloxy - O-alkyl,

- alkylthio - -S-alkyl,

- coralcola - alkyl, one or more hydrogen atoms of which have been replaced by fluorine atom,

- peralkylated - alkyloxy, one or more hydrogen atoms of which have been replaced by fluorine atom.

Preferred is the group (A) compounds of the formula (I) defined above, in which:

- X represents CH and Y represents a carbon atom, is substituted by one group, such as defined above, and preferably methyl groups, ethyl, ISO-propyl, cyclopropenes, CF3, CONH2, CO2CH3, CO2CH2CH3, CN, NO2, SCH3, SCH2CH3the atom of hydrogen, halogen, OCF3, OCH3, OCH2CH3or och(CH3)2.

Group (B) compounds of formula (I),the substituents are X and Y defined above or in the preferred group (A), such that the group R1denotes halogen, ethyl, isopropyl, trifluoromethyl, nitrile, nitro, methoxy, ethoxy, isopropoxy, thiomethyl, thioethyl or diisopropyl, is a group of preferred compounds and more specifically such that R1denotes halogen, methoxy, ethoxy, thiomethyl, thioethyl or trifluoromethyl.

The following compounds and their pharmaceutically acceptable salt, solvate and hydrate and conform or rotamer are the most preferred:

2-[(6-methoxypyridine-2-ylamino)methyl]phenol,

2-[(6-bromopyridin-2-ylamino)methyl]phenol,

2-[(6-bromopyridin-2-ylamino)methyl]-4-terfenol,

6-(2-hydroxyethylamino)pyridine-2-carbonitrile,

2-[1-(6-methoxypyridine-2-ylamino)ethyl]phenol,

2-[(6-triptorelin-2-ylamino)methyl]phenol,

2-[(6-chloropyridin-2-ylamino)methyl]phenol,

2-[(6-ethylpyridine-2-ylamino)methyl]phenol,

2-[(6-ethoxypyridine-2-ylamino)methyl]phenol,

2-[(6-isopropoxypyridine-2-ylamino)methyl]phenol,

5-chloro-2-[(6-methoxypyridine-2-ylamino)methyl]phenol,

2-[(2-cryptomaterial-4-ylamino)methyl]phenol,

2-[(6-bromopyrazine-2-ylamino)methyl]phenol,

2-[(2-chloropyrimidine-4-ylamino)methyl]phenol,

2-[(2-bromopyrimidine-4-ylamino)methyl]phenol,

2-[(2-chloro-6-methylpyrimidin-4-ylamino)methyl]phenol,

2-[(6-chloro-4-triptorelin-2-ylamino)methyl]phenol,

2-[(6-chloro-4-methylpyridin-2-yl) - Rev. Ino)methyl]phenol,

2-[(6-methoxypyrazine-2-ylamino)methyl]phenol,

2-[(2-methoxypyridine-4-ylamino)methyl]phenol,

2-[(2-methoxy-6-methylpyrimidin-4-ylamino)methyl]phenol,

2-[(6-methylsulfinylphenyl-2-ylamino)methyl]phenol,

2-[(6-methanesulfonamido-2-ylamino)methyl]phenol,

2-[(6-methanesulfonamido-2-ylamino)methyl]phenol,

2-[(6-methoxypyridine-2-ylamino)methyl]-6-METHYLPHENOL,

2-[(4-bromo-6-methoxypyridine-2-ylamino)methyl]phenol,

2-[(6-bromo-2-methoxypyridine-4-ylamino)methyl]phenol,

2-[(4-chloro-6-methoxypyridine-2-ylamino)methyl]phenol,

2-[(6-bromo-2-methoxypyridine-4-ylamino)methyl]phenol,

2-[(4-bromo-6-methoxypyridine-2-ylamino)methyl]-6-terfenol,

2-[(4-bromo-6-methoxypyridine-2-ylamino)methyl]-5-terfenol,

2-[(4-bromo-6-methoxypyridine-2-ylamino)methyl]-3-terfenol,

2-[(4-bromo-6-methoxypyridine-2-ylamino)methyl]-4-terfenol,

2-[(6-bromo-2-methoxypyridine-4-ylamino)methyl]-4-terfenol,

2-[(4-chloro-6-methoxypyridine-2-ylamino)methyl]-4-terfenol,

2-[(6-chloro-2-methoxypyridine-4-ylamino)methyl]-4-terfenol,

2-[1-(4-bromo-6-methoxypyridine-2-ylamino)ethyl]phenol,

2-[1-(4-bromo-6-methoxypyridine-2-ylamino)propyl]phenol,

2-[1-(6-bromo-4-methylpyridin-2-ylamino)-1-methylethyl]phenol,

2-[1-(4-bromo-6-methoxypyridine-2-ylamino)propyl]-4-terfenol,

2-[1-(6-bromopyridin-2-ylamino)propyl]-4-terfenol,

4-fluoro-2-[(6-methoxypyridine-2-ylamino)methyl]phenol,

4-fluoro-2-[1-(6-m is oxypyridine-2-ylamino)ethyl]phenol,

4-fluoro-2-[1-(6-methoxypyridine-2-ylamino)propyl]phenol,

2-[(6-bromo-4-methoxypyridine-2-ylamino)methyl]phenol,

2-[(6-bromo-4-methylpyridin-2-ylamino)methyl]phenol,

2-[(6-chloro-4-methoxypyridine-2-ylamino)methyl]phenol.

The object of the invention is also a method of obtaining compounds of General formula (I).

According to the invention can be obtained the compounds of formula (I) in one of three ways, described in the following Scheme 1, and maybe add one or more reactions, such as described in Scheme 2.

Scheme 1

Phenolic compounds of formula (I) in which R1, R2, R3, R4, R5, R6, R7,X and Y are as described above, can be obtained reducing amination reaction between the aldehyde or benzyl ketone (II) and the amine (III) in the presence of a reductive agent such as, for example and without limitation, triacetoxyborohydride sodium Method 1A, which illustrates scheme 1 and in analogy, for example, by the reactions described in Org.Pro.R & D (2006) 971-1031.

Phenolic compounds of formula (I) can be obtained by the interaction between the heterocycles (V) containing a leaving group and amines of the benzene, in the presence of a base such as, without limitation, 1,8-diazabicyclo[5.4.0]undec-7-ene, for example, will dissolve in the Le of this, as dimethyl sulfoxide, and such as described in Method 1b according to Scheme 1. Under the leaving group see group, well known to the specialist, such as, without limitation, halogen, mesilate, toilet or triplet.

The third way to obtain phenolic compounds of formula (I) is to restore the amide intermediate compound (VII) with a reagent of the donor-hydrides, such as, without limitation, lithium hydride and aluminum, as shown in Method 1C according to Scheme 1. These amide derivatives can be obtained by the interaction between, for example, without limitation, acylchlorides (VI) and the amine (III) in pyridine. Acylchlorides (VI) derived from acid technology, well known to the specialist, for example, by boiling under reflux in thionyl chloride.

Some compounds containing sulfoximine (X) or sulfonic group (XI) may receive the oxidation of the intermediate simple tiefer (IX), such as described in Scheme 2 way 2A. The oxidation can, for example and without limitation, to carry out in the ozone. The intermediate connection of a simple tiefer (IX) can be obtained from the compounds (VIII) containing a leaving group such as, without limitation, a chlorine atom, by interacting with tialata in dimethyl sulfoxide. Some compounds containing the group of simple ether may be obtained by interaction between the intermediate compound (VIII) the appropriate alcohol such for example and without limitation as methanol, in the presence of a base such as sodium hydroxide, perhaps when heated in a microwave oven and as described in Scheme 2 way 2b.

Scheme 2

Functional groups may be present in the reactive intermediate compounds used in the method, can be protected either permanently or temporarily protective groups, which provide an unambiguous synthesis of the target compounds. Reactions protect and unprotect conduct a well-known specialist of ways. Under the temporary protecting group of amines, alcohols or carboxylic acids see protective groups, such as those described in “Protective Groups in Organic Chemistry”, ed McOmie J. W. F., Plenum Press, 1973, in “Protective Groups in Organic Synthesis”, 2nd edition, Greene T. W. and Wuts P. G. M., ed John Wiley et Sons, 1991, and in “Protecting Groups, Kocienski P. J., 1994, Georg Thieme Verlag.

The products, which is the object of the present invention have interesting pharmacological properties; in particular, it was noted that they modulate the activity of the androgen receptor.

The tests listed in the experimental part, illustrate this modulating the activity of androgen receptor. Products, which are the objects of the present invention have activity antagonism or agonism, full or partial. This activity allows ispolzovaniya according to the invention as drugs in medicine or veterinary medicine.

These properties make the products of General formula (I) according to the present invention is suitable as pharmaceuticals for the treatment of hormone-dependent cancers, such as prostate cancer or breast cancer, as well as for the treatment of benign hyperplasia of prostate cancer, early puberty, virilization, polycystic ovary syndrome, syndrome Stein-Leventhal, decreased libido, endometriosis. Compounds with activity of partial or complete agonism, can in particular be used for the treatment of diseases such as reduction of muscle mass (sarcopenia), muscle atrophy, impotence and male infertility, abnormal male differentiation (hermaphroditism), hypogonadism, osteoporosis.

The products of General formula (I) according to the invention also have a cosmetic use for hygiene or hair.

The products of General formula (I) according to the invention are also used in the treatment of hirsutism, acne, seborrhea, oily skin androgenic alopecia, hypertrichosis or hirsutism, they can also be used for getting medicines for the prevention and/or treatment of hirsutism, androgenic alopecia, hypertrichosis, atopic dermatitis, disorders of the sebaceous glands, such as Hyperborea, acne, oily skin or seborrheic dermatitis. The products of formula (I) can, thus, is to use in dermatology: they can be used individually or in combination. They can in particular be combined with antibiotics, such as derivatives, azelaic, guidikova acid, erythromycin or derivatives of retinoids, such as tretinoin, acne treatment, or with the inhibitor of 5A-reductase, such as (5-alpha, 17-beta)-N-1,1-dimethylethyl-3-oxo-4-Asandros-1-ene-17 carboxamid (or Finasteride Merck, 13 edition) or azelaic acid, or with an agent that blocks androgen receptors, for the treatment of acne, alopecia or hirsutism, or product to promote hair growth, such as Minoxidil for the treatment of alopecia.

The object of the present invention are also the compounds of formula (I) as a drug, such as described above, and their pharmaceutically acceptable salts, pharmaceutically acceptable solvate and/or hydrate.

As an illustration and without limitation, some examples of active compounds of the formula (I) below, and the results of the biological activity of such compounds.

PROCEDURE EXPERIENCE

Example 1: 2-[(6-methoxypyridine-2-ylamine)methyl]phenol

The synthesis according to Scheme 1, Method 1A

512 mg (2,41 mmole, 1,5 EC) triacetoxyborohydride sodium added to a solution of 200 mg (1,61 mmole, 1 EQ) of 6-methoxypyridine-2-ylamine (original product 1), 236 mg (2,41 mmole, 1 EQ) 2-hydroxybenzaldehyde (original product 2) in 20 ml of tetrahydrofuran. Rest the R was stirred at room temperature for 48 hours. It is evaporated and the residue treated with 100 ml of dichloromethane, and then extracted with saturated aqueous ammonium chloride. The aqueous phase is twice extracted with dichloromethane. The combined organic phases are dried over sodium sulfate. The residue is subjected to chromatography on silica gel (ethyl acetate/heptane 5/95). 2-[(6-methoxypyridine-2-ylamine)methyl]phenol obtained in the form of a white solid.

Melting point = 103°C.

1H NMR (CDCl3): of 3.94 (s, 3H); to 4.52 (d, 2H, J=is 3.08 Hz); 4,95 (s, 1H), 6,03 (DD, 2H, J=6.2 Hz, J'=1,64 Hz); 6,85 (t, 1H, J=6,28 Hz, J'=7,4 Hz); to 6.95 (d, 1H, J=9,04 Hz); 7,15-of 7.23 (m, 2H); of 7.36 (t, 1H, J=a 7.92 Hz, J'=of 7.96 Hz); of 10.21 (s, 1H).

Obtaining an intermediate compound 6 aminopyridine-2-carbonitrile

340 mg (2,89 mmole, 1 EQ) cyanide zinc administered 500 mg (2,89 mmole, 1 EQ) of 6-bromopyridin-2-ylamine in 10 ml of dimethylformamide in a microwave tube. Enter 170 mg (0,147 mmole, 0,05 EC) tetrakis(triphenylphosphine)palladium. The medium is heated to 170°C for 1 hour and 30 minutes in a microwave oven. Add 50 ml of ethyl acetate in the environment that filtered through celite. The filtrate is washed with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate. The residue is triturated in heptane. 6-aminopyridine-2-carbonitrile receive in the form of a solid orange color.

Melting point = 92°C.

The intermediate compound 6-ethoxypyridine-2-ylamine

Mikrovolnovaya tube injected 500mg (2,89 mmole) of 2-amine-6-bromopyridine, to which is added 2 ml of ethanol, and 231 mg (5.78 mmole, 2 EQ) of sodium hydroxide. The mixture is heated for 10 hours in a microwave oven to 170°C. the Reaction medium is diluted with 50 ml dichloromethane, then washed with twice 50 ml of water. The organic phase is concentrated to dryness and the residue purified by chromatography on silica using as eluent heptane/ethyl acetate (1/1). Get the target product as a colorless oil.

The intermediate compound 6-isopropoxypyridine-2-ylamine

This intermediate connection receive in accordance with the order of receipt, as described in relation to 6-ethoxypyridine-2-ylamine, replacing the ethanol isopropanol. Get the target product as a colorless oil.

Examples 2-12

Examples 2-12 are described below in table 1. Compounds synthesized according to the procedure of obtaining described above, replacing the original products 1 and 2, referred to in example 1, the products listed in table 1.

Table 1
ExampleThe IUPAC nameThe initial product 1The original product 2Melting point (°C)1H NMR 400 MHz (s=singlet, d=doublet, t=triplet, multiplet, kV=quadruplet, J=constant interaction in Hz
22-[6-bromopyridin-2-ylamine)methyl]
phenol
6-bromopyridin-2-ylamine2-hydroxybenzaldehyde127(CDCl3) 4,48 (d, 2H, J=4,28 Hz); 5.17 to (s, 1H); 6,35(d, 1H, J=8.7 Hz); 6,77 (d, 1H, J=7,3 Hz); 6.87 in (t, 1H, J=7.4 Hz);
to 7.0 (d, 1H, J=9.1 Hz); 7,16-7,27 (m, 3H); 9,84 (s, 1H)
32-[6-bromopyridin-2-ylamine)methyl]-4-terfenol6-bromopyridin-2-ylamine5-fluoro-2-hydroxybenzaldehyde143(DMSO) 4,32 (d, 2H, J=6 Hz); and 6.5 (d, 1H, J=8,2 Hz); of 6.65 (d, 1H, J=7.4 Hz); 6,77-for 6.81 (m, 1H); 6,85-to 6.95 (m, 2H); and 7.3 (t, 1H, J=8,2 Hz); 7,32-7,35 (m, 1H); 9,59 (s, 1H)
46-(2-hydroxybenzyl-Amin)pyridine-2-carbonitrile6-aminopyridine-2-carbonitrile2-hydroxybenzaldehyde153(DMSO) 4,36 (d, 2H,J=4,8 Hz); 6.73 x (t, 1H, J=7.4 Hz); for 6.81-6,84 (m, 2H);
? 7.04 baby mortality-was 7.08 (m, 2H); 7,14 (d, 1H, J=7.4 Hz); 7,46-rate of 7.54 (m, 2H); a 9.60 (s, 1H)
52-[1-6-methoxypyridine-2-ylamine)ethyl]
phenol
6-methoxypyridine-2-ylamine109(DMSO) to 1.35 (d, 3H, J=6.8 Hz); 3,66 (s, 3H);5,13-5,16 (m, 1H); 5,79 (d, 1H, J=7,7 Hz); 5,94 (d, 1H, J=7.8 Hz); 6,7 (t, 1H, J=7,3 Hz); 6,77 (t, 2H, J=8,2 Hz); 6,97 (t, 1H, J=7,6 Hz); 7,20-7,24 (m, 2H); 9,42 (s, 1H)
62-[(6-
triptorelin-2-ylamine)methyl]
phenol
2-amino-6-
(trifluoromethyl)pyridine
2-
hydroxybenzaldehyde
125(DMSO) to 4.38 (d,
2H, J=5.4 Hz); of 6.71-PC 6.82 (m, 3H); to 6.88 (d, 1H, J=7.2 Hz); 7,06 (t, 1H, J=7,6 Hz); 7,19 (d, 1H, J=7.4 Hz); 7,37-7,40 (m, 1H); 7,56 (t, 1H, J=7.8 Hz); of 9.56 (s, 1H)
72-[(6-chloropyridin-2-ylamine)-methyl]phenol2-amino-6-chloropyridin2-hydroxybenzaldehydenot defined(DMSO) 4,34 (d, 1H, J=5.8 Hz); 6,45-6,50 (m, 2H); 6,72-6,76 (m, 2H); for 6.81 (d, 1H, J=8 Hz); 7,06 (t, 1H, J=7,6 Hz); to 7.15 (d, 1H, J=7.4 Hz);
7,26-7,29 (m, 1H); 7,38 (t, 1H, J=7.5 Hz); to 9.57 (s, 1H)
82-[(6-ethylpyridine-2-ylamine)methyl]
phenol
6-ethylpyridine-2-ylamine2-hydroxybenzaldehydenot defined(DMSO) to 1.2 (t, 3H, J=7,6 Hz); 2,54-2,60 (q, 2H, J=7.5 Hz); or 4.31 (d, 2H, J=6,12 Hz); 6,33-6,38 (who, 2H); 6,72-of 6.78 (m, 2H); 7,06 for 7.12 (m, 2H); 7.18 in (d, 1H, J=7.4 Hz); and 7.3 (t, 1H, J=7.5 Hz); 10,88 (s, 1H)
92-[(6-taxiride-2-
ylamine)methyl]
phenol
2-amine-6-ethoxypyridine2-hydroxybenzaldehyde87(CD3OD) of 1.35 (t, 3H, J=7.0 Hz);
3,31-to 3.33 (q, 2H, J=7.0 Hz); was 4.42 (s, 2H); 5,91-to 5.93 (m, 1H); 6,05 (d, 1H, J=7.8 Hz); 6,75-to 6.80 (m, 2H); 7,05-7,10 (m, 1H);7,19-7,22 (m, 1H); 7.29 trend-7,33 (m, 1H)
102-[(6-isopropoxy-ridin-2-ylamine)methyl]
phenol
2-amine-6-isopropoxypyridine2-hydroxybenzaldehydenot defined(CD3OD) of 1.26 (t, 6H, J=6,1 Hz); 4,43 (s, 2H); 5,03-5,09 (m, 1H); 5,88-5,90 (m, 1H); 6,02-6,04 (m, 1H); 6,74-6,79 (m, 2H);? 7.04 baby mortality-was 7.08 (m, 1H);
7,19-7,21 (m, 1H); and 7.3 (t, 1H, J=7.9 Hz)
115-chloro-2-[(6-methoxypyridine-2-ylamine)methyl]
phenol
6-methoxypyridine-2-ylamine4-chloro-2-hydroxybenzaldehydenot defined(DMSO) and 3.72 (s, 3H); 4,39 (d, 2H, J=5,9 Hz); 5,86 (d, 1H, J=7.8 Hz); 6,03 (d, 1H, J=7.9 Hz); 6,7 (m, 1H); 6.8 cm (s, 1H); 6,93 (m, 1H); 7,21 (d, 1H, J=8,4 Hz); 7,28 (t, 1H, J=7.8 Hz); 9,73 (s, 1H)
122-[(2-Tr is formattype-rimidine-4-
ylamine)methyl]
phenol
2-cryptomaterial-4-
ylamine
2-hydroxybenzaldehyde201(DMSO) 4,34-4,47 (m, 2H); 6,55-6,85 (m, 3H); 7,1 (t,
1H, J=7.4 Hz); 7,19 (d, 1H, J=7,3 Hz); 8,15 (d, 1H, J=5,9 Hz); 8,39-of 8.47 (m, 1H); 9,63 (s, 1H)

Example 13: 2-[(6-bromopyrazine-2-ylamine)methyl]phenol

The synthesis according to scheme 1, Method 1b

In a flask of 50 ml volume injected 1 g (4.2 mmole) of 2,6-dibromopyridine (original product 3), to which is added 15 ml of dimethyl sulfoxide, 638 mg (4.2 mmole, 1 EQ) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 1.03 g (8.4 mmole, 2 EQ) of 2-hydroxyethylamine (original product 4), stirred for 2 hours at room temperature. The reaction medium is diluted with 50 ml ethyl acetate, washed with 50 ml of saturated solution of ammonium chloride, then twice with 50 ml water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness.

The residue is purified by chromatography on silica using as eluent a mixture of heptane/ethyl acetate(8/2). 2-[(6-bromopyrazine-2-ylamine)methyl]phenol obtained as a white solid.

Melting point = 168°C.

1H NMR (DMSO): 4,36 (d, 1H, J=5.3 Hz); 6,74-6,76 (m, 1H); 6,83 (DD, 1H); 7,07-7,11 (m, 1H); 7,17 (DD, 1H); of 7.75 (s, 1H); 7,80-7,83 (m, 1H); of 7.96 (s, 1H); being 9.61 (s, 1H).

Examples 14-18

Examples 14-18 are described below in table 2. Compounds synthesized in accordance with then DCOM obtain, described above, replacing the original products 3 and 4, referred to in example 13, the products listed in table 2.

Table 2
ExampleThe IUPAC nameThe original product 3The original product 4Melting point (°C)1H NMR 400 MHz (s=singlet, d=doublet, t=triplet, m=multiplet, q=quadruplet, J=constant interaction in Hz
142-[(2-chloropyrimidine-4-ylamine)methyl]phenol2,4-dichloropyrimidine2-hydroxybenzyl-
Amin
not defined(CD3OD) a 4.53 (m, 2H); of 6.45 (d, 1H, J=6.0 Hz); 6,78-6,83 (m, 2H); 7,10-7,14 (m, 1H); 7,22 (d, 1H,
J=6.9 Hz); 7,83 (m, 1H)
152-[(2-bromopyrimidine-4-ylamine)methyl]phenol2,4-dibromopyridine2-hydroxybenzyl-
Amin
not defined(CD3OD) 4,42-to 4.52 (m, 2H); 6.48 in (d, 1H, J=6.0 Hz); 6,78-6,83 (m, 2H); for 7.12 (t, 1H, J=8,2 Hz); 7,21-of 7.23 (m, 1H); 7,76-7,86 (m, 1H)
162-[(2-x is the PR-6-methylpyrimidin-4-ylamine)methyl]phenol 2,4-dichloro-6-methylpyrimidin2-hydroxybenzyl-
Amin
not defined(DMSO) 2,17 (s, 3H); however, 4.40 (s, 2H); 6,35 (s, 1H); 6,74 (t, 1H, J=7.4 Hz);
PC 6.82 (d, 1H, J=7.9 Hz); 7,06 for 7.12 (m, 2H); 8,04 (s, 1H); 9,60 (s, 1H)
172-[(6-chloro-4-triptorelin-2-ylamine)methyl]phenol2,6-dichloro-4-triptorelin2-hydroxybenzyl-
Amin
not defined(DMSO) 4,39 (d, 2H, J=5.4 Hz); 6.73 x-6,84 (m, 4H); 7,080 (t, 1H, J=7,6 Hz); 7,17 (d, 1H, J=7.4 Hz); 7,83 (s, 1H); being 9.61 (s, 1H)
182-[(6-chloro-4-methylpyridin-2-
ylamine)methyl]phenol
2,6-dichloro-4-methylpyridin2-hydroxybenzyl-
Amin
138(DMSO) a 2.12 (s, 3H); 4,32 (l,
2H, J=5.5 Hz); 6,28 (s, 1H); 6,37 (s, 1H); 6.73 x (t, 1H, J=7.4 Hz); 6.8 cm (d, 1H, J=8 Hz);? 7.04 baby mortality (t, 1H, 7.7 Hz); 7,12-7,17 (m, 2H); 9,58 (s, 1H)

Example 19: 2-[(6-methoxypyrazine-2-ylamine)methyl]phenol

The synthesis according to scheme 2, Method 2b

In a microwave introducing 363 mg (1,29 mmole) 2-[(6-bromopyrazine-2-ylamine)methyl]phenol obtained as described above in example 12, to which is added 3 ml of methanol and 103 mg (2,58 mmole, 2 EQ) of sodium hydroxide. Reactio the ing environment heated for 30 minutes in a microwave oven at 150°C, then diluted with 50 ml ethyl acetate. Neutralize with a solution of ammonium chloride until pH=7, defend, the organic phase is washed with twice 50 ml of water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness. The residue is purified by chromatography on silica using as eluent heptane/ethyl acetate(7/3). 2-[(6-methoxypyrazine-2-ylamine)methyl]phenol obtained as white solid.

Melting point = 158°C.

1H NMR (DMSO) of 3.78 (s, 1H); however, 4.40 (d, 2H, J=5,2 Hz); 6.73 x (t, 1H, J=7.4 Hz); for 6.81 (d, 1H, J=8 Hz); 7,05 (t, 1H, J=7.8 Hz); 7,19 (d, 1H, J=7,4); 7,26 (s, 1H); 7,31-7,32 (m, 1H); 7.50 for (s, 1H); of 9.55 (s, 1H).

Example 20: 2-[(2-methoxypyridine-4-ylamine)methyl]phenol

This connection receive in accordance with the order of receipt as described in example 19 from 2-[(2-chloropyrimidine-4-ylamine)methyl]phenol. 2-[(2-methoxypyridine-4-ylamine)methyl]phenol obtained as white solid.

Melting point = 161°C.

1H NMR (CD3OD) are 3.90 (s, 3H); 4.53-in (s, 3H); x 6.15 (d, 2H, J=6.0 Hz); 6,77-for 6.81 (m, 2H); 7,07 for 7.12 (m, 1H); 7,21 (d, 1H, J=7.4 Hz); for 7.78 (s, 1H).

Example 21: 2-[(2-methoxy-6-methylpyrimidin-4-ylamine)methyl]phenol

This connection receive in accordance with the order of receipt as described in example 19 from 2-[(2-chloro-6-methylpyrimidin-4-ylamine)methyl]phenol.

1H NMR (DMSO) a 2.12 (s, 3H); 3,74 (s, 3H); to 4.38 (m, 2H); 6,04 (s, 1H); 6.73 x (t, 1H, J=7.4 Hz); to 6.80 (d, 1H, J=8.0 Hz); 7,06 (t, 1H, J=7,7 Hz); 7,11 (d, 1H, J=7,3 Hz); the 7.65 (s, 1H); 9,71 (s, 1H).

Example 22: 2-[(6-matilal Anileridine-2-ylamine)methyl]phenol

The synthesis according to scheme 2, Method 2A

In microwave administered 300 mg (1,28 mmole) 2-[(6-chloropyridin-2-ylamine)methyl]phenol, to which is added 5 ml of dimethyl sulfoxide and 448 mg (6.4 mmole, 5 EQ) methanolate sodium. Heated for 16 hours to 90°C. the Reaction medium is diluted with 50 ml ethyl acetate, then washed with 50 ml of saturated solution of ammonium chloride, then twice with 50 ml of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness. The residue is purified by chromatography on 40 g of silica using as eluent heptane/ethyl acetate (7/3). The obtained product is dissolved in ethyl acetate, add heptane until turbidity, cooled to 0°C., filtered. Get 2-[(6-methylsulfinylphenyl-2-ylamine)methyl]phenol in the form of a white solid.

Melting point = 61°C.

1H NMR (DMSO) of 2.38 (s, 3H); to 4.38 (d, 2H, J=5.6 Hz); 6,21 (d, 1H, J=8,2 Hz); 6,34 (d, 1H, J=7.4 Hz); 6,72 (t, 1H, 7,3 Hz); 6,93-of 6.96 (m, 1H);? 7.04 baby mortality (t, 1H, J=7,7 Hz); to 7.15 (d, 1H, J=7,1 Hz); of 7.23 (t, 1H, J=7,6 Hz); 9,65 (s, 1H).

Example 23: 2-[(6-methanesulfonamido-2-ylamine)methyl]phenol

Mix 160 mg (0,66 mmole) 2-[(6-methanesulfonamido-2-ylamine)methyl]phenol and 406 mg (0,66 mmole, 1 EQ) oxone in 20 ml of dioxane. Stirred for 1 hour at room temperature, after which the reaction medium is heated to 90°C for 4 hours. After cooling to room temperature the reactions is nnow medium is diluted with 50 ml ethyl acetate, then washed with twice 50 ml of water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness. The residue is purified by chromatography on silica using as eluent a mixture of heptane/ethyl acetate(1/1). 2-[(6-methanesulfonamido-2-ylamine)methyl]phenol obtained as white solid.

Melting point = 133°C.

1H NMR (CDCl3) 2,89 (s, 3H); 4,51 (d, 2H, J=6.2 Hz); 5,32-5,33 (m, 1H); 6,5 (DD, 1H); 6.87 in-to 6.95 (m, 2H); 7,19-7,28 (m, 2H); 7,30-to 7.59 (m, 1H); a 7.62 (t, 1H, J=7,3 Hz); 9.28 are (s, 1H).

Example 24: 2-[(6-methanesulfonamido-2-ylamine)methyl]phenol

Mix 80 mg (0,33 mmole) 2-[(6-methanesulfonamido-2-ylamine)methyl]phenol and 406 mg (0,66 mmole, 2 EQ) oxone in 20 ml of dioxane and heated for 16 hours to 90°C. the Reaction medium is diluted with 50 ml ethyl acetate, then washed with twice 50 ml of water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness. The residue is purified by chromatography on silica, elwira a mixture of heptane/AcOEt(1/1). 2-[(6-methanesulfonamido-2-ylamine)methyl]phenol obtained as a solid light green substance.

1H NMR (CDCl3) of 3.12 (s, 3H); 5,32-5,33 (m, 1H); to 6.58 (d, 1H, J=7.9 Hz); 6,79-6,83 (m, 1H); 6.87 in (d, 1H, J=7.4 Hz); and 7.3 (d, 1H, J=6.6 Hz); 7.5 (t, 1H, J=7.2 Hz); 8,56 (s, 1H).

Example 25: 2-[(6-methoxypyridine-2-ylamine)methyl]-6-METHYLPHENOL

The synthesis according to scheme 1, Method 1C

80 mg (2.1 mmole, 6 EQ) aluminum hydride and lithium impose a small faction the mi in a mixture of 90 mg (0.35 mmole) of 2-hydroxy-N-(6-methoxypyridine-2-yl)-3-methylbenzamide in 10 ml of dioxane. The reaction medium is heated to 80°C for 16 hours. Enter 80 mg (2.1 mmole, 6 EQ) aluminum hydride and lithium and heated to 80°C for 4 hours. The reaction medium is diluted with 50 ml ethyl acetate, washed with 50 ml of saturated solution of ammonium chloride, then twice with 50 ml water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness. The residue is purified by chromatography on silica, elwira a mixture of heptane/ethyl acetate(1/1). 2-[(6-methoxypyridine-2-ylamine)methyl]-6-METHYLPHENOL receive in the form of a white solid.

1H NMR (CDCl3) 2,19 (s, 3H); to 3.89 (s, 3H); to 4.46 (d, 2H, J=6,7 Hz); 4.75 V (s, 1H); 5,93-5,97 (m, 2H); of 6.68 (t, 1H, J=7.4 Hz); 6,92 (d, 1H, J=7.5 Hz); 7,0 (d, 1H, J=7.4 Hz); 7,27 (t, 1H, J=7.9 Hz), to 9.66 (s, 1H).

The intermediate compound 2-hydroxy-N-(6-methoxypyridine-2-yl)-3-methylbenzamide

10 ml of thionyl chloride are introduced into 1.47 g (16,11 mmole) of 2-hydroxy-3-methylbenzoic acid and the reaction mixture is heated to 90°C for 2 hours. Reaction medium was concentrated to dryness, azeotropic toluene. Then the residue is dissolved in 10 ml of pyridine, to which is added dropwise to 600 mg (a 4.83 mmole, 1 EQ) 2-methoxypyridine-6-amine and stirred at room temperature for 1 hour 30 minutes Inject 30 ml of sodium hydroxide 1M (19,34 mmole, 4 EQ) and heated to 60°C for 16 hours. The reaction medium is diluted with 100 ml of ethyl acetate, the aqueous phase is extracted and washed with 50 m is ethyl acetate. The aqueous phase is then acidified by adding dropwise HCl 37% at 0°C until pH=4. The organic phase is extracted with twice 50 ml of ethyl acetate, then washed with twice 50 ml of water. The organic phases are concentrated to dryness and the residue purified by chromatography on silica, elwira a mixture of heptane/ethyl acetate (1/1). 2-hydroxy-N-(6-methoxypyridine-2-yl)-3-methylbenzamide receive in the form of a white solid.

1H NMR (CDCl3) of 2.23 (s, 3H); of 3.84 (s, 3H); 6.48 in (d, 1H, J=8 Hz); is 6.78 (t, 1H, J=7,7 Hz); 7,26 (d, 1H, J=7,3 Hz); 7,38 (d, 1H, J=8 Hz); 7,58 (t, 1H, J=8 Hz); 7,76 (d, 1H, J=7,7 Hz); 8,31 (s, 1H); 12,12 (s, 1H).

All spectra NMR (nuclear magnetic resonance) comply with the proposed structures. The chemical displacements are expressed in millions of pieces. The internal standard is tetramethylsilane was. Use the following abbreviations: CDCl3= deuterated chloroform, DMSO = deuterated dimethylsulfoxide, CD3OD = deuterated methanol.

Example 26: Biological tests

Compounds according to the invention have the properties of inhibitors of receptors of type AR. This inhibitory activity of AR receptors is measured in the test for the transactivation via dissociation constant KdR (inactive), KdA (active) and Kdapp (apparent) by the method described in J. Molecular Biology(1965), 12(1), 88-118, Monod J., and others.

In the framework of the invention under an inhibitor of receptor type AR see any connection that has constants the dissociation Kdapp less than or equal to 1 μm and the ratio of the KdR/KdA < 10 in the test for transactivation.

Preferred compounds of the present invention have a dissociation constant less than or equal to 500 nm and preferably less than or equal to 100 nm.

Test for transactivation, make use of a cell line PALM (PC3 Androgene receptor MMTV Luciferase), which is a sustainable transfectants containing plasmid PMMTV-neo-Luc (gene-reporter) and pSG5puro-AR.

In this study, to determine the affinity of each product for 2-state receptors (KdR and KdA), and an apparent Kd (KdApp). This constant is the resultant of both Kd, but also depends on the initial equilibrium of the receptor between an active state and an inactive state (L0) and the degree of its expression. It is determined by the following formula:

1/KdApp=(L0/(1+L0))×(1/KdR)+(1/(1+L0))×(1/KdA).

To determine these constants "cross curves of the test product compared to the control agonist, methyltrienolone, performed in 96-well pad. Test the product using 10 concentrations and the control agonist use in 7 concentrations.

As an illustration, KdApp 40 nm get for compound (1), KdApp 2 nm get for compound (2), KdApp 8 nm get to connect (19), KdApp get 1000 nm for compound (18), KdApp 200 nm get for compound (4).

1. The compounds of formula (I):

in which:
- R1 means (C2-6)alkyl, (C1-6)alkyloxy, -S(O)m-(C1-6)alkyl, (C1-6)foralkyl, CN or halogen,
- R2and R3are identical or different and denote a hydrogen atom or (C1-9)alkyl,
- R4, R5, R6, R7are identical or different and denote a hydrogen atom or halogen,
- X denotes CH or N,
- Y represents either a nitrogen atom or a carbon atom substituted (C1-6)alkyl, (C1-6)alkyloxy, (C1-6)perakyla, an atom of hydrogen or halogen,
- m is 0, 1 or 2,
and their pharmaceutically acceptable salts.

2. Connection on p. 1, characterized in that
- X represents a carbon atom and Y represents a carbon atom, a substituted methyl group, CF3, a hydrogen atom, a halogen atom or och3group.

3. Connection on p. 1, characterized in that the group R1denotes halogen, ethyl, isopropyl, trifloromethyl, nitrile, methoxy, ethoxy, isopropoxy or thiomethyl group.

4. Connection on p. 3, characterized in that the group R1denotes halogen, methoxy, ethoxy, thiomethyl or triptorelin group.

5. Connection on p. 1 selected from the compounds listed below, and their pharmaceutically acceptable salts:
2-[(6-methoxypyridine-2-ylamino)methyl]phenol
2-[(6-bromopyridin-2-ylamino)methyl]the dryer is l
2-[(6-bromopyridin-2-ylamino)methyl]-4-terfenol
6-(2-hydroxyethylamino)pyridine-2-carbonitrile
2-[1-(6-methoxypyridine-2-ylamino)ethyl]phenol
2-[(6-triptorelin-2-ylamino)methyl]phenol
2-[(6-chloropyridin-2-ylamino)methyl]phenol
2-[(6-ethylpyridine-2-ylamino)methyl]phenol
2-[(6-ethoxypyridine-2-ylamino)methyl]phenol
2-[(6-isopropoxypyridine-2-ylamino)methyl]phenol
5-chloro-2-[(6-methoxypyridine-2-ylamino)methyl]phenol
2-[(2-cryptomaterial-4-ylamino)methyl]phenol
2-[(6-bromopyrazine-2-ylamino)methyl]phenol
2-[(2-chloropyrimidine-4-ylamino)methyl]phenol
2-[(2-bromopyrimidine-4-ylamino)methyl]phenol
2-[(2-chloro-6-methylpyrimidin-4-ylamino)methyl]phenol
2-[(6-chloro-4-triptorelin-2-ylamino)methyl]phenol
2-[(6-chloro-4-methylpyridin-2-ylamino)methyl]phenol
2-[(6-methoxypyrazine-2-ylamino)methyl]phenol
2-[(2-methoxypyridine-4-ylamino)methyl]phenol
2-[(2-methoxy-6-methylpyrimidin-4-ylamino)methyl]phenol
2-[(6-methylsulfinylphenyl-2-ylamino)methyl]phenol
2-[(6-methanesulfonamido-2-ylamino)methyl]phenol
2-[(6-methanesulfonamido-2-ylamino)methyl]phenol
2-[(6-methoxypyridine-2-ylamino)methyl]-6-METHYLPHENOL.

6. Compounds according to any one of paragraphs.1-5 as medicines for the treatment of diseases mediated by the androgen receptor.

7. The use of compounds according to any one of paragraphs.1-5 to obtain drugs for prevention or treatment of hirsutism, androgenic alopecia, hypertrichosis, atopic dermatitis, disorders of the sebaceous glands, such as Hyperborea, acne, oily skin or seborrheic dermatitis.

8. The use of compounds according to any one of paragraphs.1-5 to obtain drugs for the treatment of acne.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound presented by formula

,

wherein A1 means benzene or heterocycle specified in a group consisting of pyridine, pyrazine, imidazole, thiazole, pyrimidine, thiophen, pyridazine, benzoxazine and oxobenzoxazine; A2 means benzene, if needed substituted by fluorine, or thiophen; B1 means hydrogen, lower alkyl, if needed substituted by piperazinyl or morpholino, halogen-substituted lower alkyl, lower alkoxy substituted by carbamoyl, acylamino, carbamoyl or lower alkylcarbonyloxy (provided A1 means thiazole, B1 does not mean acylamino); B2 means hydrogen or a functional group containing at least one nitrogen atom specified in a group consisting of acylamino, pyrrolidinyl, morpholino, piperidinyl, if needed substituted by acyl, piperazinyl, if needed substituted by lower alkyl or acyl, pyrazolyl, diazabicyclo[2.2.1]heptyl, if needed substituted by acyl, and di-(lower alkyl)amino, if needed substituted by amino or acylamino (provided A1 means thiazole, B2 does not mean acylamino); Y means a group presented by formula

,

wherein J means ethylene or lower alkynylene; L means a bond; M means a bond; X means -(CH2)m-, -(CH2)m-O- or -(CH2)m-NR2- (wherein m is an integer of 0 to 3, and R2 means hydrogen); D means -NR3-, wherein R3 means hydrogen; and E means amino, or its pharmaceutically acceptable salt. The compounds of formula (I) are used for preparing a pharmaceutical agent or a pharmaceutical composition for treating or preventing the VAP-1 related diseases.

EFFECT: benzene or thiophen derivative as a VAP-1 inhibitor.

13 cl, 25 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound, which is N3-1H-indol-5-yl-5-pyridin-4-ylpyrazine-2,3-diamine, or a pharmaceutically acceptable salt thereof, which can act as inhibitors of protein kinase, especially FLT3 tyrosine kinase. The invention also relates to a pharmaceutical composition which contains said compound in combination with another molecularly directed (target) agent, which is a traditional cytotoxic agent or a compound used after chemotherapy, supporting therapy targeted on stem cells and in case of MLL rearrangement acute lymphoblastic leukaemia in children.

EFFECT: obtaining a novel compound which can be used in medicine for preventing or treating haematological malignant growths such as AML, MLL, T-ALL, B-ALL and CMML, myeloproliferative diseases, autoimmune diseases and skin diseases, such as psoriasis and atopic dermatitis.

16 cl, 2 tbl, 26 ex

FIELD: chemistry.

SUBSTANCE: invention relates to pyrazinone derivatives of formula (I):

, where R1, R2, R3, R4, R5, R and R7 are as defined in claim 1 of the invention. The invention also describes a crystalline form, compounds of formula I, use of the compound of formula I in producing a medicinal agent for treating chronic obstructive pulmonary disease. A pharmaceutical composition and a pharmaceutical product are also described. Methods of obtaining compounds of formula I are also described.

EFFECT: novel compounds which can be used in therapy are obtained and described.

20 cl, 334 ex, 15 tbl, 12 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula (I-a), having the capacity to simulate axonal growth coupled with the capacity to stimulate angiogenesis and can be used in treating spinal chord damage, damage to the central nervous system as a result of head injuries, ischaemic stroke, ischemic heart disease, peripheral arterial occlusive disease, vascular dementia, cerebrovascular dementia or senile dementia. In the compound of formula (I-a): R0 is a group where R3 and R4 denote a hydrogen atom; R1 is a methyl group; R2 is a methyl group; R5 is a hydrogen atom; R6 is a hydrogen atom; R7 is a methyl group; E is an oxygen atom; is a benzyl group, a cyclohexyl methyl group, an isobutyl group, a cyclohexane carbonyl group, an acetyl group, a phenylsulphonyl group, a cyclohexyl group, a piperidine-1-carbonyl group, a methylbenzyl group, a phenyl group, a fluorobenzyl group, a methoxybenzyl group or a trifluorobenzyl group; or a pharmaceutically acceptable salt thereof.

EFFECT: high efficiency of using the compounds.

4 cl, 16 dwg, 27 tbl, 148 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula in which Q together with carbon and nitrogen atoms whereto attached forms a 9-10-member bicyclic heterocycle, and R1 and R2, R3, R4, R5 and R6 are as specified in cl.1 of the patent claim, or to its enantiomers, or a mixture of its enantiomers, or to its pharmaceutically acceptable salt. Also, an invention refers to a method for activation of glucokinase activity in mammals, by introduction of the compound described above, to a method of treating the pathological conditions associated with glucokinase activity and impaired glucose tolerance by means of introduction of the compound of formula I, to a pharmaceutical composition on the basis of the presented compounds, and also to application of the compounds of formula I for preparing the pharmaceutical composition.

EFFECT: there are produced and described new compounds which are activators of glucokinase activity and can be used as therapeutic agents for preventing and treating impaired glucose tolerance, insulin-independent diabetes and obesity.

14 cl, 4 ex

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein Q together with carbon and nitrogen atoms whereto attached forms a 5-6-members monocyclic heteroaromatic ring; or Q together with carbon and nitrogen atoms whereto attached forms a 9-10-members bicyclic heterocycle; R1 and R2 independently mean hydrogen, halogen, alkyl, alkyl substituted by one or more halogen, alkoxygroup, alkoxygroup substituted by alkoxygroup, alkylthiogroup, sulphonyl, free or etherified carboxygroup, carbamoyl, sulohamoyl, morpholinyl or pyridinyl; or R2 is absent; R3 means (C3-C6)cycloalkyl; R4 means hydrogen, halogen, lower alkyl or lowest alkyl substituted by one or more halogen; R5 means (C3-C6cycloalkyl, (C6-C10) aryl, (C3-C10)heterocyclyl or (C1-C6)alkyl optionally substituted by (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or (C3-C10)heterocyclyl; R6 means free or etherified carboxygroup; and n is an integer equal to 1-6; or to its enanthiomer, or a mixture of its enanthiomers, or its pharmaceutically acceptable salt. Besides, the invention refers to a method of glucokinase activation in mammals, to a method of treating pathological conditions associated with glucokinase activation in mammals and impaired glucose tolerance, as well as to a pharmaceutical composition based on these compounds and to application of said compositions for preparing a drug.

EFFECT: there are produced and described new compounds which are activators and can be used as therapeutic agents for treating the glucokinase mediated pathological conditions.

31 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula 2: and to its pharmaceutically acceptable salts and their mixtures, where values of R, M, Q, Z, W, D radicals are described in i.1 of the invention formula. Invention also relates to pharmaceutical compositions, which possess inhibiting activity with respect to Btk, based on formula 2 compounds.

EFFECT: obtained are novel compounds and based on them pharmaceutical compositions which can be applied in medicine for treatment of patients with diseases associated with inhibiting Btk activity and/or B-cell activity.

55 cl, 19 ex

Aromatic compound // 2416608

FIELD: chemistry.

SUBSTANCE: invention describes a novel compound of general formula (1), where radicals R1, R2, X1, Y and A are as described in claim 1 of the invention. The invention also describes a method of obtaining compounds of formula (1), as well as a pharmaceutical composition based on said compounds, for treating fibrosis.

EFFECT: novel compounds with excellent collagen formation suppression, cause fewer side-effects and which are safer are obtained.

62 cl, 2717 ex, 432 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and to their pharmaceutically acceptable salts, optical isomers or their mixture as glucokinase activators. In general formula (I) where R1 is C3-8-cycloalkyl, C3-8-cycloalkenyl, a 6-member heterocyclyl with 1 nitrogen atom, condensed phenyl-C3-8-cycloalkyl, each of which is possibly substituted with one or two substitutes R3, R4, R5 and R6; R2 is C3-8-cycloalkyl, a 5-6-member heterocyclyl with 1-2 heteroatoms selected from N, O, or S, each of which can be substituted with one or two substitutes R30, R31, R32 and R33, and R3, R4, R5, R6, R30, R31, R32 and R33 are independently selected from a group consisting of halogen, hydroxy, oxo, -CF3; or -NR10R12; or C1-6-alkyl, phenyl, C1-6-alkoxy, C1-6-alkyl-C(O)-O-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; or -C(O)-R27, -S(O)2-R27; or two substitutes selected from R3, R4, R5 and R6 or R30, R31, R32 and R33, bonded to the same atom or to neighbouring atoms, together form a -O-(CH2)2-O- radical; R10 and R11 independently represent hydrogen, C1-6-alkyl, -C(O)-C1-6-alkyl, -C(O)-O- C1-6-alkyl, -S(O)2- C1-6-alkyl; R27 is C1-6-alkyl, C1-6-alkoxy, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, phenyl, phenyl-C1-6-alkyl, a 5-6-member heteroaryl with 1-2 heteroatoms selected from N or S, a 6-member heteroaryl-C1-6-alkyl with 1 nitrogen atom, a 6-member heterocyclyl-C1-6-alkyl with 1-2 heteroatoms selected from N or O, R10R11-N- C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R12; R12 is a halogen, CF3, C1-6-alkoxy, -NR10R11; A is a 5-9-member heteroaryl with 1-3 heteroatoms selected from N, O or S, which is possibly substituted with one or two substitutes independently selected from R7, R8 and R9; R7, R8 and R9 are independently selected from halogen, cyano, -CF3; or C1-6-alkyl, C2-6-alkenyl, C1-6-alkoxy, C1-6-alkylthio, -C(O)-O-C1-6-alkyl, formyl, - C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-O-C(O)-C1-6-alkyl or hydroxy-C1-6-alkyl, each of which is possibly substituted with a substitute independently selected from R16; or phenyl, 5-member heteroaryl-C1-6-alkylthio with 2-4 nitrogen atoms, phenylthio, 5-6-member heteroarylthio with 1-2 nitrogen atoms, each of which is possibly substituted on the aryl or heteroaryl part with one or two substitutes independently selected from R17; or C3-8-cycloalkyl; or a 6-member heterocyclyl with 2 nitrogen atoms, 5-7-member heterocyclyl-C1-6-alkylthio with 1-2 heteroatoms selected from N or O, each of which is possibly substituted with one substitute independently selected from R16; or C1-6-alkyl-NR19R20, -S(O)2-R21 or -S(O)2-NR19R20; or -C(O)NR22R23; R16, R17 and R18 independently represent C1-6-alkyl, carboxy, -C(O)-O-C1-6-alkyl, -NR19R20, -C(O)NR19R20; R19 and R20 independently represent hydrogen, C1-6-alkyl, phenyl, 5-member heteroaryl with 2 heteroatoms selected from N or S, 6-member heterocyclyl with 1 nitrogen atom, -C(O)-O-C1-6-alkyl or -S(O)2-C1-6-alkyl, each of which is possibly substituted with one substitute independently selected from R24; or R19 and R20 together with a nitrogen atom to which they are bonded form a 5-7-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring possibly contains one additional heteroatom selected from nitrogen, oxygen and sulphur, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R21 is selected from C2-6-alkenyl; or R22 and R23 are independently selected from hydrogen, -C1-6-alkyl-C(O)-O-C1-6-alkyl, -C1-6-alkyl-S(O)2-C1-6-alkyl, C3-8-cycloalkyl; or R22 and R23 together with a nitrogen atom to which they are bonded form a 6-member heterocyclic ring with the said nitrogen atom, where this heterocyclic ring is possibly substituted with one substitute independently selected from R24; R24 is oxo, C1-6-alkyl, carboxy- C1-6-alkyl, a 6-member heterocyclyl with 1 nitrogen atom, -NH-S(O)2R28 or -S(O)2R28, where each cyclic group is possibly substituted with one substitute independently selected from R29; R28 is C1-6-alkyl, -C1-6-alkyl-C(O)-O- C1-6-alkyl or -N(CH3)2; R29 is C1-6-alkyl.

EFFECT: obtaining compounds which can be used for treating and preventing diseases mediated by low glucokinase activity.

21 cl, 1 dwg, 608 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I) and (II), which possess the blocking activity on voltage-sensitive sodium channels, such as TTX-S channels, and their pharmaceutically salts. In general formula (I) and (II), R1 represents -CF3, -CHF2, -OCF3, -OCHF2, -OCH2CHF2/ -OCH2CF3, -OCF2CHF2; -OCF2CF3, -OCH2CH2CF3, -OCH(CH3)CF3, -OCH2C(CH3)F2, -OCH2CF2CHF2, -OCH2CF2CF3, OCH2CH2OCH2CF3, -NHCH2CF3, -SCF3, -SCH2CF3, -CH2CF3 -CH2CH2CF3, -CH2OCH2CF3 and -OCH2CH2OCF3; R2 is specified in (1) hydrogen, (2) halogen (3) -On-C1-6 alkyl, (4) -On-C3-6 cycloalkyl, (5) -On-phenyl, (6) -On-heterocyclic group, (7) -NR7 (C=O)R8; wherein n is equal to 0 or 1, p is equal to 1, 2; R3 and R4 represents hydrogen or C1-6 alkyl, X represents carbon atom; Y represents hydrogen or C1-6 alkyl; Ar represents 4-pyridyl, 4-pyrimidyl or 6-pyrimidyl, which is substituted in the 2nd position by a substitute, which is independently specified in (1) -(C=O)-NR7R8, (2) -NR7(C=O)R8; R9 is specified in: (1) hydrogen, (2) halogen, (3) -On-C1-6 alkyl, wherein alkyl is unsubstituted or substituted by hydroxyl; q is equal to 1, 2 or 3; R10 independently represents hydrogen, C1-6 alkyl, C2-6alkenyl, C3-7 cycloalkyl or phenyl, which is unsubstituted or substituted by one or substitutes independently specified in hydroxyl, -On-C1-6 alkyl and -C3-7 cycloalkyl.

EFFECT: preparing the compounds possessing the blocking activity on voltage-sensitive sodium channels.

7 cl, 2 tbl, 1281 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound presented by formula

,

wherein A1 means benzene or heterocycle specified in a group consisting of pyridine, pyrazine, imidazole, thiazole, pyrimidine, thiophen, pyridazine, benzoxazine and oxobenzoxazine; A2 means benzene, if needed substituted by fluorine, or thiophen; B1 means hydrogen, lower alkyl, if needed substituted by piperazinyl or morpholino, halogen-substituted lower alkyl, lower alkoxy substituted by carbamoyl, acylamino, carbamoyl or lower alkylcarbonyloxy (provided A1 means thiazole, B1 does not mean acylamino); B2 means hydrogen or a functional group containing at least one nitrogen atom specified in a group consisting of acylamino, pyrrolidinyl, morpholino, piperidinyl, if needed substituted by acyl, piperazinyl, if needed substituted by lower alkyl or acyl, pyrazolyl, diazabicyclo[2.2.1]heptyl, if needed substituted by acyl, and di-(lower alkyl)amino, if needed substituted by amino or acylamino (provided A1 means thiazole, B2 does not mean acylamino); Y means a group presented by formula

,

wherein J means ethylene or lower alkynylene; L means a bond; M means a bond; X means -(CH2)m-, -(CH2)m-O- or -(CH2)m-NR2- (wherein m is an integer of 0 to 3, and R2 means hydrogen); D means -NR3-, wherein R3 means hydrogen; and E means amino, or its pharmaceutically acceptable salt. The compounds of formula (I) are used for preparing a pharmaceutical agent or a pharmaceutical composition for treating or preventing the VAP-1 related diseases.

EFFECT: benzene or thiophen derivative as a VAP-1 inhibitor.

13 cl, 25 tbl, 125 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel phenylaminopyrimidine compounds of formula I, which are JAK kinase inhibitors. In particular, these compounds selectively act on JAK2 kinase. The compounds can be used to treat diseases such as immunological and inflammatory diseases; hyperproliferative diseases, myeloproliferative diseases; viral diseases; metabolic diseases; and vascular diseases. In the compound of formula I , Q and Z are independently selected from N and CR1; R1 is independently selected from hydrogen, halogen, R2, OR2, OH, R4, OR4, CN, CF3, (CH2)nN(R2)2, where n equals 1,2 or 3, NO2, R2R4, NR2SO2R3, COR4, NR2COR3, CO2H, CO2R2, NR2COR4, R2CN, R2OH, R2OR3 and OR5R4; or two substitutes R1 together with carbon atoms with which they are bonded form an unsaturated 5- or 6-member heterocyclic ring containing 1-4 N atoms; R2 is C1-4alkyl; R4 is R2, C2-4alkenyl or phenyl; R4 is NH2, NHR2, N(R1)2, substituted or unsubstituted morpholine, CH2morpholine, substituted or unsubstituted thiomorpholine, substituted or unsubstituted thiomorpholino-1-oxide, substituted or unsubstituted thiomorpholino-1,1-dioxide, substituted or unsubstituted piperazinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted imidazolyl, substituted or tetrahydrofuranyl unsubstituted and substituted or unsubstituted tetrahydropyranyl; R5 is C2-4alkylene; R6-R9 are independently selected from H, RXCN, halogen, substituted or unsubstituted C1-4alkyl, OR1, CO2R1, N(R1)2, NO2 and CON(R1)2, wherein at least one of R6-R9 is RXCN; the rest of the values of the radicals are given in the claim.

EFFECT: high efficiency of treatment.

29 cl, 7 dwg, 2 tbl, 93 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel azabiphenylaminobenzoic acid derivatives, having the chemical formula: , where R1 is selected from a group consisting of hydrogen atoms, halogen atoms, C1-4-alkyl, C3-4-cycloalkyl and -CF3, R2 is selected from a group consisting of hydrogen atoms, halogen atoms and C1-4-alkyl group, R3 is -COOR5, where R5 is selected from a group consisting of a hydrogen atom and linear or branched C1-4-alkyl groups, R4 is selected from a group consisting of a hydrogen atom and C1-4-alkyl group; R9 is selected from a group consisting of a hydrogen atom and a phenyl group, G1 is a group selected from N and CR6, where R6 is selected from a group consisting of hydrogen atoms, halogen atoms, C1-4-alkyl, C3-4-cycloalkyl, -CP3 and C6-10-aryl group, G2 is a group selected from: - a hydrogen atom, hydroxy group, halogen atom, C3-4-cycloalkyl group, C1-4-alkoxy group and -NRaRb, where Ra is C1-4-alkyl group and Rb is selected from a group consisting of C1-4-alkyl group and C1-4-alkoxy-C1-4-alkyl group, or Ra and Rb together with the nitrogen atom with which they are bonded, form a saturated 6-8-member heterocyclic ring optionally containing one oxygen atom as an additional heteroatom, -monocyclic or bicyclic 5-10-member heteroatomatic ring containing one or more nitrogen atoms which are optionally substituted with one or more halogen atoms, and a phenyl group which is optionally substituted with one or more substitutes selected from halogen atoms, C1-4-alkyl, hydroxy group, C1-4-alkoxy group, C3-4-cycloalkyl, C3-4-cycloalkoxy group, cyano group, -CF3, -OCF3, -CONR7R8, oxadiazolyl, and where R7 and R8 are independently selected from a hydrogen atom, a linear or branched C1-4-alkyl group, C3-7-cycloalkyl group, or R7 and R8 together with a nitrogen atom with which they are bonded form a group of formula: , where n equals 0-3; or G2 together with R6 form a non-aromatic C5-10-carbocyclic group or a C6-10-aryl group, and pharmaceutically acceptable and N oxides thereof. Also described are pharmaceutical compositions containing said compounds and use thereof in treatment as dehydroorotate dehydrogenase (DHODH) inhibitors.

EFFECT: novel compounds which can be used as dehydroorotate dehydrogenase inhibitors are obtained and described.

30 cl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives of general formula (I-a), having the capacity to simulate axonal growth coupled with the capacity to stimulate angiogenesis and can be used in treating spinal chord damage, damage to the central nervous system as a result of head injuries, ischaemic stroke, ischemic heart disease, peripheral arterial occlusive disease, vascular dementia, cerebrovascular dementia or senile dementia. In the compound of formula (I-a): R0 is a group where R3 and R4 denote a hydrogen atom; R1 is a methyl group; R2 is a methyl group; R5 is a hydrogen atom; R6 is a hydrogen atom; R7 is a methyl group; E is an oxygen atom; is a benzyl group, a cyclohexyl methyl group, an isobutyl group, a cyclohexane carbonyl group, an acetyl group, a phenylsulphonyl group, a cyclohexyl group, a piperidine-1-carbonyl group, a methylbenzyl group, a phenyl group, a fluorobenzyl group, a methoxybenzyl group or a trifluorobenzyl group; or a pharmaceutically acceptable salt thereof.

EFFECT: high efficiency of using the compounds.

4 cl, 16 dwg, 27 tbl, 148 ex

Cocrystals // 2470922

FIELD: chemistry.

SUBSTANCE: according to the present invention, cocrystals contain cyprodinil and a compound which forms cocrystals, which contains at least one organic acid functional group, where said compound which forms cocrystals is: a) benzoic acid. The cocrystal is characterised by X-ray powder diffraction pattern, expressed in 2 theta angle values, where the X-ray powder diffraction pattern includes 2 theta angle values of 11.201, 11.660, 13.78, 15.050, 18.584, 19.294, 20.793, 23.865, 25.697 and 26.765 and represents white rhomboid crystals. Alternatively, the compound which forms cocrystals is: b) amber acid. The cocrystal is characterised by X-ray powder diffraction pattern, expressed in 2 theta angle values, where the X-ray powder diffraction pattern includes 2 theta angle values of 12.5, 17.3, 18.7, 21.0, 22.4, 24.0, 25.4, 28.8 and 29.3. In said cocrystals, hydrogen bonds form between the compound which forms cocrystals and cyprodinil. The invention also relates to a method of producing cocrystals. The method involves a) grinding, heating or mixing cyprodinil and the compound which forms cocrystals in form of solutions under crystallisation conditions so that a solid phase forms; b) separating cocrystals containing cyprodinil and the compound which forms cocrystals. The invention also relates to a fungicide composition and a method of preventing/controlling fungal infections in plants. The method involves treating plants with a fungicidally effective amount of an agrochemical composition given in claim 4.

EFFECT: cocrystals have high stability and have activity which is comparable with that of other existing cyprodinil compositions.

5 cl, 24 dwg, 16 tbl

Chemical compounds // 2469034

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention describes compounds of formula (I) wherein: R1 means C1-6alkyl or C3-6cycloalkyl; wherein R1 may be optionally carbon-substituted by one or more R6; R2 means hydrogen; R3 and R4 are carbon substitutes, and each is independently specified in carboxy, carbamoyl, N-(C1-6alkyl)amino, N,N-(C1-6alkyl)2amino, C1-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(C1-6alkyl)2carbamoyl, N-(C1-6alkoxy)carbamoyl, phenyl-R9 - or heterocyclyl-R10-; wherein R3 and R4 may be independently carbon-substituted by one or more R11; and wherein provided said heterocyclyl contains -NH - residue, then nitrogen may be optionally substituted by a group specified in R12; m has the value of 0, 1 or 2; wherein the values R3 may be equal or different; p has the value of 0, 1 or 2; wherein the values R4 may be equal or different; the ring A means nitrogen-containing 5- or 6-member heterocyclic group; wherein drawn nitrogen represents = N- and is found in an ortho-position to R1R2NC(O)NH group in formula (I); the ring B means phenyl or heterocyclyl; wherein provided said heterocyclyl contains -NH- residue, then nitrogen may be optionally substituted by a group specified in R14; R5 is specified in hydroxy, C1-6alkoxy or -N(R15)(R16); R6 and R11 are carbon substitutes and each is independently specified in halo, C1-6alkyl or C1-6alkoxy; R15 and R16 are independently specified in hydrogen, C1-6alkyl, C1-6alkoxy, cyclopropyl or cyclopentyl; R12 and R14 mean C1-6alkyl; wherein R14 may be optionally carbon specified by one or more R23; R9 and R10 mean a direct link; and R23 means halo or methoxy; wherein said heterocyclyl means pyridine, imidazole, triazole, thiazole, benzothiazole, imodazolepyridine, dihydroquinoline or thiadiazole, or its pharmaceutically acceptable salt; provided said compound represents other than ethyl ester of 5-[2-[[(ethylamino)carbonyl]amino]pyridin-4-yl]-4-methyl-4H-1,2,4-triazole-3-carboxylic acid or their pharmaceutically acceptable salts. There are also described pharmaceutical compositions on the basis of said compounds, a method for bacterial DNA-hydrase and/or bacterial topoisomerase IV inhibition in a homoiothermal animal, as well as a method of treating an infection in a homoiothermal animal.

EFFECT: there are prepared and described new compounds showing antibacterial activity.

24 cl, 165 ex

FIELD: chemistry.

SUBSTANCE: invention relates to agriculture and specifically to chemical agents for protecting plants based on arylsulphonylurea derivatives, used for weed control in grain and vegetable crops. Disclosed is a method of producing a granular herbicidal preparation which contains water-soluble diethylethanolamine or alkaline salts of arylsulphonylurea of formula: where or n equals 0 or 1; for n-1 Z-CH2; R1-COOCH3; R2-CH3, OCH3, OC2H5; R3-OCH3, NHCH3; R4-H, CH3; X-N, CH; M-(C2H5)2NHC2H4OH, K, Na, involving reaction of the corresponding sulphonylurea and diethylethanolamine or alkali metal hydroxide in an aqueous medium at temperature 25-80°C, adding 3.5-6.5 wt % urea to the reaction product, separating the end product by crystallisation in the presence of 7-30 wt % salting agent to obtain a product in form of a melt which is then extruded at temperature 30-60°C, and subsequently drying the obtained granules.

EFFECT: obtaining chemical agents based on arylsulphonylurea for protecting plants.

4 tbl, 12 ex

New compounds // 2456273

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula: wherein B is specified in a group consisting of pyridine, pyridazine, pyrimidine and oxazole which can be optionally substituted by halogen, C1-7-alkyl or a C1-7-alkoxy group; L1 is specified in a group consisting of -NH-, -C(O)NH- and -NHC(O)-, A means C3-C12-cycloalkyl, C6-C12-aryl, a 4-7-member monocyclic heterocyclic group consisting of 1-3 heteroatoms optionally specified in O N and S, or a bicyclic heterocyclyl specified in a group consisting of benzimidazolyl, benzoxazolyl, benzothiazolyl, wherein cycloalkyl, aryl, mono- or bicyclic heterocyclyl can be optionally substituted by one or more substitutes optionally specified in a group consisting of a cyano group, halogen, an oxo group, C1-7-alkyl, C1-7-halogenalkyl, a C1-7-alkoxy group, C1-7-halogenalkoxy group, an amino group, a di-C1-7-alkylamino group, a C1-7-alkylthio group and C3-8-cycloalkyl, 1-2- means a bivalent residue specified in a group consisting of: - a bivalent alkyl group consisting of 1 to 4 carbon atoms, a bivalent alkenyl group consisting of 2 to 3 carbon atoms, - -C(O)-, - -C(O)-[R4]c-R5- wherein c is equal to 0, and R5 is specified in a group consisting of a bivalent C1-C4-alkyl group optionally substituted by another C1-4-alkyl, a C4-C8-cycloalkyl group, a phenyl group and a 5- or 6-member heterocyclyl group consisting of N heteroatoms, - -C(O)-NH-, - -(CH2)1-3-C(O)-NH-(CH2)1-3-, - -C(O)-NH-R4- wherein R4 is specified in a group consisting of a bivalent C1-C7-alkyl group optionally substituted by another C1-4-alkyl, a cyclohexyl group and a cyclopentyl group, and E is specified in a group consisting of: - COOH, - a ester group of carboxylic acid, or to its pharmaceutically acceptable salts. What is also described is a pharmaceutical composition exhibiting DGAT1 modulatory activity, on the basis of the presented compounds, and also a method of treating pathological conditions or disorders associated with DGAT1 activity.

EFFECT: there are prepared and described new compounds applicable for treating or preventing the pathological conditions or disorders associated with DGAT1 activity.

22 cl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I) , where A is selected from -C(=O)-, -S(=O)2-, and -P(=O)(R5)-, where R5 is selected from C1-6-alkyl, C1-6-alkoxy and hydroxy; B is selected from single bond, -O-, and -C(=O)-NR6-, where R6 is selected from hydrogen; D is selected from single bond, -O-, and -NR9, where R7, R8 and R9 are independently selected from hydrogen; m equals integer number 0-12 and n equals integer number 0-12, where the sum m+n equals 1-20; p equals integer number 0-2; R1 is selected from optionally substituted heteroaryl, where heteroaryl represents aromatic carbocyclic ring, where one carbon atom is substituted with heteroatom; R2 is selected from hydrogen, optionally substituted C1-12-alkyl, and substituents are selected from phenyl, morpholine, halogen and pyridine; C3-12-cycloalkyl, -[CH2CH2O]1-10-C1-6-alkyl); and R3 is selected from optionally substituted C1-12-alkyl, and substituents are selected from morpholine, phenyl, dialkylamine and C3-12-cycloalkyl, optionally substituted with halogen aryl; or R2 and R3 together with adjacent atoms form optionally substituted with alkylcarbonyl or alkyl N-containing heterocyclic or heteroaromatic ring; each of R4 and R4* independently represents hydrogen; and their pharmaceutically acceptable salts, as well as to application of said compounds for treatment of diseases/states, induced by increased level of nicotinamide phosphoribosyltransferase (NAmPRTase).

EFFECT: obtaining novel compounds.

21 cl, 1 dwg, 2 tbl, 83 ex

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