Phenol derivatives and their pharmaceutical or cosmetic application

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to novel pyridine derivatives of the general formula

and to their pharmaceutically acceptable salts, where R1 stands for (C1-6) alkyloxy, CN or halogen, R2 stands for a hydrogen atom, R3 stands for a hydrogen atom or (C1-6) alkyl, R4, R5, R6, R7 are similar or different and stand for a hydrogen atom or halogen. The invention also relates to the cosmetic application of the formula (I) compound.

EFFECT: novel pyridine derivatives, useful in the treatment of diseases associated with a receptor of androgens, are obtained.

9 cl, 1 tbl, 16 ex

 

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

and their cosmetic or pharmaceutical application.

The present invention offers 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, for example, to call phenylimidazoline described in the patent application ER or in the application WO200542464.

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

in which:

- R1means (C1-6)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 tre�I groups of R b, same or different,

- R2means (C1-6)alkyl, (C3-7)cycloalkyl, (C1-6)alkyloxy, -S(O)v-(C1-6)alkyl, (C1-6)foralkyl, (C1-6)peralkaline, -(CH2)q-(C3-9)cycloalkyl, -(CH2)q-(C3-9)cycloalkyl, (C2-6)alkyl-OH, -(CH2)q-(C1-6)alkyloxy, -(CH2)q-(C1-6)foralkyl, -(CH2)r-O-(C1-6)foralkyl, CORd, CN, NO2, NR8'R9', a hydrogen atom, 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 Re, same or different,

- R3denotes a hydrogen atom or a (C1-9)alkyl, (C3-9)cycloalkyl, (C1-6)foralkyl, -(CH2)t-(C3-9)cycloalkyl, (C2-6)alkyl-OH, -(CH2)u-(C1-6)alkyloxy, -(CH2)t-(C3-7-cycloalkyl, -(CH2)t-(C1-6)foralkyl or -(CH2)u-O-(C1-6)foralkyl,

- R4, R5, R6, R7are the same or different and represent either a hydrogen atom or a (C1-6)alkyl, (C3-7)cycloalkyl, (C1-6)alkyloxy, -S(O)i-(C1-6)alkyl, (C1-6)foralkyl, (C16 )peralkaline, -(CH2)i-(C3-9)cycloalkyl, -(CH2)i-(C3-9)cycloalkyl, -(C1-6)alkyl-OH, -(CH2)i-(C1-6)alkyloxy, -(CH2)i-(C1-6)foralkyl, -(CH2)j-O-(C1-6)foralkyl, CORa, CN, NR10R11or 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 Rc, same or different,

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

- Rb, Rcand Reare identical or different and denote halogen, (C1-6)alkyl, (C3-7)cycloalkyl, (C1-6)alkyloxy, -S(O)k-(C1-6)alkyl, (C1-6)foralkyl, (C1-6)peralkaline, -(CH2)g-(C3-7)cycloalkyl, OH, -(CH2)g-(C3-7)cycloalkyl, (C1-66)alkyl-OH, -(CH2)g-(C1-6)alkyloxy, -(CH2)g-(C1-6)foralkyl, -(CH2)w-O-(C1-6)foralkyl, CORf, CN or NR14R15,

- R8, R8',R9, R9', R10, R11, R12, R13, R14and R15are the same� or different and denote a hydrogen atom, (C1-6)alkyl, (C3-7)cycloalkyl, -(CH2)h-(C3-7)cycloalkyl or -(CH2)h-(C1-6)foralkyl.

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

- g, h, i, n, q and t are the same or different and is 1, 2 or 3,

- k, l, m and v are the same or different and is 0, 1 or 2,

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

and their pharmaceutically acceptable salts, solvates or hydrates and their conformers eliatamby.

Compounds of formula (I) can contain one or more asymmetric carbon atoms. Therefore, they can be in the form of mixtures of enantiomers or diastereomers. These enantiomers, diastereomers and mixtures thereof, including racemic mixtures, belong to the invention.

Compounds of formula (I) can be in the form of bases or of salts of accession with acids. Such salts are joining to the invention. These salts are mainly derived from a pharmaceutically acceptable acids but the salts of other acids suitable for the purification or the isolation of compounds of formula (I), also belong to the invention. These acids can, for example, picric acid, oxalic acid or an optically active acid such as tartaric acid, dibenzoyltartaric acid, mandelic acid or campuslevel acid and such, which form physiologically acceptable salts such as hydrochloride, Bromhead, sulfate, hydrogensulfate, dihydrogenphosphate, maleate, fumarate, 2-naphthalenesulfonate, paratoluenesulfonyl. To review fiziologicheskii acceptable salts, see Handbook of Pharmaceutical Salts: Properties, Selection and Use de Stahl et Wermuth (Wiley-VCH, 2002).

Solvates or hydrates can be obtained directly at the output of the method of synthesis, wherein the compound (I) is isolated in the form of a hydrate, for example mono - regenerate or solvate of the reaction solvent or cleanup.

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 C1-6-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, for example methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, pentyl, hexyl,

- cycloalkyl - carbon chain, saturated cyclic, possibly branched, containing from 3 to 7 carbon atoms. As an example, (C3-7)cycloalkyl means a carbon chain containing from 3 to 7 carbon atoms, such as 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, for example 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,

- floralcy�ω - alkyl, one or more hydrogen atoms of which have been replaced by a fluorine atom,

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

Preferred is the group (A) compounds of formula (I) as defined above, in which the group R1denotes halogen, methyl, ethyl, isopropyl, trifluoromethyl, nitrile, nitro, methoxy, ethoxy, isopropoxy, thiomethyl, thioethyl, diisopropyl and more preferably such that R1denotes halogen, methoxy, ethoxy, thiomethyl, thioethyl or trifluoromethyl.

Group (B) compounds of formula (I), the substituent R1defined above or in a preferred group (A) and such that the group R2is a hydrogen atom.

Most preferred is the group (C) compounds of formula (I), the substituents R1and R2defined above or in the preferred groups (A) or (B), and such that the group R3is a hydrogen atom or (C1-6)alkyl.

The following compounds and their pharmaceutically acceptable salts, solvates, and hydrates and their conformers or rotamer are the most preferred:

2-[(6-bromopyridin-3-ylamino)methyl]phenol,

2-[(5-bromopyridin-3-ylamino)methyl]-3-terfenol,

2-[(5-bromopyridin-3-ylamino)methyl]-4-terfenol,

2-[(5-methylpyridine-3-ylamino)methyl]phenol,

2-[(5-�ranitidin-3-ylamino)methyl]-5-terfenol,

2-[(5-bromopyridin-3-ylamino)methyl]-3,5-dichlorphenol,

2-[(5-bromopyridin-3-ylamino)methyl]-4-chlorophenol,

2-[(5-bromopyridin-3-ylamino)methyl]-4,6-diferena,

2-[1-(5-bromopyridin-3-ylamino)propyl]phenol,

2-[1-(5-bromopyrimidine-3-ylamino)ethyl]-4-terfenol,

2-[(5-methoxypyridine-3-ylamino)methyl]phenol,

2-[1-(5-bromopyridin-3-ylamino)ethyl]phenol,

2-[(5-bromopyridin-3-ylamino)methyl]-3,4-diferena,

5-(2-hydroxyethylamino)nicotinamide,

2-[(5-chloropyridin-3-ylamino)methyl]phenol,

2-[1-(5-bromopyridin-3-ylamino)butyl]phenol,

2-[1-(5-bromopyridin-3-ylamino)pentyl]phenol,

2-[(5-bromo-6-methylpyridine-3-ylamino)methyl]phenol,

2-[(5-bromo-6-methoxypyridine-3-ylamino)methyl]phenol,

5-(2-hydroxyethylamino)-3-methylpyridine-2-carbonitrile,

2-[(6-methoxy-5-methylpyridine-3-ylamino)methyl]phenol,

2-[(6-chloro-5-methylpyridine-3-ylamino)methyl]phenol,

2-[(6-bromo-5-methylpyridine-3-ylamino)methyl]phenol,

2-[(5,6-dimethylpyridin-3-ylamino)methyl]phenol,

2-[(5-methyl-6-triptorelin-3-ylamino)methyl]phenol.

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

According to the invention compounds of formula (I) can be obtained by the method described in Scheme 1, below.

Scheme 1

Phenolic compounds of formula (I) in which R1, R2, R3, R4, R56and R7are as described above, it is possible to obtain a reducing amination reaction between benzyl aldehyde or ketone (II) and an amine (III) in the presence of a reductive agent such as, for example and without limitation, triacetoxyborohydride sodium, for example in a solvent, such as dichloro methane according to Scheme 1 and in analogy to the reactions described, for example, in Org.Pro.R & D (2006) 971-1031.

Functional groups possibly 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 spend well known to those skilled ways. Under temporary protective 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.

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 receptor� androgens. Products, which are the objects of the present invention have the activity of antagonism or agonism, partial or complete. This activity allows you to use the products according to the invention as medicaments in medicine or veterinary medicine.

These properties make the products of the General formula (I) of the present invention are suitable as medicaments for the treatment of hormone-dependent cancer, such as prostate cancer or breast cancer, as well as for the treatment of benign prostatic hyperplasia, early puberty and virilization, polycystic ovary syndrome, syndrome Stein-Leventhal, decreased libido, endometriosis. Compounds having activity of partial or complete agonism, can in particular be used for the treatment of diseases such as reduced 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 the hygiene of the body 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 to retrieve Les�artenova means 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, be applied in dermatology: they can be used individually or in combination. They can in particular be combined with antibiotics, such as derivatives of azelaic, guidikova acid, erythromycin or derivatives of retinoids, such as tretinoin, acne treatment, or with an inhibitor of 5A-reductase inhibitors, such as (5-alpha, 17-beta)-N-1,1-dimethylethyl-3-oxo-4-Asandros-1-ene-17 carboxamide (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 with a product that promotes hair growth, such as Minoxidil for the treatment of alopecia.

The object of the present invention are also compounds of formula (I) as a medicament, such as those described above, and their pharmaceutically acceptable salts, pharmaceutically acceptable solvates and/or hydrates.

The PROCEDURE of the experiment

Example 1: 2-[(5-bromopyridin-3-ylamine)methyl]phenol

295 mg (1.4 mmole) of triacetoxyborohydride sodium added to a solution of 173 mg (1 mmol, 1 EQ) 5-bromopyridin-3-ylamine (raw material 1) and 122 mg (1 mmol, 1 EQ) of 2-hydroxybenzaldehyde (raw material 2) in 20 ml of d�of chloromethane. The solution was stirred at room temperature for 24 hours. Wednesday was poured into water and stirred for 2 hours. The aqueous phase was extracted with dichloromethane. The organic phases were combined and washed with water, then dried over sodium sulfate. The residue is subjected to chromatography on silica gel (heptane/ethyl acetate 80/20). 2-[(5-bromopyridin-3-ylamine)methyl]phenol was obtained as a beige solid substance.

Melting point = 184°C

1H NMR (DMSO) 4,19 (d, 2H, J=5.8 Hz); 6,62-of 6.65 (m, 1H); 6,74 (t, 1H, J=7,4 Hz); about 6,82-6,84 (d, 1H, J=9,0 Hz); 7,05-to 7.09 (m, 2H); 7,15-up 7.17 (d, 1H, J=8,8 Hz); of 7.77 (s, 1H); 7,95 (s, 1H); 9,62(s, 1H).

Examples 2-15

Examples 2-15 described in the following table 1. Compounds synthesized in accordance with the order of receipt, as described above, replacing the original products 1 and 2 mentioned in example 1, the products listed in table 1.

Table 1
ExampleThe IUPAC nameThe initial product 1The initial product 2Melting point (°C)1H NMR 400 MHz (s = singlet, d = doublet, t = triplet,
m = multiplet
q = quadruplet,
J = constant interaction
in Hz)
22-[(5-bromo
p�ridin-3-ylamine)
methyl]-3-terfenol
5-bromo
pyridin-3-ylamine
2-fluoro-6-hydroxy-benzaldehyde193-195(DMSO) 4,17 is 4.19 (d, 2H, J=4,8 Hz); 6,43-of 6.46 (m, 1H); at 6.64 (t, 1H, J=8,6 Hz); 6,7 (d, 1H, J=8,2 Hz); 7,10-made 7.16 interest (m, 1H); from 7.24 (s, 1H); of 7.77 (s, 1H); 8,02 (s, 1H); 10,24 (s, 1H)
32-[(5-bromo
pyridin-3-ylamine)
methyl]-4-terfenol
5-bromo
pyridin-3-ylamine
5-fluoro-2-hydroxy-benzaldehyde192-194(DMSO) to 4.2 (d, 2H, J=6.0 Hz); 6.67 cm and 6.7 (m, 1H); 6.80 per-6,83 (m, 1H); 6,87-at 6.92 (m, 1H); 6,95-6,98 (m, 1H); 7,07-7,11 (m, 1H); 7,80(s, 1H); 7,95(s, 1H); to 9.67(s, 1H)
45-(2-hydroxy-benzyl-amine)no-cotinental5-aminon-cotinental2-hydroxy-benzaldehydenot defined(DMSO) of 4.22 (d, 2H, J=4,8 Hz); about 6,82 (t, 1H, J=7,4 Hz); 6,83-of 6.85 (m, 2H); to 7.08 (t, 1H, J= 7,7); up 7.17 (d, 1H, J=7,4 Hz); 7.23 percent (s, 1H); of 8.07(s, 1H); USD 8.24(s, 1H); 9,68(s, 1H)
52-[(5-pompini-Dean-3-ylamine)
methyl]-5-terfenol
5-bromopyridin-3-ylamine4-fluoro-2-hydroxy-benzaldehyde172 (CD3OD) to 4.27 (s, 2H); 6,50-to 6.58 (m, 2H); of 7.77 (s, 1H); of 7.88(s, 1H)
62-[(5-pompini-Dean-3-ylamine)
methyl]-3,5-dichlorphenol
5-bromopyridin-3-ylamine2,4-dichloro-6-hydroxy-benzaldehyde182(DMSO) of 4.22 (d, 2H, J=4,8 Hz); 6,36-at 6.38 (m, 1H); to 6.88 (s, 1H); 7,06 (s, 1H); 7,26 (s, 1H); 7,79 (s, 1H); 8,03 (s, 1H); 10,83 (s, 1H)
72-[(5-bromopyridin-3-ylamine)-methyl]-4-chlorophenol5-bromopyridin-3-ylamine5-chloro-2-hydroxy-benzaldehyde226-228(CD3OD) 4,29 (s, 2H); of 6.79 (d, 1H, J=8,6 Hz); 7,07 (m, 1H); made 7.16 interest of 7.24 (m, 2H); 7,80(s, 1H); of 7.88(s, 1H)
82-[(5-pompini-Dean-3-ylamine)
methyl]-4,6-diferena
5-bromopyridin-3-ylamine3.5-debtor-2-hydroxy-benzaldehydenot defined(DMSO) to 4.27 (s, 2H); 6,73 (m, 1H); 6,86 (d, 1H, J=9,2 Hz); 7,06-7,12 (m, 2H); 7,81 (s, 1H); is 7.94 (s, 1H); to 9.81 (s, 1H)
92-[1-(5-pompini-Dean-3-ylamine)
propyl]
phenol
5-bromopyridin-3-ylamine1-(2-hydroxy-phenyl)Pro pan-1-�n 215-217(CH3OD) of 0.97 (t, 3H); of 1.84 (m, 2H) and 4.6 (t, 1H); 6.75 in (m, 2H); 7-7,2 (m, 3H); 7.67 per(s, 1H); 7,81 (s, 1H)
102-[1-(5-bromopyridin-3-ylamine)
ethyl]-4-terfenol
2-bromopyridin-3-ylamine1-(5-fluoro-2-hydroxy-phenyl)this non175-177(DMSO) to 1.38 (d, 3H, J=6,7 Hz); 4,67-4,73 (m, 1H); 6,74-of 6.96 (m, 5H); 7,76 (s, 1H); of 7.83(s, 1H); 9,72(s, 1H)
112-[(5-methoxy-pyridin-3-ylamine)
methyl]phenol
5-methoxy-pyridin-3-ylamine2-hydroxy-benzaldehyde188-190(DMSO) 3,70 (s, 3H); 4,18 (d, 2H, J=5.4 Hz); 6,30-6,33 (m, 1H); of 6.46 (d, 1H, J=4,6 Hz); 6,73 (t, 1H, J=7,4 Hz); about 6,82 (d, 1H, J=7,4 Hz); 7,03 amounted to 7.07 (m, 1H); up 7.17 (d, 1H, J=7,4 Hz); of 7.46 (s, 1H); and 7.60(s, 1H); 9,59 (s, 1H)
122-[1-(5-bromopyridin-3-ylamine)
ethyl]phenol
5-bromopyridin-3-ylamine2'-hydroxy-acetophenone178-180(DMSO) to 1.38 (d, 3H, J=6,7 Hz); 4,68-of 4.75 (m, 1H); 6,70-6,76 (m, 2H); is 6.81 (d, 1H, J=8,0 Hz); of 6.87 (d, 1H, J=4.2 Hz); 7,02 (t, 1H, J=7,9 Hz); 7,15 (d, 1H, J=9,0 Hz); 7,72 (s, 1H); of 7.83(s, 1H); 9,63(s, 1H)
132-[(-bromopyridin-3-ylamine)
methyl]-3,4-diferena
5-bromopyridin-3-ylamine5-6-debtor-2-hydroxy-benzaldehyde194-196(CD3OD) to 4.37 (s, 2H); 6,57-6,61 (m, 1H); 6.97 in-of 7.03 (m, 1H); value of 7, 37 (s, 1H); of 7.77 (s, 1H); 7,96 (s, 1H)
142-[(5-Meile-ridin-3-ylamine)
methyl]phenol
5-methylpyridine-3-ylamine2-hydroxy-benzaldehyde183-185(DMSO) to 2.13 (s, 3H); 4,18 (d, 2H, J=5.8 Hz); 6,15-6.18 of (m, 1H); 6,70 to 6.75 (m, 2H); about 6,82 (d, 1H, J=8 Hz); 7,05 (t, 1H, J=7,7 Hz); made 7.16 interest (d, 1H, J=7,4 Hz); EUR 7.57 (s, 1H); of 7.77 (s, 1H); of 9.55 (s, 1H)
152-[(5-harpie-Dean-3-ylamine)
methyl]phenol
5-chloropyridin-3-ylamine2-hydroxy-benzaldehyde231-213(DMSO) at 4.36 (d, 2H, J=5.8 Hz); 6,55 (d, 1H, J=5,5 Hz); of 6.60 (s, 1H); 6,74 (t, 1H, J=7,4 Hz); 7,15 (d, 1H, J=7.3 Hz); 7,22 of 7.24 (m, 1H); 7,92(d, 1H, J=5,5 Hz); 9,82 (s, 1H)

All spectra NMR (nuclear magnetic resonance) consistent with the proposed structures. The chemical displacements are expressed in million parts. An internal standard is to tetramethylsilane. Use the following abbreviations: CDCl3= deuterated chloroform, DMSO = deuterated dimethyl�sulfoxide, CD3OD = deuterated methanol.

Example 16: Biological tests

Compounds of the invention possess the properties of inhibitors of receptors of type AR. This inhibitory activity of AR receptors is measured in the test for transactivation using the dissociation constants of KdR (inactive), KdA (active) and Kdapp (apparent) 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 understand any compound which has a dissociation constant 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 equal to or less than 500 nm and preferentially less than or equal to 100 nm.

Test transactivation carried out using a cell line PALM (PC3 Androgene receptor MMTV Luciferase), which is stable transfectants containing plasmid PMMTV-neo-Luc (gene-reporter) and pSG5puro-AR.

In this study determine the affinity of each product for 2-state receptors (KdR and KdA), as well as the apparent Kd (KdApp). This constant is the resultant of both Kd, but also depends on the initial equilibrium of the receptor between the active state and 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/KD)

For defined�of these constants "cross curves of the product being tested compared to the control agonist, methyltrienolone, performed in 96-well plate. Test the product using 10 concentrations, and the control agonist used in 7 concentrations.

As an illustration KdApp get 6 nm for compounds (1), KdApp get 5 nm for compounds (2), KdApp get 200 nm for compounds (4), KdApp get 60 nm for compound (9), KdApp get 15 nm for compound (14).

1. Compounds of the General formula (I):

in which:
- R1means (C1-6) alkyloxy, CN or halogen,
- R2denotes a hydrogen atom,
- R3denotes a hydrogen atom or a (C1-6) alkyl,
- R4, R5, R6, R7are identical or different and denote a hydrogen atom or halogen,
and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, characterized in that R1denotes halogen, nitrile, methoxy, ethoxy or isopropoxy.

3. Compounds according to claim 2, characterized in that the group R1denotes halogen, methoxy or ethoxy.

4. Compounds according to claim 1, characterized in that the group R3denotes a hydrogen atom or a (C1-6) alkyl.

5. Compounds according to claim 1, selected from the following compounds and their pharmaceutically acceptable salts:
2-[(5-bromopyridin-3-ylamino)methyl]phenol
2-[(5-bromopyridin-3-ylamino)methyl]-3-terfenol
2-[(5-bromopyridin-3-ylamino)methyl]-4-ft�renal
2-[(5-bromopyridin-3-ylamino)methyl]-5-terfenol
2 -[(5-bromopyridin-3-ylamino)methyl]-3,5-dichlorphenol
2-[(5-bromopyridin-3-ylamino)methyl]-4-chlorophenol
2-[(5-bromopyridin-3-ylamino)methyl]-4,6-diferena
2-[1-(5-bromopyridin-3-ylamino)propyl]phenol
2-[1-(5-bromopyrimidine-3-ylamino)ethyl]-4-terfenol
2-[(5-methoxypyridine-3-ylamino)methyl]phenol
2-[1-(5-bromopyridin-3-ylamino)ethyl]phenol
2-[(5-bromopyridin-3-ylamino)methyl]-3,4-diferena
5-(2-hydroxyethylamino)nicotinamide
2-[(5-chloropyridin-3-ylamino)methyl]phenol.

6. Compounds according to any of claims.1-5 as medicaments for the treatment of diseases associated with the androgen receptor.

7. Cosmetic use of a compound such as defined according to any of claims. 1-5, for the hygiene of the body or hair.

8. Use of a compound according to any of claims. 1-5 to obtain drugs 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.

9. Use of a compound according to any of claims.1-5 to obtain drugs for the treatment of acne.



 

Same patents:

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

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

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula [I] or to its pharmaceutically acceptable salt, wherein A represents optionally substituted alkyl, wherein the substitute represents identical or different 1-3 groups specified in aryl optionally substituted by 1-3 groups specified in alkyl, halogen, alkoxy and alkanoyl; cycloalkyl optionally substituted by 1-3 groups specified in alkyl and halogen; hydroxy; alkoxy; halogen; an amino group and oxo; an optionally substituted carbocyclic group specified in a mono- and bicyclic group, wherein an aromatic ring and cycloalkyl are condensed; optionally substituted aryl, an optionally substituted completely saturated 5- or 6-merous monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, wherein the substitute of optionally substituted aryl, the optionally substituted carbocyclic group and the optionally substituted heterocyclic group for A represents identical or different 1-3 groups specified in alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen; cycloalkyl optionally substituted by alkyl or alkoxy; alkoxy optionally substituted by halogen; halogen; hydroxy; oxo; heterocycle; alkyl sulphonyl; and mono- or dialkylcarbamoyl, optionally substituted amino, wherein the substitute represents identical or different 1 or 2 alkyl or aryl, or optionally substituted carbamoyl, wherein the substitute represents identical or different 1 or 2 alkyls optionally substituted by aryl, X represents optionally substituted methylene or -O-, wherein the substitute of optionally substituted methylene for X represents alkoxy or hydroxy, Q represents N or C-R4, L1 represents a single bond, methylene, -CH=CH-, -O-, -CO-, -NR11-, -NR11CO-, -CONR11- or -CH2NR11-, L2 represents a single bond, -CR6R7- or a bivalent 5- or 6-merous completely saturated monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, R1 and R2 are identical or different, and each represents hydrogen, alkyl or halogen, R3 and R4 are identical or different, and each represents hydrogen, alkyl, alkoxy, cyano or halogen, R1 and R3 are optionally bond thereby forming 5- or 6-merous cycloalkane, or a 5- or 6-merous aliphatic heterocycle containing oxygen atom, R5 represents a carboxyl group, an alkoxycarbonyl group or a bioisosteric group of the carboxyl group, R6 and R7 are identical or different, and each represents hydrogen or alkyl, or R6 and R7 are bond thereby forming cycloalkane, R8 represents hydroxy, alkanoylamino or alkyl sulphonylamino, R9 and R10 represent hydrogen or halogen, and R11 represents hydrogen or alkyl. Besides, the invention refers to specific compounds of formula [I], a drug based on the compound of formula [I], using the compound of formula [I], a method of treating based on using the compound of formula [I], and an intermediate compound of formula [II].

EFFECT: there are prepared new compounds possessing the agonist activity on thyroid hormone β receptor.

18 cl, 36 tbl, 344 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: biotechnologies.

SUBSTANCE: invention refers to new positively charged NSAIA prodrugs of a common formula (1, 2a, 2b, 2c or 2d) of "1, 2a, 2b, 2c or 2d structure"

Structure 1, Structure 2a,

Structure 2b, Structure 2c, Structure 2d. Values of R, R1, R2, R3, R4, R5, Ary, X radicals are presented in Claims 1,2.

EFFECT: increasing agent penetration speed.

22 cl, 14 tbl

FIELD: chemistry.

SUBSTANCE: present compounds can be used, for example, in treating diseases of the central nervous system, peripheral nervous system, cardiovascular system, pulmonary system, gastrointestinal system and the endocrine system.

EFFECT: described compounds are useful in treating a range of diseases or conditions in which interaction with the histamine H3 receptor is beneficial.

9 cl, 216 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to curable compositions containing a compound of formula where R1, R2, R3, R4 and R5, L are as disclosed in claim 1, n equals 1, p equals 1 or 2, and an organic material which is capable of polymerisation or cross-linking with a base or a nucleophilic catalyst.

EFFECT: present invention relates to curable coating compositions, especially powder coating compositions, and curable adhesive compositions, as well as to the use of a thermolatent amidine base of formula I as a curing catalyst for thermally induced base-catalysed polymerisation or crosslinking reactions.

8 cl, 31 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to substituted compounds of general formula I , in which n equals 1; R1 denotes H; F; Cl; Br or I; R2 denotes H; F; Cl; Br; I; -CF3; -CN; -NH2; -OH or -OR16; R3 denotes H; F; Cl; Br; I; -NH2; -NO2; -OH; -C(=O)-NH2; -C(=NH)-NH2; -NH-C(=O)-R13; -OR16; -C(=O)-NHR18; -C(=O)-R25 or a linear or branched, saturated of unsaturated, unsubstituted or at least mono-substituted aliphatic C1-10 radical, where said substitutes are independently selected from a group which includes F; -OH; -NH2; -NH(C1-5-alkyl) and -N(C1-5-alkyl)(C1-5-alkyl); R4 denotes H; F; Cl; Br, I or a linear or branched, saturated or unsaturated, unsubstituted aliphatic C1-10 radical; R5 denotes H; F; Cl; Br or I; R6 denotes H or a linear or branched, saturated or unsaturated, unsubstituted aliphatic C1-10 radical; R7 denotes hydrogen; R8 denotes -CF3; -O-CFH2; -O-CF2H; -CFH2; -CF2H or an unsubstituted or at least mono-substituted tert-butyl radical; T denotes C-R35; U denotes C-R36; V denotes N or C-R37; W denotes C-R38 and where values of R13, R16, R18, R25, R35, R36, R37 and R38 are as given in claim 1 of the invention. The invention also relates to methods of producing the compounds described above, a medicinal compound based on said compounds for treating vanilloid receptor mediated disorders or diseases, as well as use of compounds of formula I to produce a medicinal agent.

EFFECT: novel compounds used as vanilloid receptor ligands are obtained and described.

25 cl, 34 ex, 1 tbl

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: disclosed are novel 4-dimethyl aminobutyric acid derivatives of formula (I) (pharmaceutically acceptable salts thereof), where values of A1, A2, R1, m and n are given in the claim, which inhibit activity of carnitine palmitoyltransferase (CPT), and more specifically CPT2.

EFFECT: compounds are an agent of pharmaceutical compositions, having CPT2 inhibiting activity.

18 cl, 71 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to health-promoting compositions and methods for preparing them. A method for preparing the composition of non-living lactic acid bacilli, possessing an ability of specific binding to Streptococcus mutans, involves the following stages: heating a cell suspension of lactic acid bacillus or a mixture of lactic acid bacilli possessing an ability of specific binding to Streptococcus mutans from an initial temperature of less than 40°C to a pasteurisation temperature of 75 to 85°C with a temperature variation within the range of 0.5 to 2°C/min, keeping the heated suspension at a pasteurisation temperature of 20 to 40 minutes and cooling the suspension to a final temperature of less than 40°C within the range of 0.5 to 2°C/min. The specific binding the cell suspension of the lactic acid bacillus or the mixture of lactic acid bacilli to Streptococcus mutans is stable to heat treatment and/or resistant to proteases and/or calcium-dependent and/or is observed within the range of pH values falling within the range of 4.5 and 8.5, and/or in the saliva environment.

EFFECT: invention enables producing the agent preventing or delaying the caries lesion formation.

9 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to cosmetic industry and represents a cosmetic product which has the following composition in each specific case calculated using the total composition: at least 0.1 wt % of at least one hydrophilic softening product, 2 to 40 wt % of at least one surfactant specified in a group of fatty alcohol ethoxylates, fatty alcohol ether sulphates and salts of sulphated and/or sulphonated fatty acids, 30 to 90 wt % of water, 1 to 30 wt % of one or more abrasives with the total ingredients making 10%; the product contains at least 0.1 wt % of at least one hydrophilic softening product with a hydrophilic-lipophilic balance ≥8 and flour thermally treated by saturated vapour; the flour is natural flour of shell or kernels characterized by a light absorption at wave length 660 nm of less than 1 prepared by reacting the flour 1 g with a solution prepared of water 10 ml and 0.1% aqueous methylene blue 1 ml.

EFFECT: invention provides the lower effect on viscosity, possesses the high cleaning action and high tolerability.

16 cl, 5 ex, 3 tbl

Foaming detergent // 2543713

FIELD: chemistry.

SUBSTANCE: invention relates to aqueous foaming composition for hands, containing castor oil maleate in amount from 0.1 to 1% of composition weight, PEG-7 glyceryl cocoate in amount from 0.05 to 0.3% of composition weight, glycerol in amount from 0.5 to 6% of composition weight, PEG-6 of glycerides of caprylic/capric acid in amount from 0.05 to 1% of composition weight and SAS. Glycerol is present in amount greater than amount of castor oil maleate or glyceryl cocoate PEG-7, and said composition has viscosity from 1 to 100 mPa·s (sP).

EFFECT: obtaining aqueous foaming composition for hands, which is capable of providing foam stability, has lower tendency for flowing and soiling when applied and creates more pleasant sensations for skin.

7 cl

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions refers to oral care compositions containing a basic amino acid or its salt. The presented oral care composition promoting the dentine defect closure in the oral cavity contains arginine in the free form or in the form of a salt, and an abrasive substance representing synthetic amorphous silica and containing small particle fractures making at least approximately 5% of total weight of the composition, wherein the particles of the small particle fracture having d50 from 3 to 4 mcm. What is also presented is a method of treating sensitive teeth in the oral cavity involving using the oral treatment with this composition, as well as using arginine as a part of the oral care composition and for producing a therapeutic agent, wherein the above composition and agent contain the above abrasive material containing the small particle fracture.

EFFECT: group of inventions provide the effective dentin defect closure in the patient's oral cavity.

8 cl, 1 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: rejuvenating effect is ensured by exposing high-molecular hyaluronic acid to gamma-radiation to preparing a stable low-molecular hyaluronic acid, which is used as a prescribed ingredient alongside with synthesised matrix peptide of specific amino acid sequence.

EFFECT: prescribed combination of low-molecular hyaluronic acid and matrix peptides of the developed cosmetic product enables achieving the pronounced aesthetic effect by a physiological mechanism of stimulation of developing proper hyaluronic acid in the skin.

2 dwg, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents an oral care composition, which contains 5 - 95 wt % of an orally acceptable carrier; and a film, wherein the above film contains 10 - 60 wt % of the film of an odour control active ingredient (a zinc-containing compound), 2 - 5 wt % of the film of a mucoadhesive polymer (polyacrylic acid or polyacrylate, polyalkylacrylate, polyvinylpyrrolidone, poly(acrylate)/polyvinylpyrrolidone copolymer, chitosan, 20 - 30 wt % of the film of one or more release controlling polymers (polyvinyl acetate or hydroxyethyl cellulose), 25 - 50 wt % of the film of a polymeric base (hydroxypropyl methyl cellulose, methyl cellulose, hydroxypropyl cellulose and a copolymer thereof) and a flavouring agent, wherein the above film is integrated into the above orally acceptable carrier and makes 0.1 - 5 wt % of the orally acceptable carrier.

EFFECT: invention provides creating the agent able to keep the breath fresh for a long period of time.

5 cl, 5 ex, 7 tbl, 6 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a foaming personal care composition containing: - a carrier; - an oil phase containing at least one terpene alcohol, which has a cyclic structure; - at least partially fluorinated compound; and - a stabilising agent, wherein the mass ratio of at least partially fluorinated compound and terpene alcohol makes from 2:1 to 4:1.

EFFECT: composition possesses higher stability and provides initial foaming and a longer positive skin effects, including cleansing and moistening.

16 cl, 12 tbl, 14 ex

Dry face mask // 2543355

FIELD: chemistry.

SUBSTANCE: invention represents a dry face mask containing a base, ground natural biologically active crude drugs, a natural abrasive, wherein the base is fermented malt, while the natural abrasive is ground dry rice having a particle size of 50-100 mcm; the mask ingredients are taken in certain relation, wt %.

EFFECT: invention enables reducing a possibility of skin injuries, promotes dynamic and age-related rhytid effacement, relieving skin inflammations and eliminating pigment spots.

4 cl, 6 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to liquid cosmetic preparations and is intended for formation of double eyelid. Solution for formation of double eyelid consists of volatile solvent and basic material, which is dissolved in solvent and forms film, closely adhered to eyelid skin by solvent evaporation. Content of fibrous material, which represents nitrocellulose, consists of 5 or more wt % to 25 or less wt %. Fibrous material shrinks due to evaporation of solvent, and film contracts by shrinkage of fibrous material with dense fastening of film on eyelid skin. To form double eyelid claimed solution for formation of double eyelid is applied on eyelid skin, on which user wants to make a fold.

EFFECT: application of group of inventions ensures extremely convenient formation of natural and ideal double eyelid without causing unpleasant or uncomfortable sensation to user.

7 cl, 7 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to cosmetic industry, namely to application of copolymers, containing N-vinylpyrrolidone and hydrophobically modified derivative of acrylic acid as substances, providing improved water resistance of cosmetic composition, and to application of said copolymers in sunscreen compositions in order to increase sun protection factor.

EFFECT: increase of sun protection factor.

8 cl, 17 ex, 20 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: as a first active agent a pharmaceutical composition contains drospirenone in the amount equal to a daily dose when administering the composition and making 2 to 4 mg, and as a second active agent - ethinylestradiol in the amount equal to a daily dose and making 0.01 mg to 0.05 mg, together with one or more pharmaceutically acceptable carriers or additives. Drospirenone as a part of the pharmaceutical composition has a particle surface area more than 10000 cm2/g. Preferentially, drospirenone is fine-grained or sprayed from a drospirenone solution by inert carrier particles. The preparation contains a number of separately packed and individually taken daily dosage units in a single package used for oral administration for at least 21 days running with said daily dosage units containing a combination of drospirenone and ethinylestradiol. The preparation may additionally contain 7 and less daily dosage units containing no active agent, or containing ethinylestradiol only.

EFFECT: combination of drospirenone and ethinylestradiol provides reliable contraceptive activity ensured by the use of a maximum dose of drospirenone which causes no side effects, particularly, excess diuresis.

29 cl, 5 dwg

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