Heterocyclic compound stimulating or inducing hair or eyelashes growth and/or preventing their falling down, composition that contains this compound, its application


FIELD: medicine.

SUBSTANCE: the present innovation deals with describing the efficient quantity of, at least, one heterocyclic compound of formula (I) or its salts, moreover, the compound of formula (I) should be chosen out of (i) the compounds of formula (III) or their salts, in which Z, Z' indicate O, X indicates S (thiazolidine dionic group), G indicates O or S; at least, one out of R2 and R3 indicates CF3, OR0 or COOR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C10-C10-alkyl, (ii) compounds (VI) or their salts: in which Z, Z' and G independently indicate O or S, at least, one out of R2 and R3 indicates hydrogen, CN, CF3, NO2, OR0, COOR0 or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, possibly substituted OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, (iii) compounds (VII) or their salts in which Z, Z' and G independently indicate O or S; R indicates saturated linear or branched C1-C10-alkyl; at least, one out of R2 and R3 indicates saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl, NO2, OR0, where R0 indicates H or saturated linear or branched C1-C20-alkyl and, preferably, C1-C10-alkyl. The compounds in question reveal improved action upon stimulation of keratin fibers growth, particularly, human keratin fibers, that prevents their falling down and increases their density.

EFFECT: higher efficiency.

31 cl, 13 ex, 6 tbl

 

The technical field to which the invention relates.

The invention relates to the application of an effective amount of heterocyclic compounds and more specifically phenylbutane, phenylthiophene or phenylpyrrole in the song, calling and/or stimulating the growth of keratin fibers, in particular human and/or preventing their loss, as well as the specified composition. In addition, it relates to a method of cosmetic treatment, as well as to new heterocyclic compounds, intended to stimulate the growth of keratin fibers and/or to prevent their loss.

The keratin fibers of the person to which is applied the invention are, in particular, the hair, the eyelashes, the hair of the beard, moustache and pubic hair. More specifically, the invention is applied to the hair and/or eyelashes of the person.

In particular the invention relates to compositions for care or makeup hair or eyelashes, which includes an effective amount of the heterocyclic compounds containing phenyl radical, designed to increase their density and/or improve the appearance.

Background of the invention

Hair growth and to replace them with new ones mainly due to the activity of hair follicles and their matrix environment. Their activity is cyclical in nature and includes the chief about what Asom three phases: the anaphase catapano and telophase.

After anafazy (active phase, or growth phase), which lasts for several years and during which the hair is extended, should kutafuta, very short and transient, which lasts for several weeks. During this phase the hair is developing follicle atrophies and its dermal rooting is becoming more and more superficial.

The final phase, or telophase, which lasts several months, corresponds to the resting phase of the follicle, and the hair falls out. At the end of this period of rest at the same spot regenerated a new follicle and the cycle resumes.

Thus, hair is constantly renewed in the amount of approximately 150,000 hairs that form, 10% are in the resting phase and replaced in a few months.

Loss or natural hair loss is an average of several hundred hairs per day under normal physiological condition. This process of continuous physical renewal undergoes natural changes during aging, hair thin, and their cycles become shorter.

In addition, significant hair loss, temporary or final, may be due to various reasons. Hair loss and hair damage can occur in the postpartum period (post partum), when malnutrition and and violation of a balanced diet, when fatigue or hormonal disorder, such as, for example, during menopause or post-menopausal period. Hair loss and hair damage can also depend on the time of year.

Alopecia, mainly associated with impaired capillary regeneration, calling on the first stage of acceleration change cycles occurring at the expense of quality, and further the amount of hair. Successive cycles of growth lead to thinning hair and reduce their length with the gradual formation of non-pigmented cannon, causing, therefore, a gradual reduction in the amount of hair. Men process affects mainly the temporal and frontal bulbs, women tend to have a diffuse alopecia of the crown.

The term alopecia covers all kinds of destruction of the hair follicle, which is the final partial or complete hair loss. In many cases, early loss of hair occurs in people with a genetic predisposition, in this case we are talking about andrographolides alopecia; this type of alopecia is exposed, in particular, men.

In addition, it is known that this phenomenon may increase under the influence of a number of factors, such as hormonal disorders, psychological stress, poor nutrition.

In some dermatoses hairline skull with will nosplit the local character, such as psoriasis or seborrheic eczema, hair loss can significantly increase or cause a material breach of cycles follicles.

For many years in the cosmetic and pharmaceutical industries to develop compositions that are intended to eliminate or reduce alopecia and, in particular, to cause or stimulate hair growth or decrease hair loss.

In this area has already been suggested many compositions containing a variety of active substances, for example, 2,4-diamino-6-piperidinedione-3-oxide or "Minoxidil"described in patents US 4139619 and US 4596812, or its many derivatives, such as described, for example, in patent applications EP 0353123, EP 0356271, EP 0408442, EP 0522964, EP 0420707, EP 0459890, EP 0519819.

Clinical studies have shown that analogues of PGF2-α have the ability to cause growth of hair and eyelashes in humans and in animals (Murray A. And Johnstone, MD, 1997, Am. J. Opht., 124(4), 544-547. Experimental tests conducted on the hairline of the person, showed that the analogue of prostaglandin E2 (virosta) has the property to increase capillary density (Roenik HH., 1988, Clinic Dermatol., 6(4), 119-121).

In addition, in patent WO 98/33497 described pharmaceutical compositions containing prostaglandins or derivatives of prostaglandins that are designed to combat hair loss in cheloveka.mutagenna type A2, Fα and E2 is indicated as preferred.

However, prostaglandins are molecules with very short biological half-life and acting in autocrine or paracrine mechanism that reflects local and labile nature of the metabolism of prostaglandins (Narumiya S. Et al., 1999, Physiol. Rev., 79(4), 1193-1226).

Therefore, in order to maintain and/or increase capillary density in humans, it is important to preserve endogenous reserves PGF2-αand PGF2 different compartments of the hair follicle or the surrounding skin.

The solution gives good results, is to use compounds which are inhibitors of lipoxygenase and/or inducers of cyclooxygenase, in order to promote hair growth; apparently, the use of such compounds directs the metabolism of fatty acids, preferably in the direction of other ways of endogenous synthesis of prostaglandins.

However, for best results it is desirable to extend the period of activity of the prostaglandins involved in the growth and maintenance of life hair.

In addition, it is well known that programs of differentiation of the keratinocytes of the epidermis and the hair follicle is completely different. So, it is known that the hair shaft keratins form a family (Langbein et al., 2001, J. Biol. Chem. 276: 35123-35132), distinguish the I family, used in the epidermis that markers of differentiation, such as keratins1and K10not used in the hair follicle and, in particular, in the outer shell (Lenoir et al., 1988, Dev. Biol. 130: 610-620)that trichohyalin (O Guin et al., 1992, J. Invest. Dermatol. 98: 24-32) and keratin 6irs (Porter et al., 2001, Br. J.Dermatol. 145: 558-568) are used in the hair follicle, more specifically in the inner membrane, but not in the epidermis, and that the cyclooxygenase type 1, if it is used in the epidermis, is not used in the keratinocytes of the hair follicle and the hair papilla (Michelet et al., 1997, J. Invest. Dermatol. 108: 205-209).

The applicant has found that the enzyme specifically involved in the destruction of these prostaglandins and is present in the hair papilla, which is the defining compartment for the life of the hair. Indeed, the applicant has confirmed the presence of 15-hydroxyprostaglandin (abbreviated 15-PGDH) at this level. In addition, he showed that inhibition of 15-PGDH has a beneficial effect on the growth of hair.

Thus, the present invention relates to compositions for the care or treatment of keratin fibers person, in particular for hair care products that contain at least one specific inhibitor of 15-hydroxyprostaglandin and physiologically acceptable medium.

15-PGDH is a key enzyme in the decontamination of just what landino, in particular PGF2-α and PG2, which are important mediators of growth and survival of hair. It refers to the classification of the EU 1.1.1.141 and is NAD+dependent. It is derived from the kidney of a pig, was marked by its inhibition doses of thyroid hormone, triiodothyronine, significantly higher than physiological doses.

However, it has never been proposed to use an inhibitor of 15-PGDH for maintaining and/or increasing the density of keratin fibers, in particular, capillary density and/or decrease the heterogeneity of the diameters of the keratin fibres and in particular human hair. Under the increase of the density of keratin fibers, and in particular, capillary density implies an increase in the number of keratin fibers, and specifically the hair on cm2skin or hair.

Description of the INVENTION

The applicant has unexpectedly found that certain heterocyclic compounds and, in particular, some phenylfuro, phenylthiophene, phenylpyrrole in salt or mesolevel form have activity, contributing to an increase of the density of keratin fibers person, in particular capillary density. In addition, it was found that such compounds are inhibitors of 15-hydroxyprostaglandin.

Thus, the object of the invention is the use, in particular, in osmoticeskih purposes, at least one of the heterocyclic compounds of formula (I) or one of its salts.

in which:

- Well means 4, 5, 6, or 7-membered heterocycle possibly containing at least one carbonyl functional group and/or a thiocarbonyl functional group, and said heterocycle possibly substituted by at least one Deputy, selected from halogen, groups, OR, SR, NRR', COR, CSR, NRCONR'R", C(=NR)R', C(=NR)R NR'r", NRC(=NR')NR"R"', OCOR, COSR, SCOR, CSNRR', NRCSR', NRCSNR'R", COOR, CONRR', CF3,CN, NRCOR', SO2R', SO2NRR', NRSO2R', a linear or branched saturated or unsaturated With1-C20-Akilov, 4-7-membered cycles, saturated or unsaturated, possibly containing at least one heteroatom, and these cycles can be individual or concatenated, in addition, the alkyl radicals and the cycles may be substituted, where R, R', R" and R"', identical or different, denote hydrogen, linear or branched C1-C20-alkyl or possibly substituted aryl;

G represents O, S, NH;

- R1, R2and R3independently of one another denote hydrogen, halogen, a group OR0, SR0, NR0R0', COR0, CSR0, NR0CONR0'R0", C(=NR0R0', C(=NR0)NR0'R0", NR0C(=NR0'NR0"R0 "', OCOR0, COSR0, SCOR0, CSNR0R0', NR0CSR0', NR0CSNR0'R0", COOR0, CONR0R0', CF3,NO2, CN, NR0COR0', SO2R0', SO2NR0R0', NR0SO2R0', a linear or branched saturated or unsaturated With1-C20-alkyl, at least one of a 4-7-membered cycle, saturated or unsaturated, possibly containing at least one heteroatom, and these cycles can be individual or concatenated, in addition, the alkyl radicals and the cycles may be substituted, where R0, R0', R0and R0"', identical or different, denote hydrogen, linear or branched C1-C20-alkyl, or aryl, possibly substituted;

as an agent, the caller and/or stimulating the growth of keratin fibers, in particular human, such as eyelashes and hair, and/or preventing their loss and/or increasing their density.

The invention applies also in relation to the keratin fibers mammals (e.g. dogs, horses or cats).

In addition, the invention relates to the use in cosmetics of at least one heterocycle of the formula (I) or one of its salts in cosmetic compositions for the care and/or makeup keratin fibers, the caller and/or the stimulating their growth, preventing hair loss and/or increasing their density and/or used for the treatment of androgenic alopecia, as well as to the use of at least one of the compounds of formula (I) or one of its salts to obtain a composition for the care or treatment of keratin fibers, calling and/or stimulating the growth of the fibers, preventing their loss and/or increasing their density and/or used for the treatment of androgenic alopecia.

The keratin fibers of the person to which is applied the invention are hair, eyebrows, eyelashes, beard hairs, moustache and pubic hair. More specifically, the invention applies to the hair and/or eyelashes of the person.

In addition, the invention relates to the use in cosmetics of at least one heterocyclic compound of the formula (I) or one of its salts in cosmetic compositions for hair care in order to reduce hair loss in humans and/or to increase their density. The object of the invention is also the use for cosmetic purposes, at least one heterocyclic compound of the formula (I) or one of its salts to obtain a composition for hair care, calling and/or stimulating hair growth and/or preventing their loss and/or increasing their density.

More specifically the invention of what is worn to use for cosmetic purposes, at least one heterocyclic compound of the formula (I) or one of its salts in cosmetic compositions for hair care in order to treat alopecia person, natural and, in particular, andrographolides of origin or to the use of at least one heterocyclic compound of the formula (I) or one of its salts to obtain a composition for hair care products intended for the treatment of alopecia, human, natural, and, in particular, androgenic origin. So, this song allows you to maintain a good condition of the hair and/or to interfere with the natural loss of hair and more particularly human hair.

In addition, the invention relates to the use in cosmetics of at least one heterocyclic compound of the formula (I) or one of its salts in cosmetic compositions for the care and/or makeup eyelash man, calling and/or stimulate the growth of eyelashes and/or increasing their density, as well as to the use of at least one heterocyclic compound of the formula (I) or one of its salts to obtain a composition for care and/or treatment of the eyelashes of the person calling and/or stimulate the growth of eyelashes and/or increasing their density. This composition allows to maintain the good condition of the eyelashes and/or to improve their condition and/or appearance.

The object of the invention is also a composition for care and/or makeup keratin fibers, in particular human, containing physiologically ramlau environment and at least one heterocyclic compound of the formula (I) or one of its salts.

The object of the invention is also the use of at least one heterocyclic compound of the formula (I) or one of its salts as inhibitors of 15-hydroxyprostaglandin human skin. Its subject is also the use of at least one heterocyclic compound of the formula (I) or one of its salts to obtain a composition intended for the treatment of disorders associated with 15-hydroxyprostaglandin, in particular, in humans.

The object of the invention is also a method of cosmetic treatment of keratin fibres, in particular hair and eyelashes) and/or skin on which to grow these fibers, including the hair of the forehead and eyelids, in particular stimulating the growth of keratin fibers and/or preventing their loss, characterized in that the keratin fibers and/or skin, which grow these fibers cause cosmetic composition comprising an effective amount of at least one of the compounds of formula (I) or one of its salts left in contact with the keratin fibers and/or skin, to grow these fibers, and possibly rinsed fibers and/or the specified skin.

This method of processing has signs of cosmetic way in so far as he makes keratin fibers more aesthetic is, increasing the strength and improving the appearance. In addition, it can be used daily for several months without a doctor's prescription.

More specifically the object of the invention is a method for the cosmetic treatment of hair and/or scalp the skull in order to improve their condition and/or their appearance, characterized in that on the hair and/or hair of the skull is applied cosmetic composition comprising an effective amount of at least one of the compounds of formula (I) or one of its salts left in contact with the hair and/or scalp and possibly rinse hair and/or hair.

The object of the invention is also a method of cosmetic care and/or makeup eyelash person in order to improve their condition and/or appearance, characterized in that on the eyelashes and/or eyelids cause the composition to the eyelashes, containing an effective amount of at least one of the compounds of formula (I) or one of its salts and left in contact with the eyelashes and/or eyelids. This composition for eyelashes can be worn alone or as a lower layer under normal colored mascara and remove as you would a normal colored mascara.

The object of the invention is also a composition for care or make-up of keratin fibres, containing in a cosmetically receiving the emnd environment, in particular, cosmetic, at least one compound of formula (I) or one of its salts and at least one target a Supplement that promotes the growth of keratin fibers and/or limiting the loss selected from aminexil, Minoxidil, latanoprosta, butaprost and travoprost.

The object of the invention is also the use for cosmetic purposes, at least one heterocyclic compound of the formula (I) or one of its salts in cosmetic compositions to maintain the level and/or activity of prostaglandins in the hair follicle.

The object of the invention is also the use of at least one heterocyclic compound of the formula (I) or one of its salts to obtain a composition intended to maintain the level and/or activity of prostaglandins in the hair follicle.

DETAILED DESCRIPTION of embodiments of the INVENTION

Hereinafter, and unless otherwise specified, the terms "compound of formula (I)" means a compound of formula (I) in a neutral, acidic or basic form and in salt form.

The term "inhibitor of 15-hydroxyprostaglandin" means a compound of formula (I), are able to inhibit or reduce the activity of the enzyme 15-PGDH, in particular, human, and/or is able to inhibit, reduce, or for entati reaction, the catalyst which is this enzyme.

In accordance with a preferred embodiment of the invention the compound of formula (I) is a specific inhibitor of 15-PGDH; the term "specific inhibitor" means an active substance which is to a small extent or not an inhibitor of the synthesis of prostaglandins, in particular, the synthesis of PGF2-α or PGE2. According to a particular variant of the invention, the inhibitor of 15-PGDH is to a small extent or not an inhibitor of the synthesis of prostaglandins, in particular, the synthesis of PGF2-α or PGE2. According to a particular variant of the invention, the inhibitor of 15-PGDH is to a small extent or not an inhibitor prostaglandines (PGF synthase).

Indeed, the applicant was found that PGF synthase is also used in the hair papilla. Preserving effective amount of prostaglandins at the site of activity is the result of complex biological equilibrium between synthesis and degradation of these molecules. Exogenous intake of compounds inhibiting catabolism, is, therefore, less effective, if such activity is combined with inhibition of the synthesis of these prostaglandins.

Mainly compounds of formula I in salt or mesolevel form oblad who have higher inhibitory activity against 15-PGDH, than in respect of PGF synthase. More specifically, the ratio between any abscopal activities in relation to, respectively, PGF synthase and 15-PGDH at a given concentration, for which determinants are, in particular, the concentration inhibiting 50% of the enzymatic activity, respectively PGF synthase IC50sf and 15-PGDH IC50dh, at least greater than 1 and, in particular, at least approximately 3:1, preferably greater than or equal to 5:1. The ratio IC50sf/IC50dh preferred compounds according to the invention is greater than or equal to 10:1.

The term "at least" according to the invention involves one or more (2, 3 or more). In particular, the composition may contain one or more compounds of the formula (I). This or these compounds can be isomers CIS or TRANS or Z or E, or a mixture of isomers CIS/TRANS or Z/e They may have tautomeric form. More specifically, the heterocycle may Well be in the CIS or TRANS or Z or E, and is preferably in the position Z of the double connecting link. This or these compounds may be enantiomers and/or diastereoisomers or a mixture of such isomers, in particular racemic mixture.

The term "alkyl radical" means according to the invention a hydrocarbon radical which may be linear or branched and saturated or unsaturated. Predpochtite the flax alkyl radical contains from 1 to 10 carbon atoms. As an example, alkyl radical, used according to the invention, can be called the radicals methyl, ethyl, isopropyl, n-butyl, tert-butyl, n-hexyl, ethyl-2-hexyl, ethylene, propylene. This radical can be substituted, in particular, OR0where R0denotes H or a saturated linear or branched C1-C20-alkyland preferably1-C10-alkyl, for example, With1-C5-alkyl.

According to the invention one or more heteroatoms Well can be O, N, S, P, Si, Se, in particular O, N, S. the Heterocycle may Well be saturated or unsaturated. In addition, it can be 4, 5, 6 or 7-membered and may contain one or more carbonyl or thiocarbonyl functional groups or both, and the carbon contained in these groups is included in the heterocycle.

In the private version of the invention, the Well refers to an aromatic 5-membered cycle, containing as the heteroatom sulfur, nitrogen, and a combination thereof. In addition, this heterocycle Well contains one or more carbonyl functional groups, the carbon which is included in the heterocycle. As an example of such heterocycle can lead to the following formula (II):

where Z, Z and X independently represent S or O and R is H or a saturated linear or branched C1-C10-alkyl is hydrated radical. X can also denote NH. Mainly Z and Z' represent oxygen, which corresponds to the cycle of 1,3-thiazolidin-2,4-dione.

According to the invention, the cycles used as substituent (S1), contain from 4 to 7 atoms, preferably from 5 to 6 atoms. They can be saturated or unsaturated and may contain one or more heteroatoms such as S, N, O, or a combination thereof. In addition, these cycles can be individual or United with another cycle, or not having the same chemical structure. If they are linked, they form a condensed cycle.

As applicable saturated hydrocarbon cycles can be called radical cyclopentyl or cyclohexyl, and as the unsaturated hydrocarbon cycles can be called cyclohexenyl or phenyl cycle. As linked hydrocarbon cycles can be called a naphthyl radical. As the heterocycle can be called cycles pyridine, piperidinyl, morpholinyl, pyrology, furan, titlevii. In addition, these cycles can be substituted by one or more substituents identified above as R or R0.

According to the invention the compounds of formula (I) are isolated, i.e. neprimerno form. This phenylfuro, phenylthiophene or phenylpyrrole. In addition, R1may be in position 3 or 4, elicitate, that G is in position 1 five-membered cycle. In addition, R2andR3can be in any position thereof phenyl cycle and, in particular, in the position of a pair or meta the following parts:

Preferably R1denotes a hydrogen atom.

Mainly at least one of R2andR3means CF3OR0or COOR0where R0denotes H or a saturated or unsaturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl. As an example applicable alkyl radical can be called methyl, ethyl, tert-butyl, isopropyl, n-butyl, n-hexyl. In particular COOR0denotes COOH or SOON2-CH3. In addition, OR0means, in particular, HE or och3. More specifically, R2denotes COOH or HE and R3denotes H; R2means of SOON2-CH3and R3denotes H; or R2andR3denote CF3or och3.

Salts of compounds of formula (I) according to the invention are organic or inorganic, simple or double salts of the compounds of formula (I).

As the inorganic salts used according to the invention, can be called: simple or double salt of sodium or potassium, as well as with whom and zinc (Zn 2+), calcium (Ca2+), copper (Cu2+), iron(Fe2+), strontium (Sr2+), magnesium (Mg2+), ammonium and manganese (Mn2+); hydroxides, carbonates, halides (such as chlorides, sulfates, nitrates, phosphates. Preferably the salt is a sodium salt.

Organic salts used according to the invention are, for example, salts of triethanolamine, monoethanolamine, diethanolamine, hexadecylamine, N,N,N, N'-tetrakis(hydroxypropyl-2)Ethylenediamine, trihydroxypyrimidine.

According to a particular variant of the invention, the heterocyclic compounds to which the invention relates, have the following formula (III) or preferably formula (IIIa) or a corresponding salt form (mono or dual):

in which Z, Z' and G independently represent O or S; at least one of R2andR3means CF3OR0or COOR0where R0denotes H or a saturated or unsaturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl.

The object of the invention is also a new heterocyclic compound of the following formula (IV) or one of its salts, with, in particular, the ability to inhibit 15-PGDH and/or to maintain the level and/or activity of prostaglandins, in which lastnosti, in the hair follicle person:

in which Z, Z' and G independently represent O or S; X represents O, NH or S; R represents hydrogen or a saturated linear or branched C1-C10is an alkyl radical; at least one of R2andR3denotes hydrogen, CN, NO2, CF3, phenyl radical, OR0or COOR0saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl, possibly substituted OR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl, provided that if X=S and Z=Z'=G or Z≠Z', R2and R3not represent COOH.

According to a particular variant of the implementation of the heterocyclic compound has the following formula (V) or the corresponding salt:

in which Z, Z' and G independently represent O or S; at least one of R2andR3denotes phenyl, NO2, CF3OR0, COOR0or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl, possibly substituted OR0where R0denotes H or a saturated linear or branched C1-C20-Alki and preferably 1-C10-alkyl, provided that when Z=Z'=G or Z≠Z', R2and R3not represent COOH.

Mainly, if Z=Z'=G, at least one of R2and R3means CF3OR0or COOR0where R0refers to saturated linear or branched C1-C10-alkyl and preferably1-C5-alkyl. In accordance with another preferred embodiment of the invention, if Z=Z' and not G denotes at least one of R2andR3means CF3or COOR0where R0denotes N.

In accordance with another preferred embodiment of the invention the heterocyclic compound has the following formula (VI) or a corresponding salt:

in which Z, Z' and G independently represent O or S; at least one of R2andR3denotes hydrogen, CN, CF3,NO2OR0, COOR0or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl, possibly substituted OR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl.

In accordance with another embodiment of the invention heterocyclic soy is inania has the following formula (VII) or a corresponding salt:

in which Z, Z and G independently represent O or S; R represents a saturated linear or branched C1-C10-alkyl; at least one of R2andR3refers to saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl, NO2OR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl.

Preferably the heterocyclic compound according to the invention has the shape of a Z.

As far as known to the applicant, in any document equivalent is not documented and does not imply that the heterocyclic compounds of formula (I) or one of their salts have the ability to induce and/or stimulate the growth of keratin fibers, in particular hair and eyelashes and/or to prevent their loss and that these compounds may have a local application to increase the density of keratin fibers and more specifically hair and eyelashes.

The compounds of formula (I) or their salts can be obtained by a known method described in document WO 01/066541. At room temperature the compounds of formula (I) are in the solid state.

An effective amount of the compounds of formula (I) or one of its salts corresponds to the number, not the required to obtain the desired result (namely, increasing the density of keratin fibers, more specifically hair and eyelashes, or stimulation of their growth). Therefore, the specialist can determine the effective amount depending on the nature of the applied connection from the user and from the duration of this application.

Hereinafter, unless otherwise stated, the number of different components of the composition given in weight percents relative to the total weight of the composition.

In order to give an idea of the magnitude according to the invention, the compound of formula (I) or one of its salts or a mixture of compounds of formula (I) and/or their salts can be used in the range from 10-3up to 10% relative to the total weight of the composition, and preferably in the range from 10-3up to 5% and more preferably from 10-2up to 2% relative to the total weight of the composition, for example from 0.5 to 2%.

The composition according to the invention can be used in cosmetic or medicinal purposes. Preferably the composition according to the invention used for cosmetic purposes. Thus, the composition should contain physiologically acceptable non-toxic environment, which can be applied to the skin, including hair and eye lids, and on the keratin fibers are human. Under the "cosmetic" according to the present invention mean a composition having enjoyable in the d, the smell and pleasant to the touch.

The compound of formula I in salt or mesolevel form can be used in compositions intended for oral administration, injection or application to the skin or keratin fibers (on the whole area of the skin or fibers to be processed).

According to the invention the compound of formula (I) or one of its salts can be used orally in amounts of from 0.1 to 300 mg per day, for example from 5 to 10 mg/day.

According to the invention, it is preferable composition for cosmetic use and, in particular, for local application to the skin or keratin fibers and more specifically on the hair, hair and eyelashes.

The object of the invention is also a composition for care or make-up keratin fibers, in particular a composition for hair care or for eyelashes for topical application, containing a physiologically acceptable medium and an effective amount of at least one of the compounds of formula (I) or one of its salts, as described above.

This composition can have any known and acceptable herbal form.

Composition for topical application on the skin can be in the form of a solution or aqueous, alcoholic or aqueous-alcoholic suspension or oil suspensions, emulsions, having a more or less fluid consistency and, in particular, liquid or semi-liquid, recip is nnow by dispersion of a fatty phase in an aqueous phase (H/E) or Vice versa (E/N), solid emulsion (H/E) or (F/N), water, aqueous-alcoholic or oily gel, a more or less fluid or solid, normal or compact powder, used as such or in a physiologically acceptable medium, or in the form of microcapsules or microparticles, vesicular dispersion systems, ionic and/or nonionic type.

The composition may also take the form of a foam or spray or aerosol and contain in this case, the propellant under pressure.

It can also be in the form of a lotion, serum, milk, cream N/S or E/N, gel, ointment, lipstick, balm, patch, impregnated pad, bar soap, foam.

More specifically, the composition for application to hair or hair may be in the form of a lotion of care used, for example, daily or twice a week, shampoo or drugs used after shampooing the hair care, in particular, applied once or twice a week, liquid or solid soap for daily cleansing of hair, styling hair lacquer, means for Curling, styling gel), a treatment mask, foaming cream or gel for cleansing hair. It can also be in the form of a paint or ink for eyelashes care, which is placed with a brush or hairbrush.

In addition, for application to the eyelashes or the hair composition according to the invention may be settled in the form of a colored or colorless mascara, which is applied by brush to the eyelashes or hairs of the beard or mustache.

The composition used for injection may be in the form of an aqueous lotion or oil suspensions. For oral administration, the composition may be in the form of capsules, granules, drinking syrups or tablets.

In accordance with the private embodiment the composition according to the invention may be in the form of cream or lotion for hair care, shampoo or drugs used after shampooing the hair care, mascara for care or mascara.

The contents of the various components of the composition according to the invention is the same as usually used in these areas. In addition, these compositions have traditional ways.

If the composition is an emulsion, the amount of fatty phase can reach from 2 to 80 wt.%, preferably from 5 to 50 wt.% in relation to the total weight of the composition. The content of the aqueous phase adjust depending on the content of fatty phase and the compound or compounds (I), as well as the content of possible additional components to obtain 100 wt.%. In practice, the aqueous phase is from 5 to 99.9%.

The fatty phase may contain aliphatic or oily compounds, liquid at room temperature (25°C) and atmospheric pressure (760 mm Hg), commonly called oils. These oils may be compatible or incompatible with each other to form an aliphatic liquid phase, macroscopically homogeneous or two - or three-phase system.

In addition to oils aliphatic phase may contain waxes, resins, lipophilic polymers, "pasty or viscous liquids containing solids or liquid.

The aqueous phase contains water and, possibly, the component is able to be mixed with water in any quantity, such as low (1-C8)-alcohols, such as ethanol, isopropanol, polyols such as propylene glycol, glycerin, sorbitol, or acetone, or a simple ester.

To obtain compositions in the form of an emulsion using the same emulsifiers and co emulsifiers, which are usually used in cosmetics and pharmaceuticals. In addition, their nature depends on the direction of the emulsion. In practice, the emulsifier and possibly joint emulsifier contained in the composition in an amount of from 0.1 to 30 wt.%, preferably from 0.5 to 20 wt.% and more preferably from 1 to 8%. In addition, the emulsion may contain lipid vesicles and, in particular, liposomes.

The composition is in the form of a solution or oil gel may contain aliphatic phase more than 90 wt.% of the total weight of the composition.

Preferably the composition is for treatment is an aqueous, alcoholic or aqueous-alcoholic solution or suspension, and preferably a solution or suspension of water/ethanol. Alcohol fraction can SOS is hawlati from 5 to 99.9% and preferably from 8 to 80%.

The composition according to the invention for use in the form of a mascara is a disperse system "wax-in-water or wax-in-oil', gilotinirovaniya oil, water-based gel, colored or colorless.

In addition, the composition according to the invention may contain other components commonly used in the areas that are selected from solvents, thickeners or funds gelatinous aqueous phase or oily phase, dyes, soluble in the environment, part of the composition, solid particles such as fillers or pigments, antioxidants, preservatives, fragrances, electrolytes, neutralizing means, film-forming polymers, UV blockers, such as solar filters, active cosmetic or medicinal substances that have a beneficial effect on the skin or keratin fibers, in addition to the compounds of formula (I), their mixtures. These additives may be contained in the compositions commonly used in cosmetology and dermatology quantities and, in particular, from 0.01 to 50% by weight of the total composition, preferably from 0.1 to 20%, for example, from 01 to 10%. Depending on their nature, these additives can be introduced in aliphatic phase in the aqueous phase and/or into lipid vesicles, and more specifically in liposomes.

Of course, the specialist will choose the possible target additives and/or their amounts so that the s-emptive properties of the composition according to the invention, namely, the specific inhibitory ability against 15-PGDH and more specifically increasing the density of keratin fibers (hair or eyelashes) were not or were not significantly changed these additives.

As solvents, it is acceptable for the purposes of the invention, can be called the lowest2-C8-alcohols, such as ethanol, isopropanol, propylene glycol and some light cosmetic oils, such as C6-C16-alkanes.

As fat is acceptable for the purposes of the invention, can be called oil of mineral origin (vaseline oil, hydrogenated isoparaffin), vegetable oils (liquid fraction of the fat of the fruit oil of the tree of Bessie, sunflower oil, oil of apricot pits, aliphatic alcohol or acid), oils of animal origin (perhydrosqualene), synthetic oils (a fatty acid ester, Purcellin oil), silicone oils such as linear or cyclic polydimethylsiloxane, fenitrothion) and fluorinated oils (simple parfocality). From waxes can be called silicone waxes, beeswax, rice, candelilla, Carnauba, or paraffin, polyethylene.

As emulsifiers that are acceptable for the purposes of the invention, include, for example, stearate or laurate glycerol stearates or oleates of sorbitol, alkyldimethyl the polyols (where the alkyl ≥ 8) and mixtures thereof to obtain emulsion E/N. You can also use monostearate or monolaurate of polyethylene glycol, polyoxyethylene stearate or oleate of sorbitol, dimethiconol and mixtures thereof to obtain emulsion N/a E.

As hydrophilic gelling substances that are acceptable for the purposes of the invention, can be called carboxyvinyl polymers (carbomer), acrylic copolymers such as copolymers of acrylates/alkylacrylate, polyacrylamides, polysaccharides such as hydroxypropylcellulose, natural resins and clays, and, as lipophilic gelling agents can be called a modified clay, such as bentonite, metal salts and fatty acids such as aluminum stearates, hydrophobic modificate silica, ethylcellulose, and mixtures thereof.

In addition, the composition may contain cosmetic or pharmaceutical active substance in addition to the compounds of formula (I), which may be hydrophilic and which are selected from proteins, protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, water-soluble vitamins, plant extracts (extracts chastikovyh or soy) and hydroxy acids such as fruit acids or salicylic acid; or which may be lipophilic and which are selected from retinol (vitamin a) and its derivatives, in the hour of the activity, of ester (retinol palmitate), tocopherol (vitamin E) and its derivatives, in particular, complex ether (tocopherol acetate), essential fatty acids, ceramides, essential oils, derivatives of salicylic acid such as salicylic n-octanoyl-5, esters of hydroxy acids, phospholipids, such as lecithin, and mixtures thereof.

According to a particular variant of the invention, the compound of formula (I) or one of its salts can be combined with at least one additional active compound that promotes growth and/or limiting the loss of keratin fibers (hair, eyelashes). These additional compounds chosen in particular from lipoxygenase inhibitors, such as described in EP 0648488, inhibitors of bradykinin, described in particular in EP 0845700, prostaglandins and their derivatives, in particular as described in WO 98/33497, WO 95/11003, JP 97-100091, JP 96-134242, agonists or antagonists of receptors of prostaglandins, neproshenyh analogues of prostaglandins, which are described in EP 1175891 and EP 1175890, WO 01/74307, WO 01/74313, WO 01/74314, WO 01/74315 or WO 01/72268, and mixtures thereof.

As other additional active substances that promote the growth of keratin fibers, in particular hair) and/or limiting their loss, in the composition according to the invention can be present vasodilators, anti-androgens, cyclosporine and analogues, antimicrobial is an antifungal substance, anti-inflammatory agents, retinoids, individually or in the form of a mixture.

Suitable vasodilators include, in particular, agonists of potassium channels, including Minoxidil and compounds described in patents US 3382247, 5756092, 5772990, 5760043, 5466694, 5438058, 4973474, cromakalim, nicorandil and diagnosed, individually or in combinations.

To fit the anti-androgens include, in particular, steroid or non-steroidal inhibitors of 5α-reductase, such as finasteride, and compounds described in US 5516779, cryptochironomus, azelaic acid, its salts and its prosodie and compounds described in US 5480913, flutamide, oxendolone, spironolactone, diethylstilbestrol and compounds described in patents US 5411981, 5565467 and 4910226.

Antimicrobial and antifungal agents can be selected from derivatives of selenium, octopirox, ketoconazole, triclocarban, triclosan, zinc pyrithione, Itraconazole, asitimbay acid, hinokitiol, mupirocin, tetracyclines, in particular, erythromycin and compounds described in EP 0680745, hydrochloride clinicin, peroxide benzoyl or benzyl, minocycline and compounds belonging to the class of imidazoles, such as econazole, ketoconazole or miconazole or their salts, esters of nicotinic acid, in particular tocopherol nicotinate, nicotinate of benzyl and nicotinate1-C6-alkyl, such as is ethyl or hexanicotinate.

Anti-inflammatory agents can be selected from steroidal anti-inflammatory substances, such as glucocorticoids, corticosteroids (eg, hydrocortisone) and non-steroidal anti-inflammatory substances, such as glycyrrhetinic acid and α-bisabolol, benzydamine, salicylic acid and the compounds described in EP 0770399, WO 94/06434 and FR 2268523.

Retinoids can be selected from isotretinoin, azitretina and tazarotene.

As other active compounds that promote growth and/or limiting the loss of hair, apply in combination with the compound of the formula (I), can be called aminexil, 6-0-[(9Z,12Z)-octadeca-9,12-dienoyl]hexopyranosyl, benzalkonium chloride, chloride benzene, phenol, estradiol, chlorpheniramine maleate, derivatives chloroprene, cholesterol, cysteine, methionine, menthol, peppermint oil, calcium Pantothenate, panthenol, resorcinol, activators of protein kinase C, inhibitors of glycosidase inhibitors glycosaminoglycans, esters pyroglutamic acid, hexosamine or aciphexeuhoria acids, aryl-substituted ethylene, N-acylated amino acids, flavonoids, derivatives and analogues of ascomycin antagonists of histamine, saponins, inhibitors of proteoglycans, agonists and antagonists of estrogen, pseudotherapy, cytokines and promoters of growth factors, inhibitors of IL-1 or IL-6, the promoters of IL-10, ing bitory TNF, benzophenone and as retinoic acid; vitamins such as vitamin D analogues vitamin B12 and pantothenol; triterpenes such as ursolic acid and the compounds described in US 5529769, US 5468888, US 5631282; antipruritic agents such as analgin, trimeprazine or cyproheptadine at; antiparasitic means, in particular metronidazole, crotamiton or pyrethrinoid; calcium antagonists such as Cinnarizine, diltiazem, nimodipine, verapamil and nifedipine; hormones such as estriol or its analogs, thyroxine and its salts, progesterone; agonists of the FP receptor (receptor type prostaglandins F), such as latanoprost, bimatoprost, travoprost, unoprostone; and mixtures thereof.

Mainly the composition according to the invention contains at least one inhibitor of 15-PGDH described above, and at least one prostaglandin or one derived prostaglandin, for example, the series 2 prostaglandins, in particular PGF2-α and PG2, in the form of salts or esters (for example, a complex isopropyl esters), their derivatives, such as 16,6-dimethyl PG2, 17-phenyl PGF2-α, prostaglandins series 1, such as 11-deoxyprostaglandin E1, 1-deoxyprostaglandin E1, in the form of salts or esters their analogues, in particular latanoprost, travoprost, bimatoprost, fluprostenol, cloprostenol, virosta, butaprost, misoprostol, unoprostone, their salts or their esters.

Preferably the composition contains at least one nephrostomy agonist receptors ER and/or ER, in particular described in EP 1175892.

A composition comprising at least one compound of formula I in salt or mesolevel form may have a liposomal form, which is for example described in document WO 94/22468. So, the connection, encapsulated in liposomes, can be selectively received in the hair follicle or in the base of the lashes.

The composition according to the invention can be applied to areas of the scalp affected by alopecia, human hair and can be left in contact for several hours, and it is possible to rinse.

You can, for example, to apply a composition comprising an effective amount of a compound of formula I in salt or mesolevel form, in the evening and leave it in contact for the night and possibly clear keratin fibers, for example, to wash with shampoo the next morning. Such applications can be repeated daily for one or several months depending on the state of the user.

According to the proposed method on the processed sections of hair put mainly from 5 to 500 μl of a solution or composition, described above, containing from 0.001 to 5% of the inhibitor of 15-PGDH.

As the illustrations below are examples of the invention, not about the limits of its scope.

EXAMPLES

As examples of heterocyclic compositions of formula (I)suitable for the invention include the following compounds:

Compound 1: 4-{5-[2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]-2-furyl}benzoic acid

And more specifically, compound 1A:

Compound 2: 4-{5-[(2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]-2-furyl}ethylbenzoic

Compound 3: 5-{5-[3,5-bis(trifluoromethyl)phenyl]-2-furyl}methylene-1,3-thiazolidin-2,4-dione

Compound 4: 3-{5-[(2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]-2-furyl}benzoic acid

Compound 5: 4-{5-[(2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]-2-Teofil}benzoic acid

Compound 6: 4-{5-[(2-sulfo-4-oxo-1,3-thiazolidin-5-ilidene)methyl]-2-furyl}benzoic acid

Compound 7: 4-{5-[(2,4-disulfo-1,3-thiazolidin-5-ilidene)methyl]-2-furyl}benzoic acid

Compound 8: double the sodium salt of 4-{5-[(2,4-disulfo-1,3-thiazolidin-5-ilidene)methyl]-2-furyl}benzoic acid (isomer Z)

Predominantly the compound of formula (I) is a double sodium salt of 4-{5-[(2,4-disulfo-1,3-thiazol the DIN-5-ilidene)methyl]-2-furyl}benzoic acid and in particular isomer in the form of a Z.

As other compounds of formula (I), applicable according to the invention, can also be called:

Heterocyclic structure DAppearancePurity LC*MS**Name
< / br>
Connection D1
Powder red93M + N

M + Na
5-[5-(3,4-acid)furan-2-ylmethylene]-3-ethyl-2-dioxoimidazolidin-4-one
< / br>
Connection D2
red powder100M + Na5-[5-(2,5-acid)furan-2-ylmethylene]-3-ethyl-2-dioxoimidazolidin-4-one
< / br>
Connection D3
red powder100M - N

M + Na
3-ethyl-5-[5-(4-methyl-3-nitrophenyl)furan-2-ylmethylene]-2-dioxoimidazolidin-4-one

Heterocyclic structure EAppearancePurity LCMSName
< / br>
Connection E1
Red powder91M + N

M + Na

M - N
5-[5-(3,4-acid)furan-2-ylmethylene]-2-dioxoimidazolidin-4-one
< / br>
Connection E2
Red resin100M + N

M - N
5-[5-(3-hydroxymethylene)furan-2-ylmethylene]-2-dioxoimidazolidin-4-one
< / br>
Connection E3
orange solid in-in100M - N2 thioxo-5-[5-(4-triptoreline)furan-2-ylmethylene]imidazolidin-4-one
< / br>
Connection E4
Red powder73M - N5-[5-(4-methyl-3-nitrophenyl)furan-2-ylmethylene]-2-dioxoimidazolidin-4-one
< / br>
Connection E5
Powder brown color93M - N4-[5-(5-oxo-2-dioxoimidazolidin-4-ylidenemethyl)furan-2-yl]benzonitrile
< / br>
Connection E6
Orange powder89M + N

M + Na

M - N
Methyl ester of 3-[5-(5-oxo-2-dioxoimidazolidin-4-ylidenemethyl)furan-2-yl]benzoic acid
< / br>
Connection E7
Powder chestnut color/td> 100M - N5-[5-(3,4-acid)thiophene-2-ylmethylene]-2-dioxoimidazolidin-4-one
< / br>
Connection E8
Powder Burgundy65M - N5-[5-(2,5-acid)thiophene-2-ylmethylene]-2-dioxoimidazolidin-4-one
< / br>
Connection e
Orange powder90M - N2 thioxo-5-[5-(4-triptoreline)thiophene-2-ylmethylene]imidazolidin-4-one
< / br>
Connection E10
Black powder66M - N4-[5-(5-oxo-2-dioxoimidazolidin-4-ylidenemethyl)thiophene-2-yl]benzonitrile
< / br>
Connection E11
Powder brown color90M - NMethyl ester of 3-[5-(5-oxo-2-dioxoimidazolidin-4-ylidenemethyl)thiophene-2-yl]benzoic acid
< / br>
Connection E12
Orange powder64M - N5-[4-(4-methyl-3-nitrophenyl)-thiophene-2-ylmethylene]-2-dioxoimidazolidin-4-one
< / br>
Connection E13
the yellow powder 53M - N4-[5-(5-oxo-2-dioxoimidazolidin-4-ylidenemethyl)thiophene-3-yl]benzonitrile
< / br>
Connection E14
Yellow powder91M - NMethyl ester of 3-[5-(5-oxo-2-dioxoimidazolidin-4-ylidenemethyl)thiophene-3-yl]benzoic acid
< / br>
Connection E15 motorway
Red resin100M - N5-(5-phenylfuro-2-ylmethylene)-2-dioxoimidazolidin-4-one
< / br>
Connection e
Orange solid in-in81M - N5-(5-phenylthiophene-2-ylmethylene)-2-dioxoimidazolidin-4-one

Heterocyclic structure FAppearancePurity LCMSName
< / br>
Connection F1
Orange powder90M - N5-[5-(3,4-acid)furan-2-ylmethylene]thiazolidine-2,4-dione
< / br>
Connection F2
Yellow powder88M - N5-(5-biphenyl-4-ilfu the EN-2-ylmethylene)thiazolidine-2,4-dione
< / br>
Connection F3
Yellow powder91M - N5-[5-(3-hydroxymethylene)-furan-2-ylmethylene]thiazolidine-2,4-dione
< / br>
Connection F4
Orange wool100M - N5-[5-(2,5-acid)furan-2-ylmethylene]thiazolidine-2,4-dione
< / br>
Connection F5
Yellow powder100M - N5-[5-(4-triptoreline)furan-2-ylmethylene]thiazolidine-2,4-dione
< / br>
Connection F6
Yellow powder69M + Na

M - N
5-[5-(4-methyl-3-nitrophenyl)furan-2-ylmethylene]thiazolidine-2,4-dione
< / br>
Connection F7
Resin chestnut color100M - N4-[5-(2,4-dioxothiazolidine-5-ylidenemethyl)furan-2-yl]benzonitrile
< / br>
Connection F8
Yellow powder61M - NMethyl ester of 3-[5-(2,4-dioxothiazolidine-5-ylidenemethyl)furan-2-yl]benzoic acid
< / br>
Connection F9
Orange powder93M - N5-[5-(3-hydroxymethylene)-thiophene-2-ylmethylene]thiazolidine-2,4-dione
< / br>
Connection F10
Orange powder59M - N5-[5-(2,5-acid)thiophene-2-ylmethylene]thiazolidine-2,4-dione
< / br>
Connection F11
Red solid in-in100M - N5-[5-(4-triptoreline)-thiophene-2-ylmethylene]thiazolidine-2,4-dione
< / br>
Connection F12
Powder red56M - N5-[5-(4-methyl-3-nitrophenyl)thiophene-2-ylmethylene]thiazolidine-2,4-dione
< / br>
Connection F13
Red powder41M - N4-[5-(2,4-dioxothiazolidine-5-ylidenemethyl)thiophene-2-yl]benzonitrile
< / br>
Connection F14
Red powder54M - NMethyl ester of 3-[5-(2,4-dioxothiazolidine-5-ylidenemethyl)thiophene-2-yl]benzoic acid
< / br>
Connection F15
Orange resin50M - N5-[4-(4-methyl-3-nitrophenyl)thiophene-2-ylmethylene]thiazolidine-2,4-dione
< / br>
Connection F16
Yellow powder59M - NMethyl ester of 3-[5-(2,4-dioxothiazolidine-5-ylidenemethyl)thiophene-3-yl]benzoic acid
< / br>
Connection F17
Yellow scaly crystals71M - N5-(5-phenylfuro-2-ylmethylene)thiazolidine-2,4-dione
< / br>
Connection F18
Yellow powder84M - N5-(5-phenylthiophene-2-ylmethylene)thiazolidine-2,4-dione

Heterocyclic structure GAppearancePurity LCMSName
< / br>
Connection G1
Orange powder62M + N2-[5-(3,4-acid)furan-2-ylmethylene]benzo[4,5]imidazol-[2,1-b]thiazole-3-one

*LC: liquid chromatography

**MS: Mass spectrometry

Compounds according to the invention can be synthesized as described below ways the om.

General methodology for the synthesis of compounds of structure D, E, F or G

These heterocyclic structures correspond to 3-ethyl-2-thioxo-4-oxazolidinone (CAS number: 10574-66-0, molecular weight: 145, structure D), 2-thiohydantoin (CAS number: 503-87-7, molecular weight: 116, structure E), 2,4-thiazolidinedione (CAS number: 2295-31-0, molecular weight: 117, structure F), thiazolo(2,3-b)benzimidazole-3(2H)-he (CAS number: 3042-01-0, molecular weight: 190, structure (G).

In a test tube for reactions Pyrex® system for carrying out the synthesis under microwave irradiation using Discover firms STEM administered 100 mg of the aldehyde, 1 equivalent of a heterocycle having the structure D, E, F or G, 20 μl of piperidine, and then 1.5 ml of absolute ethanol.

The tube provide a magnetic core, then close objetos tube.

Then the reaction medium is irradiated in the device Discover in accordance with the following parameters:

Net power: 250 watts

The preset temperature: 150°

Exposure time: 2 minutes

The maximum time to reach the set temperature: 4 minutes.

After cooling, the reaction medium is filtered through a porous glass, the solid is washed with a minimum amount of absolute ethanol, then dried in vacuum.

Output: 40-100%

The samples subjected to analysis of LC-UV-MS under the following conditions:

Gradient: acetonitrile 10 water 90 d is acetonitrile 90 - water 10 for 8 minutes

Column: X-terra_MS C 3.5 3 μm*50 mm

Flow rate: 0.5 ml/min

UV: diode pin 290 nm-450 nm

MS: electrospray with positive or negative ionization at atmospheric pressure.

As the example below shows the reaction scheme for the method of obtaining compounds 1, 3, 4, and 8.

Example 1: Link 1

Getting 4-{5-[2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]-2-furyl}benzoic acid

The reaction scheme

The experiment

Stage 1

In a three-neck flask with a volume of 50 ml, equipped with a cooling system, and a magnetic stir bar, dissolve 1,99 g book (6.16 mmol) of tetrabutylammonium bromide in 100 ml of water, then give 1.12 g (6.7 mmol) of 4-carboxybenzeneboronic acid (reagent), 1.08 g (6,16 mmol) 5-bromo-2-furaldehyde (reagent a), 30 mg (2 mol.%) of palladium acetate and 2.12 g (to 15.4 mmol) of potassium carbonate. The reaction medium is maintained at room temperature (20-25° (C) within 12 hours. The mixture is then washed with ethyl acetate (three times 50 ml). The aqueous phase is acidified to obtain a pH of 1-2 35% solution of hydrochloric acid. The obtained solid beige-yellow (compound A) was filtered, then washed with water (three times 20 ml) and dried under vacuum in the presence of 1.2 g of phosphorus pentoxide. The yield of the reaction is 90%.

Stage 2

In a three-neck flask with a volume of 50 ml, equipped with a system the Dean-Stark", thermometer, and magnetic stir bar, dissolve 0,38 g (3.25 mmol) of thiazolidine-2,4-dione in 20 ml of toluene, then give 0.7 g (3.25 mmol) solid beige-yellow substance obtained in stage 1 (compound A). Then add 0.15 ml of acetic acid and 0.15 ml of piperidine, after which the mixture is heated under reflux for 5 hours. Formed solid yellow color, which is filtered, then washed with toluene (twice 20 ml). Then the product is dried under vacuum in the presence of 0.85 g of phosphorus pentoxide. Yield of the crude reaction product is 78%.

Analysis

Nuclear magnetic resonance spectrum obtained corresponds to the proposed structure.

Example 2: link 3

Getting 5-({5-[3,5-bis(trifluoromethyl)phenyl]-2-furyl}-methylene-1,3-thiazolidin-2,4-dione

The reaction scheme

The experiment

In a three-neck flask with a volume of 50 ml, equipped with Dean-Stark", a thermometer, and magnetic stir bar, dissolve 0,38 g (3.25 mmol) of thiazolidine-2,4-dione (reagent a) in 20 ml of toluene, then enter 1 g (3.25 mmol) of 5-[3,5-bis(trifluoromethyl)phenyl]-2-furaldehyde (reagent). Then add 0.15 ml of acetic acid (Asón) and 0.15 ml of piperidine, after which the mixture is heated under reflux for 5 hours. In the process of the reaction is a solid yellow color. It is filtered, the m washed with toluene (twice 20 ml). Next, the product is dried under vacuum in the presence of 0,86 g of phosphorus pentoxide. The yield of the reaction is 65%.

Analysis

Mass spectrometry: detected quasimolecular ion (M-H)-target molecules With16H7F6NO3S.

Nuclear magnetic resonance spectrum obtained corresponds to the proposed structure.

Example 3: link 4

Obtain 3-{5-[2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]-2-furyl}benzoic acid

The reaction scheme

The experiment

Stage 1

In a three-neck flask with a volume of 50 ml, equipped with a cooling system, and a magnetic stir bar, dissolve 1,99 g book (6.16 mmol) of tetrabutylammonium bromide in 100 ml of water, then give 1.12 g (6.7 mmol) of 3-carboxybenzeneboronic acid (reagent), 1.08 g (6,16 mmol) 5-bromo-2-furaldehyde (reagent a), 30 mg (2 mol.%) of palladium acetate and 2.12 g (to 15.4 mmol) of potassium carbonate. The reaction medium is maintained at room temperature (20-25° (C) within 12 hours. The mixture is then washed with ethyl acetate (three times 50 ml). The aqueous phase is acidified to obtain a pH of 1-2 35% solution of hydrochloric acid. The obtained solid beige-pink color (compound A) was filtered, then washed with water (three times 20 ml) and dried under vacuum in the presence of 1.1 g of phosphorus pentoxide. The yield of the reaction is 82%.

Stage 2

In a three-neck flask with a volume of 50 is l, equipped with Dean-Stark", a thermometer, and magnetic stir bar, dissolve 0,542 g (to 4.62 mmol) thiazolidin-2,4-dione in 20 ml of toluene, then enter 1 g (4,62 mmol) solid beige-pink substance, obtained in stage 1 (compound A). Then add 0.15 ml of acetic acid (Asón) and 0.15 ml of piperidine, after which the mixture is heated under reflux for 5 hours. Formed solid yellow color, which is filtered, then washed with toluene (twice 20 ml). Then the solid was dispersed in 100 ml of water. Add an aqueous solution of 2n. sodium hydroxide to dissolve the product, and then acidified to obtain a pH of 1-2 aqueous solution of 1H. of hydrochloric acid. The obtained solid brown color is filtered, then washed with water (twice 50 ml) and dried under vacuum in the presence of 0,86 g of phosphorus pentoxide. The output is 63%.

Analysis

Nuclear magnetic resonance spectrum obtained corresponds to the proposed structure.

Example 4: Compound 8

Receive a double sodium salt of 4-{5-[2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]-2-furyl}benzoic acid

The reaction scheme

The experiment

15 g of 3-{5-[2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]-2-furyl}benzoic acid are dissolved in 500 ml of an aqueous solution of sodium hydroxide (2 equivalents). Received rastv the R washed twice with 50 ml of dichloromethane, then partially concentrated. This solution was poured into acetone. The result is 11 g sediment of the yellow-orange color, the corresponding dual sodium salt of 4-{5-[2,4-dioxo-1,3-thiazolidin-5-ilidene)methyl]-2-furyl}benzoic acid in the form of a Z.

Analysis

Nuclear magnetic resonance spectrum obtained corresponds to the proposed structure.

Example 5: Identification of specific inhibitory properties of compounds of formula (I) in respect of 15-PGDH.

1)Experience of 15-PGDH

The enzyme 15-PGDH receive, as described in the application FR-A-02/05067 company L'oréal, in suspension in an adapted environment with a concentration of 0.3 mg/ml, then block at -80°C. For the experiment this suspension is thawed and stored on ice.

Separately, prepare the buffer 100 mm Tris, pH 7.4, containing 0.1 mm dithiothreitol (D5545, Sigma-Aldrich, L'isle d'abeau Chesne, BP 701, 38297, Saint Quentin Fallavier), 1.5 mm β-NAD (N6522, Sigma-Aldrich, L'isle d'abeau Chesne, BP 701, 38297, Saint Quentin Fallavier), 50 μm of prostaglandin E2(R, Sigma-Aldrich, L'isle d'abeau Chesne, BP 701, 38297, Saint Quentin Fallavier).

In the tank spectrophotometer (Perkin-Elmer, Lambda 2), thermostated at 37°With a measuring wavelength of 340 nm, enter 0,965 ml of the specified buffer (preheated to 37°). a 0.035 ml suspension of the enzyme at 37°injected into the reservoir, while registration of the increase of optical density at 340 nm). The maximum reaction rate of polychaets is.

The data obtained (in the presence of compound (1)) compared with the control (without connection (1)); the results show, at what concentration, denoted IC50dh, connection (1) inhibits the enzymatic activity of 15-PGDH by 50%.

2)Experience in respect of PGFS

The enzyme PGF synthase receive, as described in document FR-A-02/05067, at a concentration of 0.5 mg/ml in suspension in an appropriate environment and block at -80°C. For the experiment this suspension is thawed and stored on ice.

Separately, in the dark glass flask prepare a Tris buffer 100 mm, pH 6.5, containing 20 mm 9,10-phenanthrenequinone* (* the mother solution with a titer of 1 mm is prepared in absolute ethanol at 40°With; the flask is placed in a tank in terms of ultrasonic influence, contributing to the dissolution of the product.) (R, Sigma-Aldrich, L'isle d'abeau Chesne, BP 701, 38297, Saint Quentin Fallavier) and 100 μm β-NADPH (N1630, Sigma-Aldrich, L'isle d'abeau Chesne, BP 701, 38297, Saint Quentin Fallavier).

In the tank spectrophotometer (Perkin-Elmer, Lambda 2), thermostated at 37°With measuring wave length of 340 nm, enter 0,950 ml of the specified buffer (preheated to 37°). 0.05 ml of the suspension of the enzyme at 37°injected into the reservoir, while registration (lower optical density at 340 nm). The maximum reaction rate increases.

The data obtained (in the presence of compound (1)) is compared with to troinymi (without connection (1)); the results show, at what concentration, denoted IC50fs, connection (1) inhibits the enzymatic activity of 15-PGFS by 50%.

ConnectionStructureInhibition of 15-PGDH IC50dh(μm)Inhibition of PGFS IC50fs (µm)
10,34

The table shows that the ratio of the IC50fs/IC50dh connection 1 more 13. Thus, compound 1 has inhibitory activity against 15-PGDH and, in particular, selective inhibitory activity against PGFS.

The following compounds receive traditional methods, widely used in cosmetics and pharmaceuticals.

Example 6: Lotion for hair care

Connection 10,80 g
Propylene glycol10,00 g

Isopropyl alcohol - enough to 100.00 g

This lotion is applied on the hair one to two times per day at a rate of 1 ml per application, easy to massage the hair for penetration of the active substance. Then the hair is dried in the air. This lotion reduces hair loss and with osobiste their growth.

Example 7: Lotion for hair care

Connection 21,00 g
Propylene glycol30,00 g
Ethanol40,00 g
Waterthe number to 100.00 g

This lotion is applied on the hair one to two times per day at a rate of 1 ml per application, easy to massage the hair for penetration of the active substance. Then the hair is dried in the air.

Example 8: Lotion for hair care

Connection 11,00 g
Ethanol40,00 g
NaOHa sufficient number(*)
Waterthe number to 100.00 g

(*) a quantity sufficient to neutralize the acid functional groups in the phenyl nucleus (R1).

This lotion is applied on the hair one to two times per day at a rate of 1 ml per application, easy to massage the hair for penetration of the active substance.

Example 9: Identify the effectiveness of specific inhibition of 15-PGDH in the cellular model.

The present study allows to evaluate the compounds of formula (I) at the cellular model. This study is allows to determine the penetration of active substances in cytosol, as well as its effectiveness as a selective inhibitor of 15-PGDH in more difficult conditions than just the reaction medium.

Equipment and methods

J-2. Culture U937 (CRL-1593 American Type Cells Collection) in medium RPMI 1640+10% serum bovine embryo+2 mm L-glutamine + antibiotics at 37°C in an atmosphere containing 5% CO2.

J-1. Get the suspension U937 (1·106cells/ml) in RPMI 1640+10% serum bovine embryo +2 mm glutamine + antibiotics +10 nm PMA (phorbol-12-myristate-13-acetate); 96-well plate is injected with 200 µl of this suspension per well (3 wells per molecule at the tested concentration + corresponding control samples); incubated for 36 hours at 37°C in an atmosphere containing 5% CO2.

J0. Remove the pooled liquid (cells attached to the bottom of the hole: microscopic control) and each well administered 100 μl of RPMI 1640+2 mm L-glutamine+10 ng of lipopolysaccharide (LPS)(except absolute control sample) + test molecule in the desired concentration (5 and 25 μm).

Incubated for 6 hours in an atmosphere containing 5% CO2.

Concentration of the mother solutions of the tested molecules in dimethyl sulfoxide (DMSO) is 25 mm.

All wells contain the same amount of DMSO.

Conduct rapid analysis on the content of PGFα, secreted by the cells (50 μl) in different conditions (is olekuly and control samples) using immunoenzymatic dispenser (Cayman 516011).

Below are the results in % of the control sample LPS

Molecule (5 μm)% control sample
Connection 1+76±20
Compound 8+44±16

The results confirm that the compounds according to the invention are selective inhibitors of 15-PGDH in the cellular environment and protect the prostaglandins.

Example 10: Lotion for hair care

Compound 81 g
Ethanol40,00 g
Propylene glycol30,00 g
Waterthe number to 100.00 g

Example 11: Mascara wax/water

Beeswax6,00%
Paraffin13,00%
Hydrogenated jojoba oil2,00%
Water-soluble film-forming polymer3,00%
Triethanolamine stearate8,00%
Connection 51,00%
Black dyeto 5.00%
Preservativeenough
At the and enough to 100.00%

This mascara applied to the lashes as usual mascara, using a conventional brush, used for this purpose.

Example 12: Lotion for hair care

Compound 80.10 g
Latanoprost0.10 g
Propylene glycol30,00 g
Ethanol40,00 g
Waterthe number to 100.00 g

Example 13: Lotion for hair care

Compound 81%
Ethanol49,5%
Waterthe number to 100%

This lotion is applied on the hair one to two times per day at a rate of 1 ml per application, easy to massage the hair for penetration of the active substance. Then the hair is dried in the air. This lotion reduces hair loss and promotes their growth. It also helps to improve the appearance of hair.

1. Applying an effective amount of at least one heterocyclic compound of the formula (I) or its salts

in which Z and Z′ independently represent O or S; X Ref is em Oh, NH or S; G represents O, S, NH, R denotes hydrogen or a saturated linear or branched C1-C10-alkyl; R1, R2and R3independently of one another denote hydrogen, halogen, a group OR0, SR0, NR0R0′, COR0, CSR0, NR0CONR0′R0′′, C(=NR0R0′, C(=NR0)NR0′R0′′, NR0C(=NR0′)NR0′′R0′′′, OCOR0, COSR0, SCOR0, CSNR0R0′, NR0CSR0′, NR0CSNR0′R0′′, COOR0, CONR0R0′, CF3, NO2, CN, NR0COR0′, SO2R0′, SO2NR0R0′, NR0SO2R0′linear or branched saturated or unsaturated With1-C20-alkyl, at least one of a 4-7-membered cycle, saturated or unsaturated, possibly containing at least one heteroatom, and these cycles can be individual or concatenated, in addition, the alkyl radicals and the cycles may be substituted, where R0, R0′, R0′′ and R0′′′, identical or different, denote hydrogen, linear or branched C1-C20-alkyl, or aryl, possibly substituted, wherein the compound of formula (I) in baraut from

(i) compounds of the formula (III) or their salts

in which Z, Z′ denote O, X denotes S (thiazolidinedione group), G represents O or S; at least one of R2and R3means CF3OR0or COOR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl,

(ii) compounds (VI) or their salts

in which Z, Z′ and G independently represent O or S, at least one of R2and R3denotes hydrogen, CN, CF3, NO2OR0, COOR0or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl, possibly substituted OR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl,

(iii) compounds (VII) or their salts

,

in which Z, Z′ and G independently represent O or S; R represents a saturated linear or branched C1-C10-alkyl; at least one of R2and R3refers to saturated linear or branched C1-C20-alkyl and preferably1- 10-alkyl, NO2OR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl

as an agent, the caller and/or stimulating the growth of keratin fibers, in particular human, and/or preventing their loss and/or increasing their density.

2. The use according to claim 1, characterized in that the COOR0denotes COOH or SOON2-CH3.

3. The use according to any one of claims 1 and 2, characterized in that R2denotes COOH and R3denotes H; R2means of SOON2-CH3and R3denotes H; or R2and R3denote CF3or och3.

4. The use according to any one of claims 1 and 2, characterized in that the salt of compound (I)is a salt selected from the salts of sodium, potassium, salts of zinc (Zn2+), calcium (CA2+), copper (Cu2+), iron (Fe2+), strontium (Sr2+), magnesium (Mg2+), manganese (Mn2+), ammonium; salts of triethanolamine, monoethanolamine, diethanolamine, hexadecylamine, N,N,N′N′-tetrakis(hydroxypropyl-2)Ethylenediamine, trihydroxypyrimidine, hydroxides, carbonates, halides, sulfates, phosphates, nitrates.

5. The use according to claim 1 or 2, characterized in that the compound selected from the

,2Na+

6. The use according to any one of claims 1 and 2, characterized in that the compound of formula (I) or a mixture of these compounds are used in concentrations from 10-3up to 10%, preferably from 10-2up to 2%, relative to the total weight of the composition.

7. The use according to claim 1 or 2, characterized in that the composition is a composition for local application.

8. The use of at least one heterocyclic compound of the formula (I) or its salts

in which Z and Z′ independently represent O or S; X represents O, NH or S; G represents O, S, NH, R denotes hydrogen or a saturated linear or branched C1-C10-alkyl; R1, R2and R3independently of one another denote hydrogen, halogen, a group OR0, SR0, NR0R0′, COR0, CSR0, NR0CONR0′R0′′, C(=NR0R0′, C(=NR0)NR0′R0′′, NR0C(=NR0′)NR0′′R0′′, OCOR0, COSR0, SCOR0, CSNR0R0′, NR0CSR0′, NR0CSNR0′R0′′, COOR0, CONR0 R0′, CF3, NO2, CN, NR0COR0′, SO2R0′, SO2NR0R0′, NR0SO2R0′linear or branched saturated or unsaturated With1-C20-alkyl, at least one of a 4-7-membered cycle, saturated or unsaturated, possibly containing at least one heteroatom, and these cycles can be individual or concatenated, besides the alkyl radicals and the cycles may be substituted, where R0, R0′, R0′′ and R0′′′, identical or different, denote hydrogen, linear or branched C1-C20-alkyl, or aryl, possibly substituted, wherein the compound of formula (I) are selected from

(i) compounds of the formula (III) or their salts

,

in which Z, Z′ denote O, X denotes S (thiazolidinedione group), G represents O or S; at least one of R2and R3means CF3OR0or COOR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl,

(ii) compounds (VI) or their salts

in which Z, Z′ and G independently represent O or S, at least one, and the R 2and R3denotes hydrogen, CN, CF3, NO2OR0, COOR0or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl, possibly substituted OR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably With1-C10-alkyl,

(iii) compounds (VII) or their salts

in which Z, Z′ and G independently represent O or S; R represents a saturated linear or branched C1-C10-alkyl; at least one of R2and R3refers to saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl, NO2OR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl

as an inhibitor of 15-hydroxyprostaglandin.

9. Composition for care or make-up keratin fibers, the initiator and/or stimulating the growth of keratin fibers, in particular human, and/or preventing their loss and/or increasing their density, containing a physiologically acceptable medium and an effective amount of at least one heterocyclic compound (I) or it is salt

in which Z and Z′ independently represent O or S; X represents O, NH or S; G represents O, S, NH, R denotes hydrogen or a saturated linear or branched C1-C10-alkyl; R1, R2and R3independently of one another denote hydrogen, halogen, a group OR0, SR0, NR0R0′, COR0, CSR0, NR0CONR0′R0′′, C(=NR0R0′, C(=NR0)NR0′R0′′, NR0C(=NR0′)NR0′′R0′′′, OCOR0, COSR0, SCOR0, CSNR0R0′, NR0CSR0′, NR0CSNR0′R0′′, COOR0, CONR0R0′, CF3, NO2, CN, NR0COR0′, SO2R0′, SO2NR0R0′, NR0SO2R0'linear or branched saturated or unsaturated With1-C20-alkyl, at least one of a 4-7-membered cycle, saturated or unsaturated, possibly containing at least one heteroatom, and these cycles can be individual or concatenated, in addition, the alkyl radicals and the cycles may be substituted, where R0, R0′, R0′′ and R0′′′, identical or different, denote hydrogen, linear or rasvet the n 1-C20-alkyl, or aryl, possibly substituted, wherein the compound of formula (I) are selected from

(i) compounds of the formula (III) or their salts

in which Z, Z′ denote O, X denotes S (thiazolidinedione group), G represents O or S; at least one of R2and R3means CF3OR0or COOR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl,

(ii) compounds (VI) or their salts

in which Z, Z′ and G independently represent O or S, at least one of R2and R3denotes hydrogen, CN, CF3, NO2OR0, COOR0or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl, possibly substituted OR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl,

(iii) compounds (VII) or their salts

in which Z, Z′ and G independently represent O or S; R represents a saturated linear or branched C1-C10-alkyl; at least one of R2and R3 refers to saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl, NO2OR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl.

10. The composition according to claim 9, characterized in that the COOR0denotes COOH or SOON2-CH3.

11. Composition according to any one of p-10, characterized in that R2denotes COOH and R3denotes H; R2means of SOON2HE3and R3denotes H; or R2and R3denote CF3or och3.

12. Composition according to any one of p-10, characterized in that the salt of the compounds of formula (I) salt is selected from salts of sodium, potassium, salts of zinc (Zn2+), calcium (CA2+), copper (Cu2+), iron (Fe2+), strontium (Sr2+), magnesium (Mg2+), manganese (Mn2+), ammonium; salts of triethanolamine, monoethanolamine, diethanolamine, hexadecylamine, N,N,N′N′-tetrakis(hydroxypropyl-2)Ethylenediamine, trihydroxypyrimidine, hydroxides, carbonates, halides, sulfates, phosphates, nitrates.

13. The composition according to claim 9 or 10, characterized in that the compound of formula (I) selected from the

,2Na+

14. Composition according to any one of p-10, characterized in that the compound of formula (I) or a mixture of these compounds are used in concentrations from 10-3up to 10%, preferably from 10-2up to 2%, relative to the total weight of the composition.

15. Composition according to any one of p-10, characterized in that it has the form of a cream or lotion for hair care, shampoo or drugs used after shampoo, mascara for hair or eyelashes.

16. Composition according to any one of p-10, characterized in that the composition has the form of aqueous, alcoholic or aqueous-alcoholic solution or suspension.

17. Composition according to any one of p-10, characterized in that it contains other components that are selected from solvents, thickeners or funds gelatinosa the aqueous phase or oil phase, dyes, soluble in the medium, forming part of the composition, fillers or pigments, antioxidants, preservatives, fragrances, electrolytes, neutralizing means, film-forming polymers, UV blockers, active cosmetic or therapeutic substances, in addition to the compounds of formula (I), their mixtures.

18. Composition according to any one of p-10, characterized in that it contains at least an additional active compound, contribute ro the specifications and/or limiting the loss of keratin fibers.

19. Composition according to any one of p-10, characterized in that it contains at least an active connection, promoting growth and/or limiting the loss of hair, which are chosen from aminexil, 6-0-[(9Z,12Z)-octadeca-9,12-dienoyl]hexopyranosyl, agonists potassium channels, lipoxygenase inhibitors, inhibitors of bradykinin, prostaglandins and their derivatives, agonists or antagonists of receptors of prostaglandins, neproshenyh analogues of prostaglandins, vasodilators, anti-androgens, cyclosporine and their analogues, antimicrobial agents, anti-inflammatory agents, retinoids, benzalkonium chloride, chloride benzene, phenol, estradiol, maleate of chlorpheniramine derived chloroprene, cholesterol, cysteine, methionine, menthol, peppermint oil, calcium Pantothenate, panthenol, resorcinol, activators of protein kinase C, glycosidase inhibitors, inhibitors of glycosaminoglycans, esters pyroglutamic acid, hexosamine or aciphexeuhoria acids, aryl-substituted atilano, N-acylated amino acids, flavonoids, derivatives and analogs of ascomycin, histamine antagonists, saponins, inhibitors of proteoglycans, agonists and antagonists of estrogen, pseudoterranova, cytokines and promoters of growth factors, inhibitors of IL-1 or IL-6, the promoters of IL-10, inhibitors of NF, vitamins, benzophenone, as octopirox, retinoic acid, antipruritic agents, anti-parasite substances, antifungal agents, esters of nicotinic acid calcium antagonists, hormones, triterpenes, anti-androgens, steroid or non-steroidal inhibitors of 5-α-reductase, agonists of the receptor FP, and mixtures thereof.

20. The composition according to claim 19, wherein the additional compound selected from aminexil, agonists of the receptor FP and vasodilators.

21. Composition according to any one of p-10, characterized in that, in addition, it contains other active substance selected from proteins, protein hydrolysates, amino acids, polyols, urea, allantoin, sugars and sugar derivatives, plant extracts, hydroxy acids, derivatives of retinol or tocopherol, essential fatty acids, ceramides, essential oils, salicylic acid and its derivatives such as salicylic n-octanoyl-5, esters of hydroxy acids and phospholipids.

22. The composition according to claim 20, wherein the additional active substance selected from aminexil, Minoxidil, latanoprosta, butaprost and travoprost.

23. Method of cosmetic treatment of keratin fibers and/or skin on which to grow these fibers, wherein the fibers and/or cause skin cosmetic composition described in which the yubom of PP-22, leave it in contact with the fibers and/or skin and possibly rinsed.

24. Way, calling stimulate the growth of eyelashes, and/or preventing their loss and/or increasing their density, characterized in that on the eyelashes and/or eyelids composition is applied mascara that contains at least one compound (I) or one of its salts, and leave it in contact with the eyelashes and/or eyelids.

25. Way, calling stimulating growth of human hair and/or preventing their loss and/or increasing their density, characterized in that on the hair and/or hair cause cosmetic composition comprising an effective amount of at least one compound (I) or one of its salts specified in claim 1, leave it in contact with the hair and/or scalp and possibly rinse hair and/or hair.

26. Heterocyclic compound selected from the following compounds:

,2Na+

27. Heterocyclic compound of the following formula (VI) or its corresponding salt:

in which Z, Z′ and G independently represent O or S; at least one of R 2and R3denotes hydrogen, CN, CF3OR0, COOR0or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl, possibly substituted OR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl.

28. Heterocyclic compound of the following formula (VII) or its corresponding salt:

in which Z, Z′ and G independently represent O or S; R represents a saturated linear or branched C1-C10-alkyl; at least one of R2and R3refers to saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl, NO2OR0where R0denotes H or a saturated linear or branched C1-C20-alkyl and preferably1-C10-alkyl.

29. Connection item 27 or 28, characterized in that it has the shape of a Z.

30. Use for cosmetic purposes, at least one heterocyclic compound of the formula (I) as defined in claim 1, or one of its salts in cosmetic compositions as agent for maintaining the level and/or activity of prostaglandins in the hair follicle.

31. Use less than the least one heterocyclic compounds of the formula (I) as defined in claim 1, or one of its salts to obtain a composition intended for maintaining the level and/or activity of prostaglandins in the hair follicle.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel indolyl-derivatives of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkyl substituted with from one to three halogen atoms; R2 means hydrogen atom, (C1-C8)-alkyl; R3 means (C1-C8)-alkoxy-group; R4 means hydrogen atom; A means oxygen atom or sulfur atom; n = 1,2 or 3. Synthesized compounds possess agonistic activity with respect to PPARα- and/or PPARγ-receptors. Also, invention relates to methods for their synthesis, a pharmaceutical composition based on thereof and their using for preparing medicinal agents, and to a method for treatment and/or prophylaxis of diseases.

EFFECT: improved method of synthesis and treatment, valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 7 sch, 17 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

44 cl, 77 dwg, 13 ex

FIELD: organic chemistry, biochemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to novel diaminothiazoles of the formula (I) , their pharmaceutically acceptable salts and esters, and to a pharmaceutical composition based on thereof. Proposed compounds inhibit activity of cyclin-dependent kinase 4 (Cdk4), shows selectivity with respect to Cdk2 and Cdk1 and can be used in treatment against cancer, in particular, against solid tumors. In the general formula (I) R2 and R3 represent hydrogen atom; R4 is chosen from group comprising lower alkyl, (C3-C6)-cycloalkyl, O-lower alkyl, halogen atom, -NO2, S-lower alkyl, -CF3 and -CN; R5 is chosen from group comprising hydrogen atom, O-lower alkyl, lower alkyl, halogen atom and -OH, or, alternatively, R4 and R in common with two carbon atoms and a bond binding them belonging to benzene cycle (C) to which R4 and R5 are bound can form a cycle consisting of 5-6 atoms comprising one or two heteroatoms chosen from oxygen atom and optionally substituted with (C1-C4)-alkyl; R6 and R are chosen independently from group comprising hydrogen atom, lower alkyl and -COOR12, or, alternatively, group -NR6R7 can mean cycle consisting of 5-6 atoms optionally comprising heteroatom chosen from nitrogen or oxygen atoms; R8 and R9 are chosen independently from group comprising hydrogen atom and lower alkyl; R10 is chosen from group comprising hydrogen atom, lower alkyl, lower alkyl substituted with hydroxyl, and -COOR12; R11 is chosen from group comprising hydrogen atom, lower alkyl and -COOR12 wherein R12 means lower alkyl; m can mean 1 or 2; n can mean 0, 1 or 2 under condition that if m means 2 and R4 means fluorine atom then R5 is not hydrogen atom, and under condition if m means 1 and R4 means lower alkyl then R5 is not hydroxyl.

EFFECT: valuable biochemical and medicinal properties of compounds and pharmaceutical compositions.

20 cl, 6 sch, 3 tbl, 153 ex

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EFFECT: valuable properties of compounds and pharmaceutical composition.

7 cl, 37 ex

FIELD: organic chemistry, medicine.

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EFFECT: new compounds with value biological properties.

32 cl, 56 ex

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18 cl, 388 ex, 68 tbl, 3 dwg

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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I):

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel indolyl-derivatives of the formula (I): and their pharmaceutically acceptable salts and esters wherein R1 means phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkyl, (C1-C8)-alkoxy-group and (C1-C8)-alkyl substituted with from one to three halogen atoms; R2 means hydrogen atom, (C1-C8)-alkyl; R3 means (C1-C8)-alkoxy-group; R4 means hydrogen atom; A means oxygen atom or sulfur atom; n = 1,2 or 3. Synthesized compounds possess agonistic activity with respect to PPARα- and/or PPARγ-receptors. Also, invention relates to methods for their synthesis, a pharmaceutical composition based on thereof and their using for preparing medicinal agents, and to a method for treatment and/or prophylaxis of diseases.

EFFECT: improved method of synthesis and treatment, valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 7 sch, 17 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means hydrogen atom or lower alkyl; R2 means substituted or unsubstituted thiazolinyl or oxazolinyl residue; each R5 and R6 means independently hydrogen atom or protective group; X means oxygen (O), sulfur atom (S) or -NR7 wherein in each case R7 means hydrogen atom or lower alkyl; RB means in each case independently hydrogen atom, (C1-C6)-alkyl, -CY3, -CHY2 or -CH2Y wherein Y means F, Br, Cl or J. Also, invention relates to a pharmaceutical composition containing compounds of the formula (I) and possessing cytotoxic activity, and using this compound in treatment of malignant tumor with multiple drug resistance.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

44 cl, 77 dwg, 13 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of aminotetraline of the formula (I) wherein R1 means (C1-C6)-alkyl; R2 means halogen atom or -OR'; R3 means hydrogen atom (H) or -OR' wherein R' means (C1-C6)-alkyl or -SO2R'' wherein R'' means phenyl, thienyl, isoxazolyl; R4 means (C1-C6)-alkyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepinyl, furanyl, isoxazolyl, imidazolyl and pyrazolyl that can be substituted optionally, and pharmaceutical compositions containing derivatives of aminotetraline. Proposed compounds are selective antagonists of M2/M3 muscarinic receptors and designated for treatment and prophylaxis of diseases associated with smooth muscle disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 1 tbl, 16 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to alkylated (1H-benzimidazol-5-yl)-(-4-substituted phenyl)-amine derivatives, in particular compound of formula and pharmaceutically acceptable salts or solvates thereof, wherein R1, R2, and R9, are independently hydrogen, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluorimethoxy, azido, etc.; R7 is optionally substituted C1-C10-alkyl, C3-C10-cycloalkyl, etc.; A is-OR3 or NR4R3; R8 is hydrogen, -Cl, -Br, -F, cyano, nitro, etc.; and meanings of the rest substituents are as defined in specification. Also disclosed is composition for MEK inhibition and uses of benzinidazole compounds.

EFFECT: new compounds with value biological properties.

32 cl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): wherein R means -C(O)R1 wherein R1 is chosen from the series: (C1-C6)-alkyl, -C=CH-COOH, -NHCH2-CH2R2, -N(CH2-CH2OH)CH2-CH2OH, -N(CH3)CH2-CH2-NHCH3, -N(CH3)CH2-CH2N(CH3)CH3, saturated 4-, 5- and 6-membered cycles and saturated and unsaturated 5- and 5-membered cycles comprising at least one heteroatom from a series sulfur (S), nitrogen (N) and oxygen (O), and optionally substituted with a group chosen from the series: (C1-C6)-alkyl, -C=O-R5, -OH, (C1-C6)-alkyl substituted with hydroxy-group optionally, (C1-C6)-alkyl substituted optionally with a group of the series: -NH2, -N-(C1-C6)-alkyl, -SO2CH3, =O, and 5- and 6-membered saturated cycles comprising at least one heteroatom chosen from N and O, and wherein R5 is chosen from the series: hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-alkyl substituted with hydroxy-group optionally, and (C1-C6)-alkyl substituted with NH2-group optionally; R2 is chosen from the series: -N(CH3)CH3, -NH2, morpholinyl and piperazinyl; X1, X2 and X3 are chosen independently from the series: -OH, (C1-C2)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CH2OCH3 and -CH2OCH2CH3, or one among X1, X2 or X3 means hydrogen atom, and two others are chosen independently from the series: hydroxy-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, -Cl, -Br, -F, -CF3, -CH2OCH3, -CH2OCH2CH3, -OCH2-CH2R3, -OCH2-CF3 and -OR4, morpholylmethyl, -N(CH3)CH3, -CH2OH, -COOH, or one among X1, X2 or X3 means hydrogen atom, and two others in common with two carbon atoms including bonds between them in benzene cycle to which they are bound optionally form 5- or 6-membered saturated cycle comprising at least one heteroatom chosen from S, N and O, and wherein R3 is chosen from the series: -F, -OCH3, -N(CH3)CH3, saturated 5-membered cycle comprising at least one heteroatom N; R4 means 3-5-membered saturated cycle, and each Y1 and Y2 is chosen independently from the series: -Cl, -Br, -NO2,-C≡N and C≡N, and compound of the formula (II) also given in the invention description. Also, invention relates to a pharmaceutical composition possessing anti-proliferative activity and based on these compounds. Invention provides preparing novel compounds possessing the useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

28 cl, 39 ex

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to N3-alkylated benzimidazole derivatives for preparing a drug used in inhibition of MEK activity. Invention describes benzimidazole compound of the formula (I): and its pharmaceutically acceptable salts and solvates wherein R1, R2, R9 and R10 are chosen independently from hydrogen atom, halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-, azido-group, -OR3, -C(O)R3, -C(O)OR3, -OC(O)R3, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group; R3 is chosen from hydrogen atom, trifluormethyl group, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl group is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R' wherein R' is chosen independently from hydrogen atom, lower alkyl; R4 represents independently hydrogen atom or (C1-C6)-alkyl; R6 is chosen from trifluoromethyl group or (C1-C10)-alkyl, (C3-C10)-cycloalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R', -C(O)OR', -OC(O)R', -OR'; R7 is chosen from (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkylalkyl wherein each alkyl and cycloalkyl moiety is substituted possibly with groups in the amount from one to five and chosen independently from halogen atom, trifluoromethyl group, difluoromethoxy-, trifluoromethoxy-group, -C(O)R3, -C(O)OR3, -OC(O)R3, -SO2R6, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; W is chosen from -C(O)OR3, -C(O)NR3R4, -C(O)NROR3, -C(O)R4OR3, -C(O)(C3-C10)-cycloalkyl, -C(O)(C1-C10)-alkyl. Also, invention describes compositions used for inhibition of MEK activity, using such compounds for preparing a drug used in inhibition of MEK activity and preparing a drug used in cancer treatment.

EFFECT: valuable medicinal and biochemical properties of compounds and composition.

17 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I) wherein p, R1, R2, R3 and A are determined in the invention description, their individual isomers and their pharmaceutically acceptable salts. Proposed compounds possess antagonistic effect with respect to muscarinic receptors that allows their using in treatment and prophylaxis of diseases yielding to treatment with muscarinic receptor antagonist. Also, invention describes a pharmaceutical composition containing these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 22 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds represented by the general formula (I): and their pharmaceutically acceptable salts and esters possessing agonistic activity with respect to peroxisome proliferator receptors PPARα and/or PPARγ, to a pharmaceutical composition based on thereof and their using for preparing medicines wherein R1 means thiophenyl or phenyl optionally substituted with from one to three substitutes chosen independently from halogen atom, (C1-C8)-alkoxy-group, (C1-C8)-alkyl and (C1-C8)-alkyl substituted with one-three halogen atoms; R2 means hydrogen atom or (C1-C8)-alkyl; R3 means phenoxy-, (C2-C8)-alkenyloxy- or (C1-C8)-alkoxy-group; R4 means hydrogen atom or (C1-C8)-alkyl wherein one of substitutes R5 and R6 means compound of the formula and another one means hydrogen atom and wherein the bond between carbon atoms Ca and Cb means a carbon-carbon simple or double bond; R7 means hydrogen atom or (C1-C8)-alkyl; R8 means hydrogen atom or (C1-C8)-alkyl being any of A and A1 means nitrogen atom and another means oxygen or sulfur atom; n means 1, 2 or 3.

EFFECT: valuable medicinal properties of compound and pharmaceutical composition.

30 cl, 1 tbl, 14 sch, 86 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I):

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: medicine, pharmacology.

SUBSTANCE: invention relates to new enantiomerically pure (-)3-((S)-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-thienyl)methyl)phenol, pharmaceutical composition containing the same having antagonistic activity in relates to μ- and/or δ-opioid receptors; methods for treatment of pain, cough, functional diarrhea, functional pain, heart diseases, emesis; method for receptor-mediated analgesia; method for amelioration, treatment and prevention of drug-mediated respiratory depression; method for screening of compounds suppressing opioid respiratory depression; pharmaceutical composition containing biologically active agent for treatment of pain, cough, functional diarrhea, functional pain, heart diseases, emesis, respiratory depression and claimed compound; and method for performance of reaction mediated with opioid receptors.

EFFECT: therapy of increased effectiveness.

17 cl, 6 dwg, 4 tbl, 7 ex

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