Novel imidazolidine compounds as androgen receptor modulators

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to novel 2,5-dioxo-imidazolidine derivatives of general formula lb , or pharmaceutically acceptable salts and solvates thereof, or solvates of pharmaceutically acceptable salts, where X denotes O; R1 is H; or R1 is selected from C1-C6 alkyl and C1-C6 alkynyl, where the alkyl can optionally be substituted with a cyano group; R2a is selected from H, P(O)(OH)2 and C(O)(CH2)n1C(O)OH; or R2a is selected from -C(O)-C1-C6 alkyl, which is substituted with amino; n1 equals 1 or 2; each R2 and Rc is independently selected from H and C1-C6 alkyl; R3a is H, a halogen atom or cyano; each R3b is independently a halogen atom or cyano; or each R3b is independently C1-C6 alkyl, optionally substituted with three halogen atoms; each R4a and R4b is independently H or a halogen atom; or each R4a and R4b is selected from C1-C6 alkyl, and C1-C6 alkoxy, where the alkyl is substituted with three halogen atoms; R4c is a halogen atom or cyano; and ml equals 0 or 1. The invention also relates to a pharmaceutical composition based on a compound of formula lb and use thereof.

EFFECT: obtaining novel 2,5-dioxo-imidazolidine derivative which modulate androgen receptor activity.

20 cl, 5 tbl, 31 ex

 

BACKGROUND of the INVENTION

The invention relates to imidazolidinone compounds that can affect the activity of androgen receptors (AR). In one aspect the compound according to the invention is an antagonist or partial antagonist and is suitable for the prophylaxis and/or treatment of androgen-dependent tumors and/or any conditions that may be harmful AR-stimulation, such as acne, alopecia and/or hirsutism; or, in another aspect, the compound according to the invention is a selective androgen receptor modulator (agonist or mixed agonist/antagonist), which can be used to treat conditions of cachexia and diseases with muscle depletion (including, but not limited to, induced cancer cachexia, HIV-induced, glucocorticoid-induced, induced by immobilization, diet-induced loss of muscle mass, burns, chronic renal failure, congestive heart failure, chronic obstructive pulmonary disease), age-related deterioration in functional status (including, but not limited to, sarcopenia) and/or male or female osteoporosis. The present invention also relates to methods of preparing compounds according to the invention, pharmaceutical compositions containing the compound according to image ateneu, and use of the compounds according to the invention for the prevention or treatment disclosed here diseases.

In men, androgens, the main typical endogenous representatives of which are testosterone and its metabolite 5α-DHT, associated with the development and retention of primary male sexual characteristics (epididymis, seminal duct, prostate, external genitalia and secondary male sexual characteristics (development of hair, muscles of the larynx, the distribution of adipose tissue, behavior and libido). In addition, they contribute to the development of muscles and bones, and act on disorders, Central nervous system and sexual function.

In women, androgens are involved, inter alia, in the development and maintenance of bone tissue and libido.

Progressive decline in levels of circulating androgens in the aging male (PADAM - partial reduction of the levels of androgens in the aging male) contributes to a number of specific clinical manifestations, including osteoporosis, loss of muscle mass and muscle strength, reduced libido and sexual dysfunction, anemia and change in cognitive ability, mood swings, depression (see review in: Kaufman JM and Vermeulen, A., 2005, Decreased levels of androgens in elderly men and its clinical and therapeutic implications, Endocr Rev. 26:833-76). However, the clinical safety of androgen therapy is serdechno-vascular diseases and diseases of the prostate questionable. Thus, androgeny supplements are not recommended for healthy older men (Liu FY, etc. 2004, Clinical overview 171: rationale, efficacy and safety of androgen therapy in older men: future research and current practice recommendations, J. Clin. Endocrinol. Metab. 89: 4789-96).

The syndrome is associated with reduced levels of circulating androgens (ADIF - reduction of androgens in women), described also in women. It can have various causes, including aging, chemotherapy and infection with the AIDS virus. Accompanying symptoms include: osteoporosis/osteopenia, sarcopenia and muscle weakness, decreased libido, sexual dysfunction, change in cognitive ability, mood swings and depression. Also described endometriosis and increased risk of cancer of the breast, uterus and ovaries (Davison SL, Davis SR, 2003, Androgens in women, J. Steroid Biochem. Mol. Biol. 85: 363-366). Introduction women of high doses of androgens may lead to signs of mazepodobnoe, mood swings and acne. This risk should be taken into consideration in the introduction of androgens to women.

Limiting the use of steroid agonists or antagonists of androgen receptors become apparent, as their application is burdened with unwanted effects as a result of their metabolism in other sex hormones and steroids, which, in its ocher is d', induce unwanted effects.

Therefore, we highly desirable steroid alternatives, as they allow the beneficial effects of testosterone on particular organs (bone and muscle) and to maintain libido and less likely to give secondary effects in certain tissues, such as the prostate in men and the uterus in women, as they do not harm the hormonal system. They are a safe alternative to conventional methods of treatment of any pathological conditions associated with androgen deficiency, including osteoporosis or sarcopenia and decreased libido associated with syndromes PADAM - ADIF-type. They can also be used to treat cachexia caused by specific diseases, such as cancer or AIDS, or to treat loss of muscle mass caused by prolonged treatment with glucocorticoids. In addition, they can be used for the treatment of androgen-dependent tumors such as prostate cancer or hyperplasia, which have increased at an early stage can usually be adjusted by introducing steroidal antiandrogens.

Selective androgen receptor modulators (SARM - selective androgen receptor modulators) with non-steroid structure are molecules which act as ligands of the androgen receptor (AR) with some degree of tissue specificity.

The importance of AR as mi is Yeni is huge in many areas of the detection of drugs and drug therapy. It is assumed that disclosed here, the compounds according to the invention operate in two main ways:

as antagonists (full or partial) inhibitors of AR can be applied in Oncology and can be partially suitable for the treatment of androgen-dependent prostate cancer. They can also be used for male contraception and for the treatment of benign prostate hyperplasia, ovarian cancer and breast cancer (comparative review, see Mohlerand other, Expert Opin. Ther. Patents (2005) 15 (11), 1565-1585);

- as agonists (full or partial, including mixed agonists/antagonists) they can be partially suitable for the treatment of metabolic and endocrine diseases, disorders, particularly age-related diseases and conditions of cachexia. In addition, due to the presence in the bone cells, SARM can usefully applied to the development and maintenance of the skeleton.

Unfortunately, currently available androgens still cause side effects such as gynecomastia or soreness of the breast), due to the low tissue selectivity and efficiency are highly desirable SARM with fewer side effects.

EP-A-0966447 reveals some imidazolidinone compounds suitable for treating conditions mediated by inflammatory and immune cells, which act by inhibiting the interaction of cell adhesi the different molecules. Although disclosed here, compounds similar to the compounds of the present invention, in some respects, there is no disclosure of any compounds falling within the scope of the present invention.

EP-A-0572191 reveals certain imidazolidinyl, substituted improperly group, suitable as antimicrobial agents.

WO 2007/137874 reveals imidazolidinone compounds similar to the compounds of the present invention, but in which in the formula (I), at least one of R3aor R3brepresents OH, SH or their derivative. These connections require that the OH group or SH was available in the active compounds to bind His-874 androgennogo receptor. These compounds show high in vitro activity, but it is low in vivo activity, so that these compounds are not considered to be commercially viable.

It has been unexpectedly discovered that it is possible to improve the in vivo activity of eliminating R3slightly phenolic OH or SH group, or derivatives, which can give this OH or SH group.

The INVENTION

Compounds according to the invention can exhibit good absorption, good half-life, good solubility, good bioavailability, and good metabolic stability. In a separate aspect from the unity according to the invention shows unexpected significant improvement of pharmacological properties, specific improved bioavailability.

Thus, the present invention relates to imidazolidinone derivatives and methods of identification and design of compounds according to the invention, which affects the activity of androgen receptors.

In particular, the present invention relates to compounds according to the invention according to the following formula Ia:

where

X represents O or S;

R1means H; or R1selected from C1-C6of alkyl, C3-C7cycloalkyl,C3-C6alkenyl,C3-C6the quinil and C1-C6acyl; each of which optionally can be substituted by ceanography, one or more atoms of halogen, hydroxyl, or represent unsubstituted C1-C6alkoxy;

R2aselected from H, S(O2)OH, P(O)(OH)2and C(O)(CH2)n1C(O)OH; or R2aselected from C1-C6of alkyl, C1-C6acyl andC3-C6alkenyl; each of which optionally can be substituted by aryl, amino or carboxy; n1 is 0, 1, 2, 3 or 4;

each R2band R2cindependently selected from H and C1-C6of alkyl; or R2band R2ccan be joined together with formation of C3-C7cycloalkyl;

R3aoznachaet is H, halogen atom, cyano or nitro; or R3arepresents a C1-C6alkyl, optionally substituted with halogen, cyano, nitro, hydroxyl or C1-C4alkoxy; or R3ais aminogroup, optionally substituted C1-C6by alkyl;

each R3bindependently denotes a halogen atom, cyano or nitro; or each R3bindependently represents a C1-C6alkyl, optionally substituted by cyano or halogen; or each R3bis aminogroup, optionally substituted C1-C6by alkyl;

each R4aand R4bindependently represents H, halogen atom, cyano, carboxy or nitro; or each R4aand R4bselected from C1-C6the alkyl and C1-C6alkoxy; each of which optionally may be substituted by one or more halogen atoms or C1-C6alkoxy; or R4aand R4btogether with the formation of 5 - or 6-membered cycloalkyl, 5 - or 6-membered geterotsiklicheskie, 5 - or 6-membered aryl or 5 - or 6-membered heteroaryl;

R4cmeans halogen atom, cyano or nitro; and

m1 is 0, 1 or 2.

In another embodiment, the present invention relates to compounds according to the invention, corresponding to the following formula Ib:

where

X represents O or S;

R1means H; or R1selected from C1-C6of alkyl, C3-C7cycloalkyl,C3-C6alkenyl, C3-C6the quinil and C1-C6acyl; each of which optionally may be substituted by cyano, one or more atoms of halogen, hydroxyl or unsubstituted C1-C6alkoxy;

R2aselected from H, P(O)(OH)2and C(O)(CH2)n1C(O)OH; or R2aselected from C1-C6acyl and C3-C6alkenyl; each of which optionally may be substituted by amino or carboxy; n1 is 0, 1, 2, 3 or 4;

each R2band R2cindependently selected from H and C1-C6of alkyl; or R2band R2ccan be joined together with formation of C3-C7cycloalkyl;

R3ameans H, halogen atom, cyano or nitro; or R3arepresents a C1-C6alkyl, optionally substituted with halogen, cyano, nitro, hydroxyl or C1-C4alkoxy; or R3ais aminogroup, optionally substituted C1-C6by alkyl;

each R3bindependently represents a halogen atom, cyano or nitro; or each R3bindependently represents a C1-C6alkyl, optionally substituted by cyano is whether halogen; or each R3bis aminogroup, optionally substituted C1-C6by alkyl;

each R4aand R4bindependently represents H, halogen atom, cyano, carboxy or nitro; or each R4aand R4bselected from C1-C6the alkyl and C1-C6alkoxy; each of which optionally may be substituted by one or more halogen atoms or C1-C6alkoxy; or R4aand R4btogether with the formation of 5 - or 6-membered cycloalkyl, 5 - or 6-membered geterotsiklicheskie, 5 - or 6-membered aryl or 5 - or 6-membered heteroaryl;

R4cmeans halogen atom, cyano or nitro; and

m1 is 0, 1 or 2.

In another embodiment, the compound according to the invention corresponds to the formula (VI):

where

R5means H, C1-C6alkyl, C2-C6alkenyl, C2-C6quinil or C1-C4alkyl substituted by cyano or by one or more halogen groups;

R6means H or C1-C4alkyl;

R7means halogen atom, cyano, C1-C4alkyl or C1-C4perfluoroalkyl;

R8means halogen atom, cyano, nitro, C1-C4alkyl or C1-C4perfluoroalkyl;

p is 0, 1 or 2;

q is 1, 2 or 3;

if p is 2, then all R7are the same or different;

if q is 2 or 3, then all R8are the same or different, and

its pharmaceutically acceptable esters.

In another embodiment, the compound according to the invention correspond to the formula VII

where

X represents O;

R5means H, C1-C6alkyl, C3-C6alkenyl or C3-C6quinil, each of which can be unsubstituted or substituted by cyano, one or more halogen atoms;

R6ameans H or phosphate ester or its derivative, or ether carboxylic acid, preferably P(O)(OH)2C(=O)-(CH2)2-CO2H or-C(=O)CH(NH3Cl)iPr;

R6bmeans H;

R6cindependently selected from H and C1-C6of alkyl;

R7ameans H, halogen atom, cyano, C1-C4alkyl which may be unsubstituted or substituted by one or more halogen atoms;

R7bmeans halogen atom, cyano or C1-C4alkyl which may be unsubstituted or substituted with halogen; each R8aand R8bindependently represents H, halogen atom, cyano, C1-C4alkyl, each of which can be unsubstituted or substituted by one or more halogen atoms; R means halogen atom, cyano or nitro; and p1 is 0, 1 or 2.

In another aspect, the present invention relates to pharmaceutical compositions comprising the compound according to the invention and a pharmaceutical carrier, excipient or diluent. In this aspect of the invention the pharmaceutical composition may contain one or more compounds described herein according to the invention. In addition, received and used the connection according to the invention are suitable for the disclosed here pharmaceutical compositions and methods of treatment, is pharmaceutically acceptable.

In another aspect, the invention relates to a method of treating a mammal susceptible to or affected by a condition selected from these States, and, in particular, age-related diseases, including, but not limited to these, sarcopenia, the state of cachexia and loss of muscle mass caused by diseases, including, but not limited to these, cancer and AIDS, diseases of bones and joints, such as osteoporosis, decreased libido and sexual dysfunction or anemia, this method includes the introduction of an effective number of connections-agonist or mixed agonist/antagonist according to the invention or a pharmaceutical composition containing the compound-agonist or mixed agonist/antagonist according to the invention, which in the estuaries and the ü is described.

In another aspect the present invention concerns a method of treating a mammal susceptible to or affected androgen-dependent tumors, such as prostate cancer or hyperplasia, the method includes introducing an effective amount of the compound is an antagonist according to the invention or a pharmaceutical composition containing the compound is an antagonist according to the invention, which are described here.

In another aspect, the present invention relates to compounds according to the invention for use for the treatment or prevention of a condition selected from these States, and, in particular, age-related diseases, including but not limited to this, sarcopenia, the state of cachexia and loss of muscle mass caused by diseases, including, but not limited to these, cancer and AIDS, chronic obstructive pulmonary disease, chronic renal failure, burns, diseases of bones and joints, such as osteoporosis, decreased libido and sexual dysfunction or anemia, this method includes the introduction of an effective number of connections-agonist or mixed agonist/antagonist according to the invention or a pharmaceutical composition containing the compound is an agonist or mixed agonist/antagonist according to the invention, which are described here.

In another aspect of the present from retina relates to compounds according to the invention for use for the treatment or prevention of a condition, selected of these conditions, such as prostate cancer or hyperplasia, and this method includes the introduction of an effective amount of the compound is an antagonist according to the invention or a pharmaceutical composition containing the compound is an antagonist according to the invention, which are described here.

In additional aspects, the invention relates to methods of synthesis of compounds according to the invention disclosed hereafter typical protocols and ways of synthesis.

In another aspect, the present invention relates to methods for determining agonistic or antagonistic activity of the compounds described herein according to the invention.

Thus, the main purpose of this invention is the provision of a new series of compounds that can modulate the activity of the androgen receptor (AR) and thus to prevent or treat any disease that can be caused by disruption of their activity.

Another objective of the present invention is the provision of compounds according to the invention, which is mentioned above and can act as an agonist or mixed agonist/antagonist AR and thus is effective in the treatment or alleviation of diseases such as age-related diseases, including, but not limited to this, sarcopenia, the state of cachexia and loss of muscle mass is, caused by diseases, including, but not limited to these, cancer and AIDS, diseases of bones and joints, such as osteoporosis, decreased libido and sexual dysfunction or anemia.

Another object of this invention is the provision of a number of compounds that can act as AR antagonists and thus is effective in the treatment or alleviation of diseases or their symptoms, such as androgen-dependent prostate cancer for male contraception and in benign prostate hyperplasia, ovarian cancer and breast cancer. In one aspect the compound according to the invention is an antagonist or partial antagonist and is suitable for the prophylaxis and/or treatment of androgen-dependent tumors and all conditions that may be harmful AR-stimulation, such as acne, alopecia and hirsutism; or, in another aspect, the compound according to the invention is a selective androgen receptor modulator (agonist or mixed agonist/antagonist), which can be used to treat conditions of cachexia and diseases with muscle depletion (including, but not limited to, induced cancer cachexia, HIV-induced, glucocorticoid-induced, induced by immobilization induced diet loss of muscle mass, burns, chronic renal nedostate the face, chronic obstructive pulmonary disease), age-related deterioration in functional status (including, but not limited to, sarcopenia) and male and female osteoporosis.

The present invention also relates to methods for producing compounds according to the invention, pharmaceutical compositions containing the compound according to the invention and use of the compounds according to the invention for the prevention or treatment of any of the disclosed diseases here.

Another object of this invention is to provide pharmaceutical compositions containing or comprising the compound according to the invention, listed here for therapeutic applications.

Another aim of the invention is to provide methods of treatment using the compounds according to the invention and/or pharmaceutical compositions according to the invention.

Other objectives and advantages will be clear to experts in this area from consideration of the following further detailed description.

DETAILED description of the INVENTION

Definitions

It is assumed that the following terms shall have the values given to them below and are useful for the understanding of the specification and the proposed scope of the present invention.

When the description of the invention, which may include compounds according to the invention, pharmaceutical compositions containing such compounds the ia according to the invention, and methods of using such compounds according to the invention and compositions, the following terms, if present, shall have the following meanings, unless otherwise indicated. It should also be understood that when describing any specific hereafter fragments, they can be substituted by various substituents, and it is assumed that the relevant definitions include substituted fragments in your area, as shown below. While nothing else is stated, the term "substituted" shall be defined as specified below. It should also be understood that when used herein, the terms "group" and "radicals" can be considered interchangeable.

The form of the singular can be used here to mean one or more (i.e. at least one) of interest. For example, "similar" means one similar or more than one equivalent.

The term "acyl" refers to the radical-C(O)R20where R20means a hydrogen atom, a C1-C6alkyl, C3-C7cycloalkyl, C3-C10cycloalkenyl, (4-10)-membered heteroseksualci, aryl, arylalkyl, (5 to 10)-membered heteroaryl or heteroaromatic that are defined here. Typical examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylcarbonyl, benzoyl and benzylcarbamoyl. Typical "acyl" groups are-C(O)H, -C(O)-C1 -C6alkyl, -C(O)-(CH2)t(C6-C10aryl), -C(O)-(CH2)t((5 to 10)-membered heteroaryl), -C(O)-(CH2)t(C3-C10cycloalkyl) and-C(O)-(CH2)t((4-10)-membered heteroseksualci), where t is an integer from 0 to 4.

The term "acylamino" refers to a radical-NR22C(O)R23where R22means a hydrogen atom, a C1-C6alkyl, C3-C7cycloalkyl, (4-10)-membered heteroseksualci, C6-C10aryl, arylalkyl, (5 to 10)-membered heteroaryl or heteroaromatic and R23means a hydrogen atom, a C1-C6alkyl, C3-C10cycloalkyl, (4-10)-membered heteroseksualci, C6-C10aryl, arylalkyl, (5 to 10)-membered heteroaryl or heteroaromatic that are defined here. Typical "acylamino" groups include, but are not limited to this, formylamino, acetylamino, cyclohexylcarbodiimide, cyclohexyldimethylamine, benzoylamine, benzylmorphine. Typical "acylamino" groups are-NR21'C(O)-C1-C6alkyl, -NR21'C(O)-(CH2)t(C6-C10aryl), -NR21'C(O)-(CH2)t((5 to 10)-membered heteroaryl), -NR21'C(O)-(CH2)t(C3-C7cycloalkyl) and-NR21'C(O)-(CH2)t((4-10)-membered heteroseksualci), where t is an integer from 0 to 4, each R21'independently represents the th H or C 1-C6alkyl.

The term "alkoxy" refers to the group-OR26where R26means C1-C6alkyl. Specific alkoxygroup are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentox, n-hexose and 1,2-Dimethylbutane. Specific alkoxygroup are low alkoxygroup, i.e. groups containing from 1 to 6 carbon atoms. Additional specific alkoxygroup have from 1 to 4 carbon atoms.

The term "alkoxycarbonyl" refers to the radical-C(O)-OR27where R27represents a C1-C6alkyl, C3-C7cycloalkyl, C3-C10cycloalkenyl, (4-10)-membered geterotsiklicheskikh, aralkyl or (5 to 10)-membered heteroaromatic that are defined here. Typical "alkoxycarbonyl" groups are C(O)O-C1-C6alkyl, -C(O)O-(CH2)t(C6-C10aryl), -C(O)O-(CH2)t((5 to 10)-membered heteroaryl), -C(O)O-(CH2)t(C3-C7cycloalkyl) and-C(O)O-(CH2)t((4-10)-membered heteroseksualci), where t is an integer from 1 to 4.

The term "O-arylcarbamoyl" refers to the radical-C(O)-OR29where R29represents a C6-C10aryl, which is defined here. A typical O-arylcarboxylic" group is-C(O)O-(C6-C10aryl).

The term "GE is EPO-O-arylcarbamoyl" refers to the radical-C(O)-OR 31where R31represents (5 to 10)-membered heteroaryl, which is defined here.

The term "alkyl" means a linear or branched aliphatic hydrocarbon, steriade from 1 to 6 carbon atoms. Additional, specific groups have from 1 to 4 carbon atoms. Typical linear groups include methyl, ethyl, n-propyl and n-butyl. The term "branched" means that one or more lower alkyl groups such as methyl, ethyl, propyl or butyl, attached to a linear alkyl chain, a typical branched groups include isopropyl, isobutyl, tert-butyl and isoamyl.

The term "amino" refers to the radical-NH2.

The term "alkylamino" refers to the group-other34where R34represents a C1-C6alkyl.

The term "alkylamino" refers to the group-NR36R37where R36represents a C6-C10aryl and R37represents a C1-C6alkyl.

The term "arylamino" means the radical-other40where R40selected from C6-C10aryl and (5 to 10)-membered heteroaryl that are defined here.

The term "dialkylamino" refers to the group-NR42R43where each of R42and R43independently selected from C1-C6Akilov.

The term "diarylamino" refers to the group-NR46R47where each of R46The R 47independently selected from C6-C10arrow.

The term "aminosulfonyl" or "sulfonamide" refers to the radical-S(O2)NH2.

The term "aralkyl" or "arylalkyl" refers to an alkyl group as defined above, substituted by one or more aryl groups defined above. Specific Uralkalij or arylalkyl groups are alkyl groups substituted with one aryl group.

The term "aryl" refers to a monovalent aromatic hydrocarbon group obtained by removing one hydrogen atom from a single carbon atom of the original aromatic cyclic system. In particular, the aryl refers to an aromatic cyclic structure, monocyclic or polycyclic, which includes from 5 to 10 ring members, usually from 6 to 10. If the aryl group is a monocyclic ring system, it preferably contains 6 carbon atoms. Typical aryl groups include, but are not limited to, groups derived of aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, Exacta, hexagen, hexylene, as-indacene, s-indacene, indane, indene, naphthalene, octazen, octavina, octalene, evalena, Penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, Fe is entrena, Picena, pleiadene, pyrene, pesantren, rubiana, triphenylene and Trenitalia. In particular, the aryl group include phenyl, naphthyl, indenyl and tetrahydronaphthyl.

The term "amido" refers to the radical-C(O)NH2.

The term "carboxy" refers to the radical-C(O)OH.

The term "cycloalkyl" refers to cyclic non-aromatic hydrocarbon groups having from 3 to 7 carbon atoms. Such cycloalkyl groups include, for example, patterns with a single ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

The term "cyano" refers to the radical-CN.

The term "halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I). Specific halogen group is fluorine or chlorine.

The term "hetero"is used to describe compounds or groups present on the compound, indicates that one or more of the carbon atoms in the compound or group is replaced by the heteroatoms nitrogen, oxygen or sulfur. The prefix "hetero" may be used with any of the above hydrocarbon groups such as alkyl, for example heteroalkyl, cycloalkyl, such as heteroseksualci, aryl, such as heteroaryl, cycloalkenyl, for example cyclogeranyl, and such groups having from 1 to 5, and, in particular, from 1 to 3 heteroatoms.

The term "heteroaryl" means aromatic tsiklicheskoe the structure, monocyclic or polycyclic, which includes one or more heteroatoms and from 5 to 12 ring members, more often from 5 to 10 ring members. Heteroaryl group may represent, for example, five-membered or six-membered monocyclic ring or bicyclic structure formed from condensed five - and six-membered cycles, or two condensed six-membered cycles, or (as an additional example) two condensed five-membered cycles. Each loop can contain up to four heteroatoms typically selected from nitrogen atoms, sulfur and oxygen. Usually heteroaryl cycle contains up to 4 heteroatoms, usually up to 3 heteroatoms, more often up to 2, for example one heteroatom. In one embodiment, the heteroaryl cycle contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl cycles can be primary, as in the case of imidazole or pyridine, or essentially non-core, as in the case of nitrogen, indole or pyrrole. In General, the number of basic nitrogen atoms present in the heteroaryl group, including Vice-amino cycle, is less than five. Examples of five-membered monocyclic heteroaryl groups include, but are not limited to, pyrrole, furan, thiophene, imidazole, furazane, oxazoline, oxadiazoline, oxadiazoline, isok the azole, thiazole, isothiazol, pyrazol, triazole and tetrazole group. Examples of six-membered monocyclic heteroaryl groups include, but are not limited to, pyridine, pyrazin, pyridazine, pyrimidine and triazine. Specific examples of bicyclic heteroaryl groups containing five-membered cycle, condensed with other five-membered cycle, include, but are not limited to this, imidazothiazole and imidazolides. Specific examples of bicyclic heteroaryl groups containing a six-membered cycle, condensed with a five-membered cycle, include, but are not limited to, the following groups: benzofuran, benzothiophen, benzimidazole, benzoxazole, samesexual, benzisoxazol, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindoline, indolizine, indoline, isoindoline, purine (e.g. adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyrimidine. Specific examples of bicyclic heteroaryl groups containing two condensed six-membered cycle, include, but are not limited to, the following groups: quinoline, isoquinoline, chroman, thiochroman, chrome, isochroman, chroman, isochroman, benzodioxan, hemolysin, benzoxazin, benzodiazpin, iridoviridae, cinoxacin, hinzelin, cinnolin, phthalazine, naphthiridine and pteridine. Specific heteroaryl groups which we are a group, derivatives of thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

Examples of typical aryl having heteroatoms and containing substituents include the following compounds:

and,

where each W is selected from C(R54)2, NR54, O and S, and each Y is selected from carbonyl, NR54, O and S; and R54independently represents a hydrogen atom, a C1-C6alkyl, C3-C7cycloalkyl, (4-10)-membered heteroseksualci, C6-C10aryl and (5 to 10)-membered heteroaryl.

Examples of typical heteroaryl include the following compounds:

where each Y is selected from carbonyl, N, NR55, O and S; and R55independently represents a hydrogen atom, a C1-C6alkyl, C3-C7cycloalkyl, (4-10)-membered heteroseksualci, C6-C10aryl and (5 to 10)-membered heteroaryl.

Used herein, the term "heteroseksualci" refers to a 4-10-membered, stable non-aromatic heterocyclic cycles and/or groups, including condensed with them loops containing one or more heteroatoms, independently selected from N, O and S. cyclic Condensed heterocyclic system may include carbocyclic rings and need to include only one who heterocyclics ring. Examples of heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (for example, 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, Piran (2H-Piran or 4H-Piran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazolo, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (for example, 4-tetrahydropyranyl), imidazolin, imidazolidine, oxazoline, thiazoline, 2-pyrazolin, pyrazolidine, piperazine and N-alkylpiperazine, such as N-methyl piperazine. Additional examples include thiomorpholine and its S-oxide and S,S-dioxide (in particular, thiomorpholine). Still other examples include azetidin, piperidone, piperazine and N-alkylpiperidines, such as N-methylpiperidin. Specific examples geterotsiklicheskikh groups shown in the following illustrative examples:

where each W is selected from CR56C(R56)2, NR56, O and S; and each Y is selected from NR56, O and S; and R56independently represents a hydrogen atom, a C1-C6alkyl, C3-C7cycloalkyl, (4-10)-membered heteroseksualci, C6-C10aryl, (5 to 10)-membered heteroaryl. These heterocytolysine ring optionally can be substituted by one or more groups selected from the group, enabling the th acyl, acylamino, acyloxy (-O-acyl or-OC(O)R20), alkoxy, alkoxycarbonyl, alkoxycarbonyl (-NR"-alkoxycarbonyl or-NH-C(O)-OR27), amino, substituted amino, aminocarbonyl (amido or -- C(O)-NR2), aminocarbonyl (-NR"-C(O)-NR2), aminocarbonyl (-O-C(O)-NR2), aminosulfonyl, sulfonylamino, aryl, -O-aryl, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O)2-alkyl and-S(O)2-aryl. The substituting groups include carbonyl or thiocarbonyl, which give, for example, lactam derivatives of urea.

The term "hydroxy" refers to the radical-OH.

The term "nitro" refers to the radical-NO2.

The term "substituted" refers to a group in which one or more hydrogen atoms are independently replaced with the same or different substituents. Typical substituents can be selected from the group comprising: halogen, -R57, -O, =O, -OR57, -SR57-S-, =S, -NR57R58, =NR57, -CCl3, -CF3, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -S(O)2O-, -S(O)2OH, -S(O)2R57, -OS(O2)O-, -OS(O)2R57, -P(O)(O-)2, -P(O)(OR57)(O-), -OP(O)(OR57)(OR58), -C(O)R57, -C(S)R57, -C(O)OR57, -C(O)NR57R58, -C(O)O-, -C(S)OR57, -NR59C(O)NR57R58, -NR59C(S)NR57 58, -NR60C(NR59)NR57R58and-C(NR59)NR57R58;

where each R57, R58, R59and R60independently represents:

is a hydrogen atom, a C1-C6alkyl, C6-C10aryl, arylalkyl, C3-C7cycloalkyl, (4-10)-membered heteroseksualci, (5 to 10)-membered heteroaryl, heteroaromatic; or

- C1-C6alkyl, substituted by a halogen atom or hydroxy; or

- C6-C10aryl, (5 to 10)-membered heteroaryl, C6-C7cycloalkyl or (4-10)-membered heteroseksualci, substituted unsubstituted C1-C6by alkyl, halogen atom, unsubstituted C1-C4alkoxy, unsubstituted C1-C4halogenation, unsubstituted C1-C4hydroxyalkyl or unsubstituted C1-C4halogenoalkane or hydroxy.

In a specific embodiment, the substituted groups are substituted by one or more substituents, in particular 1 to 3 substituents, in particular one substituting group.

Used herein, the prefix "PERFLUORO" refers to a group where all the hydrogen atoms of the specified group are replaced with fluorine atoms. In particular, the term perfluoroalkyl refers to alkyl (as defined here), in which all the hydrogen atoms are replaced with fluorine atoms. Specific perforaciones group is CF3 .

In another specific embodiment, the replacement group or groups selected from: halogen atoms, cyano, nitro, trifloromethyl, triptoreline, azido, -NR"'SO2R", -SO2NR"R"', -C(O)R", -C(O)OR", -OC(O)R", -NR"'C(O)R", -C(O)NR"R"', NR"R"', (CR”'R "')mOR OR', where each R" is independently selected from H, C1-C6of alkyl, -(CH2)t(C6-C10aryl), -(CH2)t((5 to 10)-membered heteroaryl), -(CH2)t((C3-C7)cycloalkyl) and -(CH2)t((4-10)-membered geterotsiklicheskie), where t is an integer from 0 to 4; and

any present alkyl groups may themselves be substituted by a halogen atom or hydroxy-group; and

- present any aryl, heteroaryl, cycloalkyl or heterocytolysine groups may themselves be substituted by unsubstituted C1-C4by alkyl, halogen atom, unsubstituted C1-C4alkoxy, unsubstituted C1-C4halogenation, unsubstituted C1-C4hydroxyalkyl or unsubstituted C1-C4halogenoalkane or hydroxy. Each R"' independently represents H or C1-C6alkyl.

The term "sulfo" or "sulfonic acid" refers to such radicals as-SO3H.

Specialist in the field of organic synthesis it is clear that the maximum number of heteroatoms in a stable, chemically real hetero is aliceson ring, whether aromatic or non-aromatic, is determined by the size of the cycle, degree of unsaturation and the valence of the heteroatom. In General, the heterocyclic ring may have from one to four heteroatoms, provided that the heteroaromatic cycle is real and chemically stable.

The expression "pharmaceutically acceptable" means an agent, approved or to be approved by Federal regulators or government or the relevant authorities in countries other than the United States, or listed in the U.S. Pharmacopoeia or other generally recognized Pharmacopoeia for use in animals, and in particular on the people.

The expression "pharmaceutically acceptable salt" refers to salts of the compounds according to the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic, can be an additive salts of inorganic or organic acid additive salts of the bases. In particular, such salts include: (1) additive, acid salts, formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, propion the Wai acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, econsultancy acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonate acid, 4-toluensulfonate acid, camphorsulfonic acid, 4-methylbicyclo[2,2,2]-Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid and the like; or (2) salts formed when an acidic proton present in the original connection, or replaced by a metal ion, for example an alkali metal ion, alkali earth metal ion or an aluminum ion; or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and like that. In addition, salt include (for example) the sodium, Ali, calcium, magnesium, ammonium, tetraalkylammonium, and the like and, if the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesilate, acetate, maleate, oxalate and the like. The expression "pharmaceutically acceptable cation" refers to acceptable the cationic counterion of the acid functional group. Examples of such cations are the cations of sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.

"Pharmaceutically acceptable esters are esters, which are sufficiently non-toxic to be approved by regulators. Preferred esters are phosphoric esters and their derivatives and the esters of carboxylic acids. Generally, pharmaceutically acceptable esters can be obtained with pharmaceutically acceptable acids, such as phosphoric acid and its afrobrazilian derivatives, such as alkalemia and dialkylamino esters of phosphoric acid and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid is you, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, Mandelieu acid, 4-methylbicyclo[2,2,2]-Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 3-phenylpropionic acid, trimethylhexanoic acid, tert-butylalcohol acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid and the like.

The expression "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or carrier with which enter the connection according to the invention.

The term "prodrug" refers to compounds, including derivatives of the compounds according to the invention, which have otsepleniya group, and the solvolysis or under physiological conditions become compounds according to the invention which are pharmaceutically activein vivo. Such examples include, but are not limited to, derivatives halinowego ether, esters of N-alkylphosphine, esters of glycine, valine, or other amino acids and similar compounds, esters of carboxylic acids, esters, sulfates or phosphates.

The term "MES" refers to the forms of connection that is associated with the solvent, usually obtained by the reaction of solvolysis. This physical interactions include hydrogen binding. Conventional solvent which include water, ethanol, acetic acid and the like. Compounds according to the invention can be obtained, for example, in crystalline form and can be solvated or gidratirovana. Suitable solvate include pharmaceutically acceptable solvate such as a hydrate and additionally include a stoichiometric solvate and non stoichiometric solvate. In some cases, the MES can be selected, for example, when the crystal lattice of the crystalline solids include one or more molecules of solvent. The term "MES" includes phase-solution, and allocated a solvate. Typical solvate includes hydrates, utility and motility.

The term "subject" includes humans. The terms "person," "patient" and "subject" are used here interchangeably.

The expression "therapeutically effective amount" means an amount of compound according to the invention that when administered to a subject to treat diseases is sufficient for such treatment of the disease. "Therapeutically effective amount" can vary depending on the compounds according to the invention, the disease and its severity, the age, weight and other characteristics of the subject to be treated.

The term "preventing" or "prevention" refers to reducing the risk of occurrence or development of diseases or disorders (that is. the creation of the causes of non-development, at least one of the clinical symptoms) in a subject who is exposed to the agent causing the disease or predisposed to the disease, prior to the onset of the disease.

The term "prevention" is associated with the term "prevention" refers to a measure or procedure which aims warning rather than treatment of illness or healing. Non-restrictive examples of preventive measures may include the introduction of vaccines, the introduction of heparin with low-molecular-weight patients at risk of thrombosis due to, for example, immobilization and introduction antimalarial agent such as chloroquine, prior to visiting the geographic region where malaria is epidemic disease or a high risk of malaria.

The term "treatment" or "treating" a disease or disorder in one embodiment relates to the improvement of the disease condition or disorder (i.e., the delay of the disease or reducing the symptoms, the degree or severity of at least one of its clinical symptoms). In another embodiment, the term "therapy" or "treatment" refers to improving at least one physical parameter, which may not be noticeable to the subject. In another embodiment, the term "therapy" or "treatment is their" concerns the modulation of the disease or disorder, physical (e.g., stabilization of a discernible symptom), physiological (e.g., stabilization of a physical parameter), or both. In another embodiment, "treatment" or "treating” refers to slowing the progression of the disease.

Used herein, the term "cancer" refers to a malignant or benign growth of skin cells or organs of the body, such as, but not limited to, breast, prostate, lung, kidney, pancreas, stomach or intestines. Cancer has a tendency to invade adjacent tissue and spread (to give metastases in distant organs such as the bones, liver, lungs or brain. Used herein, the term “cancer” includes both types of cells metastatic tumors such (but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma and mastocytoma, and these types of carcinoma tissues (but not limited to)as colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, kidney cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, prostate cancer and leiomyosarcoma of the uterus.

Used herein, the term "agonist" is used to describe the type of connection that binds to a receptor and triggers a response signal is randalli. The ability to alter the activity of the receptor, also known as agonistic efficacy refers to the ability of the compound to induce a biological response in its molecular target.

Used herein, the term "antagonist" is used to describe compounds which itself does not provoke a biological response upon binding to a receptor, but blocks or attenuates agonist-mediated responses.

Consider that when used herein, the expression "compound(I) according to the invention", and equivalent expressions encompass compounds of the formulae described herein previously, the expression includes pharmaceutically acceptable salt and solvate compounds or a solvate of pharmaceutically acceptable salts, e.g. hydrates, where the context allows. Similarly, suppose that the reference to intermediate products, announced they or not, including their salts and solvate, where the context allows.

When the specified ranges, for example (but without limitation) C1-C6alkyl, then at the mention of the range should be justified representation of each member of the specified range.

Other derivatives of the compounds according to the invention have activity in both forms, in the form of acids and acid derivatives, but islamochristiana form often offers advantages of solubility, tissue is eve compatibility or delayed release in the body of a mammal (see work Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to professionals in this field, such as, for example, esters, obtained by the interaction of the source of the acid with a suitable alcohol, or amides obtained by the interaction of the original acid compounds with substituted or unsubstituted amine, or acid anhydrides or mixed anhydrides. Particularly useful prodrugs are simple aliphatic or aromatic esters, amides and anhydrides, acid derivative groups, hanging on the compounds according to the invention. In some cases it is desirable to obtain prodrugs of type double complex ester, such as (acyloxy)alkalemia esters or ((alkoxycarbonyl)oxy)alkalemia esters. Such specific prodrugs are C1-C8alkalemia, C2-C8alkenilovyh, arrouye, C7-C12substituted arrowie and C7-C12arylalkyl esters of the compounds according to the invention.

Used herein, the expression "isotopic variant" refers to a compound that contains unnatural proportions of isotopes of one or more of the atoms that constitute such a connection. For example, an "isotopic variant" of a compound may contain one or more non-radioactive isotopes, such as who, for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N) or similar. It is clear that the connection that produced this isotopic substitution, the following atoms (where present) may vary, for example, any hydrogen atom may be a2H/D, any carbon atom can be a13C or any nitrogen atom may represent a15N, and specialists in this field can determine the presence and position of these atoms. Also the invention may include isotopic variants with radioisotopes, for example, in the case when the resulting connection can be used for studies of the distribution in the tissue of the drug and/or substrate. Radioactive isotopes tritium, i.e3H, and carbon-14, i.e14C, is particularly useful for this purpose from the point of view of the simplicity of their inclusion and ease of detection. In addition, it is possible to obtain compounds that are substituted positron-emitting isotopes, such as11C,18F,15O, and would be suitable for research by means of positron issuable topography (PET) to study the degree of employment receptor substrate.

It is assumed that all here isotopic variants of the compounds according to the invention, radioactive or non-radioactive, included in the scope of compounds p the invention, which is defined here.

It is also clear that compounds that have identical molecular formulas but differ in the nature or sequence of bonding of atoms or the arrangement of their atoms in space are referred to as "isomers". Isomers that differ in the arrangement of their atoms in space are called stereoisomers".

Stereoisomers that are not mirror images of each other are termed "diastereomers"and those stereometry, which are mirror images that are not shared with the overlapping each other, are called "enantiomers". If the compound has an asymmetric center, for example, associated with four different groups, there may be a pair of enantiomers. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the rules of R - and S-sequence Kahn and Prelog or the way in which the molecule rotates the plane of polarized light, and mean as programalso or levogyrate (i.e., as (+) or (-)-isomers respectively). Chiral compound can exist in the form of an individual enantiomer or mixture of enantiomers containing equal proportions of the enantiomers is called a "racemic mixture".

All stereoisomers of the compounds included in used here is expressed the e-connection according to the invention”. The connection according to the invention is usually available in the form of stereoisomers by stereocenter on imidazole cycle. For compounds where there is an optical center, the present invention provides for the use of either enantiomer or racemic mixtures in any proportions.

The term "tautomers" refers to compounds that are interchangeable forms of specific patterns of connections and which are offset hydrogen atoms and electrons. Thus, two structures can be in equilibrium when the movement of the π electrons and atoms (usually H). For example, enols and ketones are tautomers, as they quickly vzaimoprevrascheny when handling acid or base. Another example of tautomerism are ACI - nitro form familytreedna, which are also formed by treatment with acid or base.

Tautomeric forms may be essential for optimal chemical reactivity and biological activity of interest connections. Used herein, the expression “compound according to the invention includes the tautomeric forms of the disclosed compounds.

CONNECTIONS

The present invention relates to imidazolidinone derivatives and methods of identification and design of such compounds. In particular, the present invention relates to a connection is ment according to the invention, corresponding to the following formula Ia;

where

X represents O or S,

R1means H; or R1selected from C1-C6of alkyl, C3-C7cycloalkyl, C3-C6alkenyl, C3-C6the quinil and C1-C6acyl; each of which optionally may be substituted by cyano, one or more atoms of halogen, hydroxyl or unsubstituted C1-C6alkoxy;

R2aselected from H, S(O2)OH, P(O)(OH)2and C(O)(CH2)n1C(O)OH; or R2aselected from C1-C6of alkyl, C1-C6acyl and C3-C6alkenyl; each of which optionally can be substituted by aryl, amino or carboxy, n1 is 0, 1, 2, 3 or 4;

each R2band R2cindependently selected from H and C1-C6of alkyl; or R2band R2ccan be joined together with formation of C3-C7cycloalkyl;

R3ameans H, halogen atom, cyano or nitro; or R3arepresents a C1-C6alkyl, optionally substituted by halogen atom, cyano, nitro, hydroxyl or C1-C4alkoxy; or R3ais aminogroup, optionally substituted C1-C6by alkyl;

each R3bindependently represents a halogen atom, cyano or nitro; or is jdy R 3bindependently represents a C1-C6alkyl, optionally substituted by cyano or halogen atom; or each R3bis aminogroup, optionally substituted C1-C6by alkyl;

each R4aand R4bindependently represents H, halogen atom, cyano, carboxy or nitro; or each R4aand R4bselected from C1-C6the alkyl and C1-C6alkoxy; each of which may be optionally substituted by one or more halogen atoms or C1-C6alkoxy; or R4aand R4btogether with the formation of 5 - or 6-membered cycloalkyl, 5 - or 6-membered geterotsiklicheskie, 5 - or 6-membered aryl or 5 - or 6-membered heteroaryl;

R4cmeans halogen atom, cyano or nitro; and

m1 is 0, 1 or 2.

In particular, the present invention relates to compounds according to the invention, corresponding to the following formula Ib:

where

X represents O or S;

R1means H; or R1selected from C1-C6of alkyl, C3-C7cycloalkyl, C3-C6alkenyl, C3-C6the quinil and C1-C6acyl; each of which optionally may be substituted by cyano, one or more atoms of halogen, hydroxyl or C1-C6 alkoxy;

R2aselected from H, P(O)(OH)2and C(O)(CH2)n1C(O)OH; or R2aselected from C1-C6acyl and C3-C6alkenyl; each of which may be optionally substituted amino group or carboxy; n1 is 0, 1, 2, 3 or 4;

each R2band R2cindependently selected from H and C1-C6of alkyl; or R2band R2ccan be joined together with formation of C3-C7cycloalkyl;

R3ameans H, halogen atom, cyano or nitro; or R3arepresents a C1-C6alkyl, optionally substituted by halogen atom, cyano, nitro, hydroxyl or C1-C4alkoxy; or R3ais aminogroup, optionally substituted C1-C6by alkyl;

each R3bindependently denotes a halogen atom, cyano or nitro; or each R3bindependently represents a C1-C6alkyl, optionally substituted by cyano or halogen atom; or each R3ais aminogroup, optionally substituted C1-C6by alkyl;

each R4aand R4bindependently represents H, halogen atom, cyano, carboxy or nitro; or each R4aand R4bselected from C1-C6the alkyl and C1-C6alkoxy; each of which optionally can be substituted one or the larger the number of atoms of halogen or C 1-C6alkoxy; or R4aand R4btogether with the formation of 5 - or 6-membered cycloalkyl, 5 - or 6-membered geterotsiklicheskie, 5 - or 6-membered aryl or 5 - or 6-membered heteroaryl;

R4cmeans halogen atom, cyano or nitro; and

m1 is 0, 1 or 2.

In one embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, X is O.

In one embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans H.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans Me or Et.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2cmeans C1-C6alkyl.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2cmeans H, Me or Et.

In one embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2band R2ctogether with the formation of cyclopropanes or cyclobutene rings.

In one embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, each R2band R2cmeans H.

In another embodiment, with respect to the connection according to the invention, soo the relevant formula Ia, R2bmeans H, S(O2)OH, or P(O)(OH)2C1-C6alkyl (C1-C6alkyl optionally can be substituted by aryl), or C1-C6acyl (C1-C6acyl optionally may be substituted amino, carboxy).

In another embodiment, with respect to the connection according to the invention corresponding to formula Ib, R2ameans H or P(O)(OH)2or C1-C6acyl (C1-C6acyl may be optionally substituted amino, carboxy).

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia, R2ameans C1-C6alkyl, optionally substituted by aryl.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans C1-C6acyl, optionally substituted amino group or carboxy.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans H.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans C3-C6alkenyl.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans CH2-CH=CH2.

In another embodiment, with respect to the connection p of the invention, corresponding to the formula Ia, R2ameans benzyl.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia, R2ameans S(O2)OH, or P(O)(OH)2.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia, R2ameans pharmaceutically acceptable salt S(O2)OH.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia, R2ameans S(O2)ONa.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ib, R2ameans P(O)(OH)2.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans pharmaceutically acceptable mono - or bis-Sol P(O)(OH)2.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans P(O)(ONa)2.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans C(O)(CH2)n1C(O)OH and n1 is 0, 1, 2, or 3.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans C(O)-CH2CH2-C(O)OH.

In another embodiment, with respect to the connection according to the invention, the respective forms of the Le Ia or Ib, R2ameans pharmaceutically acceptable salt C(O)-CH2CH2-C(O)OH.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans C(O)-CH2CH2-C(O)ONa.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans C(O)-CH(iPr)NH2.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R2ameans C(O)-CH(iPr)NH3Cl.

In one embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R1means H.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R1means C1-C6alkyl substituted by halogen, cyano or hydroxyl.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R1means C1-C6alkyl substituted by cyano.

In one embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R1meansC3-C6quinil.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R1means-CH2-C≡CH.

In one embodiment, with respect to the connection from which retenu, corresponding to the formula Ia or Ib, R1means C1-C6alkyl.

In one embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R1means Me, Et, i-Pr, or n-Pr.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R1means Me.

In one embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R3ameans H, halogen atom, cyano or nitro.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R3ameans C1-C6alkyl.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R3ameans C1-C6alkyl, substituted with halogen, cyano, nitro, hydroxyl or C1-C4alkoxy.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R3ameans aminogroup.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R3ameans aminogroup, substituted C1-C6the alkyl.

In one embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R3bmeans halogen atom, cyano or nitro.

In one embodiment, p is the nominative to the connection according to the invention, corresponding to the formula Ia or Ib, m1 is 0.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R3bmeans C1-C6alkyl.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R3bmeans C1-C6alkyl substituted by halogen, by cyano.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R3bmeans amido.

In another embodiment, with respect to the connection according to the invention corresponding to formula Ia or Ib, R3bmeans aminogroup, substituted C1-C6the alkyl.

As for the compounds according to the invention corresponding to the formula Ia or Ib, in one embodiment, the compound according to the invention corresponds to the formula II:

where R3a, R3b, R4a, R4b, R4cand m1 such as described in either of the preceding paragraphs.

In one embodiment, with respect to the connection according to the invention corresponding to formula II, R4cmeans cyano, halogen atom or nitro.

In one embodiment, with respect to the connection according to the invention corresponding to formula II, R4cmeans cyano.

In another embodiment, with respect to the connection according to the invention corresponding to formula II, R4b means H, halogen atom, cyano, C1-C6alkyl or C1-C6halogenated.

In another embodiment, with respect to the connection according to the invention corresponding to formula II, R4bmeans Cl, F, CN or CF3.

In another embodiment, with respect to the connection according to the invention corresponding to formula II, R4bmeans CF3.

In one embodiment, with respect to the connection according to the invention corresponding to formula II, R4ameans H, halogen atom, cyano, C1-C6alkyl or C1-C6halogenated.

In another embodiment, with respect to the connection according to the invention corresponding to formula II, R4amean Cl or F.

In another embodiment, with respect to the connection according to the invention corresponding to formula II, R4ameans H.

As for the compounds according to the invention corresponding to the formula II, in one embodiment, the compound according to the invention corresponds to the formula IIIa or IIIb:

where R3a, R3b, R4band m1 such as described in either of the preceding paragraphs.

In one embodiment, with respect to the connection according to the invention corresponding to formula IIIa or IIIb, R4bmeans H, halogen atom, cyano, C1-C6alkyl or C1-C6halogenated.

In the preferred embodiment, as applied to connect the tion according to the invention, corresponding to formula IIIa or IIIb, R4bmeans Cl, F, CN or CF3.

In a more preferred embodiment, with reference to the connection according to the invention corresponding to formula IIIa, R4bmeans CF3.

In another preferred embodiment, with reference to the connection according to the invention corresponding to formula IIIb, R4bmeans Cl.

In one embodiment, with respect to the connection according to the invention corresponding to formula II, the compound according to the invention corresponds to formula IVa or IVb:

where R3a, R3band m1 such as described in either of the preceding paragraphs.

In one embodiment, with respect to the connection according to the invention corresponding to formula IVa or IVb, R3ameans H, halogen atom, cyano, C1-C6alkyl or C1-C6halogenated.

In the preferred embodiment, with reference to the connection according to the invention corresponding to formula IVa or IVb, R3ameans H, Me, Cl, F, CN or CF3.

In another embodiment, with respect to the connection according to the invention corresponding to formula IVa or IVb, m1 is 1 or 2.

In another embodiment, with respect to the connection according to the invention corresponding to formula IVa or IVb, R3bmeans halogen atom, cyano, C1-C6alkyl or C1-C6halogenated.

In preferably the variant with respect to the connection according to the invention, corresponding to the formula IVa or IVb, R3bmeans Me, Cl, F, CN or CF3.

In another embodiment, with respect to the connection according to the invention corresponding to formula IVa or IVb, m1 is 0.

In one embodiment, as for the compounds according to the invention of formula 1, a compound according to the invention corresponds to formula Va, Vb, Vc or Vd:

where R3asuch as described in either of the preceding paragraphs;

R3cmeans H, halogen atom, cyano or nitro; or

R3cmeans C1-C6alkyl, optionally substituted by cyano or halogen atom; or R3cmeans aminogroup, optionally substituted C1-C6the alkyl.

As for the compounds according to the invention of the formula I, in one embodiment, the compound according to the invention corresponds to formula Va.

As for the compounds according to the invention of the formula I, in one embodiment, the compound according to the invention corresponds to the formula Vb.

As for the compounds according to the invention of the formula I, in one embodiment, the compound according to the invention corresponds to the formula Vc.

As for the compounds according to the invention of the formula I, in one embodiment, the compound according to the invention corresponds to the formula Vd.

In one embodiment, with respect to the connection according to the invention of formula Va, Vb, Vc or Vd, R3ameans H, halogen atom or cyano; and R3cmeans H.

<> In one embodiment, with respect to the connection according to the invention corresponding to formula Va, Vb, Vc or Vd, R3adenotes H, CN, Cl or F; and R3cmeans H.

In one embodiment, with respect to the connection according to the invention corresponding to formula Va, Vb, Vc or Vd, R3ameans H; and R3cmeans H, a halogen atom, a C1-C6alkyl, C1-C6halogenated or cyano.

In another embodiment, with respect to the connection according to the invention corresponding to formula Va, Vb, Vc or Vd, R3ameans H; and R3cmeans CN, Cl, F, Me or CF3.

In another embodiment, with respect to the connection according to the invention corresponding to formula Va, Vb, Vc or Vd, each R3aand R3cmeans H.

In a preferred embodiment, the compound according to the invention corresponds to the formula Vb where R3aand R3crepresent H.

In another preferred embodiment, the compound according to the invention corresponds to the formula Vd, where R3aand R3crepresent H.

In one embodiment, the compound according to the invention is selected from compounds according to the invention listed in table 1.

In one embodiment, the compounds according to the invention are compounds of the formula (VI):

where

R5means H, C1-C6alkyl, C2-C6alkenyl, C2-C6quinil, or R5 means C1-C4alkyl substituted by cyano or one or more halogen groups;

R6means C1-C4alkyl;

R7means halogen atom, cyano, C1-C4alkyl or C1-C4perfluoroalkyl;

R8means halogen atom, cyano, nitro, C1-C4alkyl or C1-C4perfluoroalkyl;

p is 0, 1 or 2;

q is 1, 2 or 3;

if p is 2, then all R7are the same or different;

if q is 2 or 3, then all R7are the same or different; and

their pharmaceutically acceptable esters.

In one embodiment, preferably, R6represented H.

In another aspect, preferably, R5represented a methyl or ethyl.

Preferably also, to R5represented PROPYNYL.

In one aspect, preferably, p is 1. In this aspect, preferably, R7was a Cl or F.

If p is equal to 1, preferably, R7was in the para-position.

In another aspect, preferably, p is 0.

Particularly preferably, any performanceline group represented triptorelin group.

In another aspect, preferably, q is 2. In this embodiment, it is preferable that the AC is every R 8was selected from F, Cl, cyano, trifloromethyl and bromide.

If q is equal to 2, preferably one substituent R8was in the para-position and the other in the meta-position.

If q is equal to 2, in one embodiment, preferably, each R8was a Cl. In another embodiment, preferably, each R8was selected from cyano and trifloromethyl, and particularly preferably, the first R8was a para-cyano and the second R8was a meta-trifluoromethyl.

Particularly preferred pharmaceutically acceptable ester is a phosphate.

Particularly preferred pharmaceutically acceptable ether is hemisuccinate.

Particularly preferred pharmaceutically acceptable ether is validat.

In another aspect, the present invention relates to compounds according to the invention of the formula (VII):

where

X represents O;

R5means H, C1-C6alkyl, C3-C6alkenyl or C3-C6quinil, each of which can be unsubstituted or substituted by cyano, one or more halogen atoms;

R6ameans H or phosphate ester or its derivative, or ether carboxylic acids and preferably P(O)(OH)2C(=O)-(CH2)2-CO2H or-C(=O)CH(NH3Cl)iPr;

R6 means H;

R6cindependently selected from H and C1-C6of alkyl;

R7ameans H, halogen atom, cyano, C1-C4alkyl which may be unsubstituted or substituted by one or more halogen atoms;

R7bmeans halogen atom, cyano or C1-C4alkyl which may be unsubstituted or substituted by a halogen atom; each R8aand R8bindependently represents H, halogen atom, cyano, C1-C4alkyl, each of which can be unsubstituted or substituted by one or more halogen atoms;

R8cmeans halogen atom, cyano or nitro; and

p1is 0, 1 or 2.

In a separate aspect, R6cselected from H and C1-C4the alkyl.

In a separate aspect, R7aselected from H, halogen atom and cyano.

In a separate aspect, R7ameans C1-C4alkyl.

In a separate aspect, R7ameans C1-C4alkyl, substituted by one or more halogen atoms.

In a separate aspect, R7ameans CF3.

In a separate aspect, R7bselected from a halogen atom, cyano or C1-C4of alkyl, which may be unsubstituted or substituted by one or more halogen atoms.

In a separate aspect, each R8aand R8bregardless of predstavljaet a H, halogen atom, cyano or C1-C4alkyl which may be unsubstituted or substituted by one or more halogen atoms.

In a separate aspect, R6cmeans H.

In a separate aspect, R6ameans H.

In a separate aspect, R6ameans P(O)(OH)2.

In a separate aspect, R5means methyl or ethyl.

In another specific aspect, R5means PROPYNYL.

In a separate aspect of the p10.

In a separate aspect, R7amean Cl or F.

In a separate aspect, R7ameans H.

In other specific aspects, where the alkyl group is substituted by a halogen atom, halogen represents F. in Another specific aspect, the substituted alkyl group is triptorelin group.

In a separate aspect, each R8aand R8bselected from F, Cl, cyano, nitro, trifloromethyl and methyl, and R8cselected from F, Cl, cyano and nitro.

In a separate aspect, R8ameans H.

In a separate aspect, R8band R8cmean Cl. In another embodiment, R8band R8cselected from cyano and trifloromethyl, and in a specific embodiment, R8cmeans cyano and R8bmeans trifluoromethyl.

Preferred compounds according to the invention is selected from the following:

4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazo the one-1-yl]-2-cryptomathematical;

4-[2,5-dioxo-4-(1-hydroxypropyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical;

4-[2,5-dioxo-4-(1-hydroxyethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical;

4-[2,5-dioxo-4-(4-forfinal)-4-(hydroxymethyl)-3-methylimidazolidine-1-yl]-2-cryptomathematical;

4-[4-(4-chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl)-2-cryptomathematical;

4-[2,5-dioxo-4-(4-forfinal)-4-hydroxymethyl-3-(2-PROPYNYL)imidazolidin-1-yl]-2-cryptomathematical;

4-[4-(3-chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl)-2-cryptomathematical;

(S)-4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical;

(R)-4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical;

4-[2,5-dioxo-3-ethyl-4-(hydroxymethyl)-4-phenylimidazoline-1-yl]-2-cryptomathematical;

4-[4-(4-cyanophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl)-2-cryptomathematical;

4-[4-(3-cyanophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl)-2-cryptomathematical;

4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-(3-triptoreline)imidazolidin-1-yl)-2-cryptomathematical;

1-(3,4-dichlorophenyl)-4-hydroxymethyl-3-methyl-4-phenylimidazoline-2,5-dione;

4-[2,5-dioxo-4-(hydroxymethyl)-3-(1-methylethyl)-4-phenylimidazoline-1-yl]-2-triptime benzonitrile;

4-[3-cyanomethyl-2,5-dioxo-4-(hydroxymethyl)-4-phenylimidazoline-1-yl]-2-cryptomathematical;

4-[2,5-dioxo-4-(hydroxymethyl)-4-phenyl-3-(1-PROPYNYL)imidazolidin-1-yl]-2-cryptomathematical;

4-[2,5-dioxo-4-hydroxymethyl-4-phenylimidazoline-1-yl]-2-cryptomathematical;

4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-(3-were)imidazolidin-1-yl)-2-cryptomathematical;

4-[4-(2-chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl)-2-cryptomathematical;

[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl dihydrophosphate;

4-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methoxy-4-oxobutanoic acid;

(2S)-1-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methoxy-3-methyl-1-oxobutyl-2-amine chloride;

4-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methoxy-4-oxobutanoic acid;

(S)-(1-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,5-dioxo-4-phenylimidazole-4-yl)methyl dihydrophosphate;

(S)-4-((1-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,5-dioxo-4-phenylimidazole-4-yl)methoxy)-4-oxobutanoic acid.

In one embodiment, the compound according to the invention corresponding to any of the options described here, is not isotopic option.

As for the compounds of formula I, in one embodiment, Obedinenie selected from compounds listed in table 1.

In one aspect the compound according to the invention corresponding to any of the options described here, is present as a free base.

In one aspect the compound according to the invention corresponding to any of the options described here, represents a pharmaceutically acceptable salt.

In one aspect the compound according to the invention corresponding to any of the options described here, is a MES.

In one aspect the compound according to the invention corresponding to any of the options described here, represents a MES pharmaceutically acceptable salt.

Although specified for each option group mainly separately listed above, the connection according to the invention includes a compound in which several or each option in the above formula, as well as other present here a formula selected from one or more specific members or groups, respectively specified for each variable. Thus, it is expected that this invention includes in its scope all combinations of these options.

The present invention concerns the use of compounds according to the invention, which is defined above, for the prevention or treatment of cachexia.

The PHARMACEUTICAL COMPOSITION

When used and as a pharmaceutical compound according to the invention is usually administered in the form of pharmaceutical compositions. Such compositions can be obtained by a method well known in the pharmaceutical field, and they contain at least one active connection. Basically, the connection according to the invention is administered in a pharmaceutically effective amount. In fact, enter the number of connection is usually determined by the treating physician in the light of the relevant circumstances, including the subject to the treatment condition, the chosen route of administration, in fact, entered the compound, the age, weight and individual response of the patient, the severity of the symptoms of the patient.

The pharmaceutical compositions according to this invention can be administered in a number of ways, including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended method of delivery, the compounds according to the invention is preferably prepared in the form of compositions for injection or oral administration or in the form of ointments, lotions or patches (all preparations for transdermal administration).

Compositions for oral administration can be in the form of bulk liquid solutions or suspensions, or bulk powders. More often, however, to facilitate accurate dosing of the composition are in the form of a standard dosage forms. The expression "standard dosage forms" refers to physically dis is specific units, suitable as a standard doses for subjects-people and other mammals, each unit contains a predetermined quantity of the active substance, calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient, diluent or carrier. Typical standard dosage forms include pre-filled with liquid compositions dimensional ampoules or syringes, or in the case of solid compositions pills, tablets, capsules or the like. In such compositions the active compound is usually a smaller component (from about 0.1 to about 50% wt. or preferably from about 1 to about 40% wt.), the remainder consists of various diluents or carriers and processing AIDS helpful for obtaining the desired dosage form.

Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous media buffer, suspendresume and dispersing agents, colorants, flavorings and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, tragacanth gum or gelatin; an excipient such as starch or lactose; agrihotel, such as alginic acid, primogel or corn starch; a lubricant such as magnesium stearate; a substance promoting sliding, such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring, such as peppermint, methyl salicylate or orange flavor.

Compositions for injection are usually as the basis of a sterile saline solution for injection or saline solution with a phosphate buffer, or other media for injection, known in the field. As above, the active compound in such compositions is typically a smaller component, often comprising from about 0.05 to 10 wt.%, while the rest of the number is the carrier for injection and the like.

Transdermal compositions are usually obtained in the form of ointment or cream of local action, containing the active ingredient(s), usually in an amount of about 0.01 to about 20 wt.%, preferably from about 0.1 to about 20 wt.%, preferably from about 0.1 to about 10% wt. and more preferably from about 0.5 to about 15 wt.%. Upon receipt ointment active ingredients are usually combined with paraffin or miscible with water based ointment. Differently, you can get drugs the active ingredients in the form of a cream, for example, applying a basis for kr the mA type oil-in-water". Such transdermal preparations are well known in this field and, as a rule, include additional ingredients to enhance skin permeability, stability of the active ingredients or preparation. All such known transdermal preparations and ingredients included in the scope of this invention.

Compounds according to the invention can also be entered using the device for transdermal administration. Therefore, transdermal introduction can be performed by applying a patch, or a tank, or a porous membrane, or a variety of solid matrix.

The above-described components for the compositions, administered orally, by injection or injected locally, are only typical. Other materials and methods of processing and the like are set out in part 8 of the work Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

Compounds according to the invention can also be entered in the form of a long-release or delivery systems of drugs with a long release. Description of typical materials with prolonged release can be found in Remington''s Pharmaceutical Sciences.

The following examples illustrate typical preparations of pharmaceutical compositions which can be obtained according to this invention. However, the present invention is not limited to the listed next of pharmaceutical compositions.

The drug 1 - pills

The connection according to the invention in the form of a dry powder can be mixed with a dry gelatin binder in a mass ratio of approximately 1:2. You can add as lubricant a small amount of magnesium stearate. The mixture is molded in the form of 240-270 mg tablets (80-90 mg of active compound per tablet) in the press to obtain tablets.

Preparation of 2 - capsules

The connection according to the invention in the form of a dry powder can be mixed with a starch diluent in a mass ratio of approximately 1:1. The mixture can be filled 250 mg capsules (125 mg of active compound per capsule).

Preparation of 3 - fluid

The connection according to the invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan-gum (4 mg), and the resulting mixture can be mixed, passed through a sieve No. 10 mesh U.S. and then mixed with a previously prepared solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavoring and coloring diluted with water and add with stirring. Then add with stirring a sufficient amount of water. Then add water in sufficient quantity to obtain a volume of 5 ml

The drug is 4 tablets

The connection according to the invention in the form of a dry powder can be mixed with a dry gelatin binder in a mass ratio of the sample is about 1:2. Add as lubricant a small amount of magnesium stearate. The mixture is molded in the form of 450-900 mg tablets (150-300 mg of active compound) on the press to obtain tablets.

The drug 5 - for injection

The connection according to the invention can be dissolved or suspended in water for injection - sterile physiological solution with buffer to a concentration of approximately 5 mg/ml

The drug 6 - for local use

Stearyl alcohol (250 g) and medical petrolatum (250 g) may be melted at about 75°C, and then you can add a mixture of compounds according to the invention (50 g)methylparaben (0.25 g), propyl paraben (0.15 g), sodium lauryl sulphate (10 g) and propylene glycol (120 g)dissolved in water (about 370 g), and the resulting mixture is stirred until hardened.

TREATMENT

The present invention relates to new imidazolidinone compounds that modulate the activity of androgen receptors. These compounds can be used for the treatment and/or prevention of several disorders, as will be discussed below with additional details. Specialists in this field it is clear that the activity of the compounds according to the invention as antagonist (partial or full) or agonist (full or partial) is the continuous spectrum. Therefore, despite the fact that some compounds Bud is t obvious agonists or obvious antagonists, some compounds will demonstrate both types of activity, agonistic and antagonistic. These compounds with mixed activities potentially applicable for the treatment of various disorders. Here the example shows the details as the relative activity of the compounds according to the invention can be identified and can be classified as agonists, antagonists or mixed agonist/antagonists. Thus, it is clear that the experts in this field are quite capable of using their usual General knowledge together with listed here the examples of information to determine whether a particular connection according to the invention is an agonist, antagonist or mixed agonist/antagonist, and, therefore, clarify the appropriate uses of the specified connection.

The connection according to the invention can exhibit good absorption, good half-life, good solubility, good bioavailability, low affinity binding protein, less drug-drug interactions and good metabolic stability. In a separate aspect, the compound of the present invention shows unexpected significant improvement of pharmacological properties, in particular improved bioavailability. If the connection according to the invention is played is the duty to regulate any one or more of these improvements, this may affect its application described here States. For example, if the connection according to the invention shows an improved bioavailability, it is assumed that the connection according to the invention it is possible to enter at a lower dose, reducing, thus, the possibility of any unwanted side effects. Similarly, the other improvements listed above property also benefits potential applications of the compounds according to the invention.

These compounds are suitable as therapeutic agents for treating conditions caused by or inherent in the changing levels of circulating androgens in mammals. Thus, in one aspect, the present invention relates to compounds according to the invention for use in medicine.

In one embodiment, the present invention relates to compounds according to the invention for use for the prevention and/or treatment of age-related diseases, including but not limited to this, sarcopenia, the state of cachexia and loss of muscle mass caused by diseases, including, but not limited to these, cancer and AIDS, or induced thermal burns or prolonged immobilization; and bone and joint diseases such as osteoporosis, decreased libido and sexual dysfunction or anemia. In a separate aspect, the variant with the unity of the invention is an agonist or mixed agonist/antagonist of AR.

In one embodiment, the present invention relates to a method of treatment and/or prevention of age-related diseases, including but not limited to this, sarcopenia, the state of cachexia and loss of muscle mass caused by diseases, including, but not limited to these, cancer and AIDS, bone and joint diseases such as osteoporosis, decreased libido and sexual dysfunction or anemia, and this method includes the introduction of the needy in this subject a therapeutically effective amount of the compounds according to the invention or pharmaceutical compositions according to the invention. In a separate aspect of this option, the connection according to the invention is an agonist or mixed agonist/antagonist AR, or the pharmaceutical composition contains agonist or mixed agonist/antagonist of AR.

In one embodiment, the present invention relates to compounds according to the invention for use for the prevention and/or treatment of androgen-dependent tumors, such as prostate cancer or hyperplasia. In a separate aspect of this option, the connection according to the invention is an antagonist of AR.

In another embodiment, the present invention relates to a method of treatment and/or prevention of androgen-dependent tumors, such as prostate cancer or hyperplasia, and this method includes the introduction of the needy in this is the subject of therapeutically effective amounts of compounds according to the invention or pharmaceutical compositions according to the invention. In a separate aspect of this option, the connection according to the invention is an AR antagonist, or a pharmaceutical composition comprises the antagonist of AR.

In one aspect, the present invention relates to compounds according to the invention, which is an antagonist of the androgen receptor corresponding to any of the above formulas I-VII, where a value of KSchildbelow 1 μm, for use for the prevention or treatment of androgen-dependent tumors, such as prostate cancer or hyperplasia.

In one aspect the present invention relates to a method of treatment and/or prevention of androgen-dependent tumors, such as prostate cancer or hyperplasia, and this method includes the introduction of the needy in this subject a therapeutically effective amount of the compounds according to the invention, corresponding to either of the above formulas I-VII, where the specified connection according to the invention is an antagonist androgennogo receptor, which has a value of KSchildbelow 1 micron.

In one aspect, the present invention relates to compounds according to the invention which is an androgen receptor agonist or mixed agonist/antagonist that corresponds to any of the above formulas I-VII, where the values of EC50and KSchildboth below 1 micron, for use for the prevention or the ecene age-related diseases, including but not limited to this, sarcopenia, the state of cachexia and loss of muscle mass caused by diseases, including, but not limited to these, cancer and AIDS, and bone and joint diseases such as osteoporosis, decreased libido and sexual dysfunction or anemia.

In one aspect the present invention relates to a method of treatment and/or prevention of age-related diseases, including but not limited to this, sarcopenia, the state of cachexia and loss of muscle mass caused by diseases, including, but not limited to these, cancer and AIDS, and bone and joint diseases such as osteoporosis, decreased libido and sexual dysfunction or anemia, and this method includes the introduction of the needy in this subject a therapeutically effective amount of the compounds according to the invention, corresponding to either of the above formulas I-VII, where the specified connection according to the invention is an agonist of androgen receptor or mixed agonist/antagonist, whose values EC50and KSchildboth below 1 micron.

Transdermal dose is usually chosen so as to provide the same or lower blood levels than are obtained with doses that are given by injection.

If the compounds according to this invention is used to prevent the state of sarcopenia, toobin they are administered to a patient at risk of developing this condition on the recommendation and under the supervision of the attending physician at the above dose levels. Patients at risk of developing a specific condition, typically include the elderly, which results in reduction of muscle mass loss occurs mobility or difficulty of movement.

If the compounds according to this invention is used to prevent the condition of osteoporosis, usually they are administered to a patient at risk of developing this condition on the recommendation and under the supervision of the attending physician at the above dose levels. Patients at risk of developing a specific condition, as a rule, include the elderly who have reduced bone density can cause increased risk of fractures.

If the compounds according to this invention is used to prevent a bad condition, resulting from the primary disease, such as, but not limited to, cancer, HIV, stable chronic obstructive pulmonary disease (COPD), congestive heart failure or last-stage renal disease, they are usually administered to the patient on the recommendation and under the supervision of the attending physician at the above dose levels. Typical patients include patients undergoing treatment for cancer, HIV or AIDS.

The connection according to the invention can be entered as a single active agent, or you can enter it in combination with other therapeutic agents, including on the natives compounds demonstrating the same or similar therapeutic activity and for which it is determined that they are safe and effective when such combined introduction. In a specific embodiment, the joint introduction of two (or more) agents allows the treatment of the primary condition and the associated side effects.

In one embodiment, the compound according to the invention is administered together with another therapeutic agent for the treatment and/or prophylaxis of a condition of sarcopenia; particular agents include, but are not limited to this, testosterone, carotenoid, androgens, SARM and insulin-like growth factor 1.

In one embodiment, the compound according to the invention to introduce another therapeutic scheme for the treatment and/or prophylaxis of a condition of sarcopenia; specific schemes include, but are not limited to, exercise, alone or in combination with creatinemonohydrate or food proteins.

In one embodiment, the compound according to the invention is administered together with another therapeutic agent for the treatment and/or prevention of osteoporosis; particular agents include but are not limited to, bisphosphonates (alendronate, risedronate, ibandronate sodium or zoledronic acid, teriparatide, strontium ranelate, agents for hormone replacement therapy (raloxifene), supplementation with calcium or vitamin is m D.

In one embodiment, the compound according to the invention is administered together with another therapeutic agent for the treatment and/or prevention of cachexia; particular agents include but are not limited to, appetite stimulants/anti-emetics (for example, but without limitation, magistralata, tetrahydrocannabinol), ACE-inhibitors, beta-blockers, steroids (for example, but without limitation, Oxandrolone, nandrolone, ghrelin).

In one embodiment, the compound according to the invention is administered together with another therapeutic agent for the treatment and/or prevention of HIV-induced cachexia; particular agents include but are not limited to, nucleotide analogue - nucleoside reverse transcriptase inhibitor (NtARTI or NtRTI) (for example, but without limitation, Tenofovir®, Adefovir®), non-nucleoside reverse transcriptase inhibitors (NNRTIS) (for example, but without limitation, Efavirenz®, Nevirapine®, Delavirdine®, Etravirine®), protease inhibitors (for example, but without limitation, Saquinavir®, Ritonavir®, Indinavir®, Nelfinavir®, Amprenavir®, Lopinavir®, Atazanavir®, Fosamprenavir®, Tipranavir®, Darunavir®), inhibitors of penetration (for example, but without limitation, Maraviroc®, Enfuvirtide®) or integrase inhibitors (for example, but without limitation, raltegravir).

In one embodiment, the compound according to the invention is administered together with another therapeutic agent for the treatment and/or prevention of cachexia induced congestive heart what nedostatochnosty; specific agents include, but are not limited to, oral loop diuretics (furosemide, torsemide or bumetanide), beta-blockers (bisoprol, carvedilol and metoprolol long release), ACE-inhibitors (captopril, zofenopril, enalapril, ramipril, inapril, perindopril, lisinopril, benazepril or fosinopril), antagonists of angiotensin II receptors (candesartan) or vasodilator agents.

In one embodiment, the compound according to the invention is administered together with another therapeutic agent for the treatment and/or prevention of cachexia induced end-stage renal failure; particular agents include, but are not limited to this, ACE-inhibitors (captopril, zofenopril, enalapril, ramipril, inapril, perindopril, lisinopril, benazepril or fosinopril), antagonists of angiotensin II receptors (candesartan), vitamin D3 or calcium in Association with phosphate binder.

As it is obvious to the specialist at the joint introduction include any means of delivery to the patient two or more therapeutic agents as part of the above-mentioned regimen. While two or more agents can be administered simultaneously in a single drug, it is not significant. Agents can be introduced in the form of different drugs at different times.

GENERAL SYNTHETIC METHODS

Total

Connection is according to the invention can be obtained from readily available starting compounds, using the following General methods and techniques. It is clear that if given typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, and others), it is also possible to apply other conditions of the process, until you specify otherwise. Optimum reaction conditions may vary depending on the specific reactants or solvent used, but the person skilled in the art can determine such conditions through routine optimization techniques.

In addition, as clearly experts in this field, to prevent undesirable interactions with certain functional groups may be necessary conventional protective group. The choice of suitable protective groups for functional groups, as well as suitable conditions for the introduction and removal of protecting well-known in this field. For example, many of the protective groups and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protective groups in organic synthesis, second edition, Wiley, New York, 1991, cited in the references.

The following methods are presented with details in respect of the receipt of typical compounds as listed here above. The person skilled in the art of organic synthesis can obtain a connection according to the invention from the known is s or commercially available starting materials and reagents.

All reagents have a commercial degree of purity and, while nothing else is stated, are used, as is customary, without additional purification. For interactions carried out in an inert atmosphere, using commercially available anhydrous solvents. In other cases the use of solvents of reagent purity, until you specify otherwise. Column chromatography is performed on silica gel 60 (35-70 μm). Thin-layer chromatography carried out using plates with pre-applied coating of silica gel F-254 (0.25 mm thick),1H NMR spectra were recorded on a NMR spectrometer Bruker DPX 400 (400 MHz). Chemical shifts (δ) for1H NMR spectra are expressed in ppm (ppm) relative to tetramethylsilane (δ 0,00) or the corresponding peak of the residual protons of the solvent, i.e. CHCl3(δ 7,27)as internal standard. Multipletness expressed as singlet (s), doublet (d), triplet (t), Quartet (q), multiplet (m) and wide (W.) signal. Constant interaction (J) are given in Hz. Mass spectra with elektrorazpredelenie (MS) were obtained on IHMS spectrometer Micromass. For all IHMS analyses used column: Chromolith Performance RP-18 100 mm ×3 mm (Merck AG). All methods used the following gradient:

solvent A: MeCN; solvent B: H2O, both solvents containing 0.1% formic acid;

gradient: from 100% B to 0% B, ot to 3.5 min; 0% B, 3.5 to 4.5 min; from 0% to 100% B, from 4.5 to 4.6 min; 100% B from 4.6 to 5 minutes flow Rate: 2.5 ml/min

The list used in the experimental section abbreviations:

DHMdichloromethane
DiPEAN,N-diisopropylethylamine
MeCNacetonitrile
BOCtert-butyloxycarbonyl
DMFN,N-dimethylformamide
TFAtriperoxonane acid
NMRnuclear magnetic resonance
DMSOthe sulfoxide
DFFAdiphenylphosphoryl
IHMSliquid chromatography in combination with mass spectrometry
ppmmillion share
Frfront ratio
Rtretention time
the singlet
W. a broad singlet
mmultiplet
ddoublet
TPLmelting point
countroom temperature
TEAthe triethylamine

GENERAL PROCEDURES

The General scheme

Compounds according to the invention can be obtained according to the following methods.

Method A. Scheme 1

Method B. Scheme 2

Example 1: 4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical (method A)

Stage 1: 1-phenyl-2-(2-propenyloxy)alanon

This compound is obtained from 2-hydroxy-1-phenylethanone according to the methodology used in the work G.A, Molander and J.A. McKie 1-hydroxy-2-butanone, J. Org. Chem. (1995), 60, 872-882.

Stage injection protection (optional)

1-Hydroxy-2-butanone can be protected using a variety of well-known groups according to routine methods well known to specialists in this field. For example, 2-(tre is butyldimethylsilyloxy)-1-phenylethane get quantitatively, mixing 1-hydroxy-2-butanone, tBDMSCl and imidazole in DMF (see reference 10). Then use this intermediate product, as described in the following stages.

Stage 2: 4-phenyl-2-(propenyloxy)imidazolidin-2,5-dione

0,775 g of 1-phenyl-2-(2-propenyloxy)ethanone, 0,575 g of potassium cyanide and 1.6 g of ammonium carbonate is heated to 55°C for 3 h in 23 ml of a mixture of ethanol/water 50/50. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic solution was washed with saturated aqueous sodium chloride, then dried over sodium sulfate and evaporated, obtaining the desired product (pale yellow solid).

TLC: Fr=0,42 (heptane/ethyl acetate 50/50).

1H NMR (CD3OD): δ 3,68 (d, 1H); 4,13 (m, 3H); 4,22 (d, 1H); 4.92 in (s, 2H); 5,22 (DD, 1H); of 5.34 (DD, 1H); 5,95 (DDT, 1H); was 7.45 (m, 3H); to 7.64 (d, 2H).

JHMS: (Rt=5,79 min): 288+(MH, MeCN+).

Stage 3: 4-[2,5-dioxo-4-phenyl-4-[(2-propenyloxy)methyl]-imidazolidin-1-yl]-2-cryptomathematical

To a solution of 0.47 g of 4-phenyl-2-(propenyloxy)imidazolidin-2,5-dionein 30 ml of dimethylacetamide added 0.28 g of copper oxide(I) and 0.81 g of 4-bromo-2-triftormetilfosfinov. The mixture is heated at 160°C for 3 hours. In the room. so the mixture is diluted with 50% aqueous ammonia solution and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel, e is wiroa a mixture of heptane/ethyl acetate 70/30 and obtaining the desired product.

TLC: Fr=0,30 (heptane/ethyl acetate 70/30).

1H NMR (CDCl3): δ 3,86 (d, 1H); to 4.14 (s, 2H); 4,27 (d, 1H); 5,28 (d, 1H); 5,32 (d, 1H); of 5.89 (DDT, 1H); 7,52 (m, 3H); of 7.70 (m, 2H); 7,98 (m, 2H); to 8.14 (m, 1H).

JHMS: (Rt=6,91 min); 414-(M-H-).

Stage 4: 4-[2,5-dioxo-3-methyl-4-phenyl-4-[(2-propenyloxy)methyl] imidazolidin-1-yl]-2-cryptomathematical

To a solution of 0,86 g of 4-[2,5-dioxo-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov and 0.26 ml of iodomethane in 30 ml DMF added 430 mg of potassium carbonate. The mixture is stirred at room t for 5 hours, evaporated to dryness, diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 70/30 and obtaining the desired product.

TLC: Fr=0,37 (heptane/ethyl acetate 70/30).

1H NMR (CDCl3): δ of 3.07 (s, 3H); 3,98 (d, 1H); 4,14 (broad s, 2H); of 4.44 (d, 1H); 5,28 (d, 1H); 5,32 (d, 1H); by 5.87 (DDT, 1H); 7,39 (m, 2H); 7,49 (m, 3H); a 7.92 (d, 1H); 8,00 (d, 1H); 8,13 (m, 1H).

JHMS: (Rt=7,11 min): 471+(MH, MeCN+).

Stage 5: 4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-phenylimidazoline-1-yl]-2-trifluoromethyl-benzonitrile

To a solution of 0.52 g of 4-[2,5-dioxo-3-methyl-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov in 40 ml of dichloromethane is added 2 ml of complex trevormoran-dimethyl sulfide in 10 ml of dichloromethane. With the ect is stirred at room so for 3 hours, poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 70/30 and obtaining the desired product.

TPL=160°C.

TLC: Fr=0,33 (heptane/ethyl acetate 50/50).

1H NMR (CDCl3): δ to 3.09 (s, 3H); 4,18 (d, 2H); to 4.73 (d, 1H); 7,38 (m, 2H); to 7.50 (m, 3H); to 7.93 (d, 1H); 8,02 (d, 1H); 8.17 and (m, 1H).

JHMS: (Rt=6,53 min): 358-(M-CH2OH-).

Examples 2 and 3: 4-[2,5-dioxo-4-(1-hydroxypropyl)-3-methyl-4-phenylimidazoline-1-yl]-2-trifluoromethyl-benzonitrile (method B)

Stage 1: methyl 2-methylamino-2-phenylacetate

6,63 ml of thionyl chloride are slowly added to a solution of 1.5 g of 2-methylamino-2-phenylacetic acid in 100 ml of methanol. The mixture is heterogeneous and becomes transparent after two hours of mixing. The mixture is stirred for 48 hours at room etc, then the solvent is evaporated to dryness. The crude product is diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with water, then with saturated salt solution and dried over magnesium sulfate, filtered and evaporated, obtaining the desired product, which is used as is for the next stage.

TLC: Fr=0,56 (dichloromethane/methanol 90/10).

1H NMR (CDCl3): δ 196-1,99 (broad s, 1H); 2,43 (s, 3H); to 3.73 (s, 3H); 4,30 (s, 1H); 7,31-7,42 (m, 5H).

Stage 2: 4-[2,5-dioxo-3-methyl-4-phenylimidazoline-1-yl]-2-trifluoromethyl-benzonitrile

To a solution of 1.26 g of triphosgene in 20 ml of anhydrous toluene is added slowly a solution of 1.18 g of 4-amino-2-triftormetilfosfinov in 16 ml of anhydrous dioxane. The mixture is refluxed for 1.5 hour. After cooling at room T. the mixture is evaporated to dryness. To this crude product, diluted with 50 ml anhydrous THF, added 1.13 g of methyl 2-methylamino-2-phenylacetate in 10 ml of THF. The mixture is stirred at room t for 30 minutes Add a 1.96 ml of TEA, the mixture is refluxed for 1.5 hours and stirred at room t for 16 h, then evaporated to dryness. The crude product is diluted with aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is washed with water, then with saturated salt solution and dried over magnesium sulfate, filtered and evaporated. The crude product is crystallized from ethyl acetate, filtered and rinsed with ethyl ether, obtaining the desired product.

TLC: Fr=0,67 (dichloromethane/ethyl ether 90/10).

1H NMR (CDCl3): δ of 3.06 (s, 3H); of 5.06 (s, 1H); 7,35-7,39 (m, 2H); of 7.48-7,56 (m, 3H); of 7.96 (d, 1H); 8,03 (DD, 1H); 8,18 (d, 1H).

JHMS: (Rt=2.91 in min, apolar way): niinisaari.

Stage 3: 4-[2,5-dioxo-4-(1-hydroxypropyl)-3-methyl-4-phenylimidazoline-1-yl]-2-triptorelin the nitrile

To a cooled to -78°C solution of 200 mg of 4-[2,5-dioxo-3-methyl-4-phenylimidazoline-1-yl]-2-triftormetilfosfinov in 4 ml of anhydrous THF is added slowly of 0.64 ml lithium
bis(trimethylsilyl)amide 20% in hexane. The solution becomes dark brown. The mixture was stirred at -78°C for 10 minutes Then slowly add 121 μl propane aldehyde, the solution becomes dark red. Adding another 121 μl propane aldehyde gives a General discoloration of the mixture. The mixture was stirred at -78°C for 30 min and quenched the reaction mixture at -78°C with an aqueous solution of ammonium chloride. The mixture is heated at room T. and extracted the aqueous phase with ethyl acetate. The organic phase is washed with water, then with saturated salt solution and dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/dichloromethane from 1/1 to 0/1, then a mixture of dichloromethane/ethyl ether from 99/1 to 95/5, receiving two diastereoisomer: isomer A and isomer B.

Analytical data for isomer A:

TLC: Fr=0,45 (dichloromethane/ethyl ether 9/1);

1H NMR (CDCl3): δ 1,19 (t, 3H); 1,48-to 1.63 (m, 1H); 1,65-of 1.78 (m, 1H); 3,26 (s, 3H); 4,70-of 4.77 (m, 1H); 7,46 to 7.62 (m, 5H); to 7.93 (d, 1H); to 7.99 (d, 1H); 8,13 (s, 1H);

JHMS: (Rt=3,47 min): 358-(M-CH3CH2CHOH)-.

Analytical data for isomer B:

TLC: Fr=0,36 (dichloromethane/ethyl ether 9/1);

1H NMR (CDClsub> 3): δ of 1.18 (t, 3H); 1,42-of 1.55 (m, 1H); 1,72-of 1.84 (m, 1H); is 3.08 (s, 3H); 4.63 to-4,70 (m, 1H); 7,39-of 7.55 (m, 5H); to 7.95 (d, 1H); 8,02 (d, 1H); 8,15 (s, 1H);

JHMS: (Rt=3.46 in min); 358-(M-CH3CH2CHOH)-.

Examples 4 and 5: 4-[2,5-dioxo-4-(1-hydroxyethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-trifluoromethyl-benzonitrile

4-[2,5-dioxo-4-(1-hydroxyethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical receive, using the same Protocol as used for examples 2 and 4, from 4-[2,5-dioxo-3-methyl-4-phenylimidazoline-1-yl]-2-triftormetilfosfinov when using acetaldehyde instead of propionic aldehyde. The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/dichloromethane from 1/1 to 0/1, then a mixture of dichloromethane/ethyl ether from 99/1 to 95/5, receiving two diastereoisomer: isomer C and isomer D.

Analytical data for isomer C:

TLC: Fr=0,32 (dichloromethane/ethyl ether/NH4OH 90/10/0,1);

1H-NMR (CDCl3): δ of 1.42 (d, 3H); 3,26 (s, 3H); 5,03-5,61 (m, 1H); 7,47-of 7.60 (m, 5H); to 7.93 (d, 1H); to 7.99 (d, 1H); to 8.12(s, 1H);

JHMS: (Rt=3,35 min): 358-(M-CH3CHOH)-.

Analytical data for isomer D:

TLC: Fr=0,26 (dichloromethane/ethyl ether/NH4OH 90/10/0,1);

1H NMR (CDCl3): δ of 1.44 (d, 3H); 3,10 (s, 3H); 4,98-of 5.06 (m, 1H); 7,42-7,56 (m, 5H); to 7.95 (d, 1H); 8,02 (d, 1H); is 8.16 (s, 1H);

JHMS: (Rt=3,34 min): 358-(M-CH3CHOH)-.

Example 6: 4-[2,5-dioxo-4-forfinal-4-hydroxymethyl-3-methylimidazolidine the-1-yl]-2-cryptomathematical (method A)

Stage 1: 1-(4-forfinal)-2-hydroxyethane

2 g of 2-bromo-1-(4-forfinal)ethanone and 6 EQ. formate sodium in 15 ml of a mixture of ethanol/water is subjected to microwave irradiation for 5 min at 150°C 11 bar. After filtration and evaporation of the ethanol, water is added. The expected product are filtering.

1H NMR (DMSO-D6): δ 4,78 (s, 2H); 5,12 (m, 1H); 7,35 (m, 2H); 8,00 (m, 2H).

JHMS: (Rt=of 2.51 min): without ionization.

Stage 2: 1-(4-forfinal)-2-(2-propenyloxy)alanon

Mix together with 2.4 g of 1-(4-forfinal)-2-hydroxyethane obtained in stage 1, 10 ml allylbromide and 9.4 g CaSO4in an argon atmosphere. Add portions of 6.2 g Ag2O for 1.5 hour. This mixture is stirred for 3 hours at room T., diluted with ethyl ether, filtered and the solvent evaporated. The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 90/10.

1H NMR (DMSO-D6): δ of 4.05 (m, 2H); 4,82 (s, 2H); 5.17 to (DD, 1H); 5,28 (DD, 1H); of 5.92 (DDT, 1H); 7,37 (m, 2H); 8,00 (m, 2H).

JHMS: (Rt=2,69 min): without ionization.

Stage 3: 4-(4-forfinal)-4-[(2-propenyloxy)methyl]imidazolidin-2,5-dione

1.8 g of 1-(4-forfinal)-2-(2-propenyloxy)ethanone obtained in stage 2, to 1.21 g of potassium cyanide and 4,69 g of ammonium carbonate is heated to 55°C for 2 h in 50 ml of a mixture of ethanol/water 50/50. Heating the mixture at 55°C, add 4,69 g of ammonium carbonate 3 times in 1 hour, 4 and 15 h, with therefore, its. Then the reaction mixture was diluted with water and extracted with ethyl acetate. The organic solution is dried over sodium sulfate and evaporated, obtaining the desired product.

1H NMR (DMSO-D6): δ 3,50 (d, 1H); 3,95 (d, 1H); is 4.03 (d, 2H); further 5.15 (DD, 1H); 5.25-inch (DD, 1H, (DD, 1H); to 5.85 (DDT, 1H); 7,25 (m, 2H); 7,58 (m, 2H); 8,65 (s, 1H); 10,80 (s, 1H).

JHMS: (Rt=2,43 min); without ionization.

Stage 4: 4-[2,5-dioxo-4-(4-forfinal)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

Added 0.33 g of copper oxide(I) and 0.95 g of 4-bromo-2-triftormetilfosfinov to a solution of 1 g of 4-(4-forfinal)-4-[(2-propenyloxy)methyl]imidazolidin-2,5-dione, obtained in stage 3, in 3 ml of DMAC. The mixture is heated at 160°C for 3 hours. After cooling, the mixture is diluted with 50% aqueous solution of ammonia and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 2/1.

1H NMR (DMSO-D6): δ 3,62 (d, 1H); 4,07 (m, 2H); 4,15 (d, 1H); further 5.15 (d, 1H); 5,22 (d, 1H); to 5.85 (DDT, 1H); 7,30 (m, 2H); of 7.70 (m, 2H); 8,00 (d, 1H); 8,10 (s, 1H), with 8.33(d, 1H).

IHMS; (Rt=3,30 min): 432-(M-H-).

Stage 5: 4-[2,5-dioxo-4-(4-forfinal)-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

Add 325 mg of potassium carbonate and 0.25 ml of iodomethane to a solution of 0.85 g of 4-[2,5-dioxo-4-(4-forfinal)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov, obtained in stage 4 and dissolved in 3 ml of DMF. The mixture is stirred at room t for 4 h in an argon atmosphere, evaporated to dryness, diluted with water and saturated salt solution and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and evaporated, obtaining the desired product.

1H NMR (DMSO-D6): δ 2,85 (s, 3H); to 4.17 (m, 2H); 4,20 (d, 1H); however, 4.40 (d, 1H); further 5.15 (d, 1H); to 5.21 (d, 1H); by 5.87 (DDT, 1H); 7,30 (m, 2H); at 7.55 (m, 2H); 8,00 (d, 1H); to 8.12 (s, 1H), with 8.33 (d, 1H).

JHMS: (Rt=3,43 min): without ionization.

Step 6: 4-[2,5-dioxo-4-(4-forfinal)-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical

The crude mixture of 4-[2,5-dioxo-4-(4-forfinal)-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov obtained at stage 5, is dissolved in 5 ml DHM in argon atmosphere. Add 0.9 ml of complex trevormoran-dimethyl sulfide. The mixture is stirred at room t for 7 hours. Slowly add saturated aqueous solution of sodium bicarbonate, the product is extracted with DHM and the organic layer dried over sodium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel, elwira mixture DHM/ethyl acetate 4/1.

1H NMR (DMSO-D6): δ 2,87 (s, 3H); 4,08 (m, 1H); however, 4.40 (m, 1H); 5,80 (m, 1H); 7,30 (m, 2H); 7,52 (m, 2H); with 8.05 (d, 1H); 8,19 (s, 1H), 8,32 (d, 1H).

JHMS: (Rt=2,97 min): 376-(M-CH2OH-).

Example 7: 4-[4-(4-chlorophenyl)2.5 dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical (method A)

Scheme 3

Stage 1: 1-(4-chlorophenyl)-2-hydroxyethane

The interaction of 2 g of 2-bromo-1-(4-chlorophenyl)ethanone using the Protocol of example 6, stage 1 gives the desired product.

1H NMR (DMSO-D6): δ 4,78 (s, 2H); further 5.15 (m, 1H); of 7.60 (d, 2H); 7,94 (d, 2H). JHMS: (Rt=2,55 min): without ionization.

Stage 2: 1-(4-chlorophenyl)-2-(2-propenyloxy)alanon

The interaction of 2.64 g of 2-bromo-1-(4-chlorophenyl)ethanone using the Protocol of example 6, stage 2 gives the desired product.

1H NMR (DMSO-D6): δ 4,08 (m, 2H); 4,84 (s, 2H); by 5.18 (DD, 1H); from 5.29 (DD, 1H); of 5.92 (DDT, 1H); to 7.61 (d, 2H); a 7.92 (d, 2H).

Stage 3: 4-(4-chlorophenyl)-4-(2-propenyloxy)imidazolidin-2,5-dione

The interaction of 2.5 g of 1-(4-chlorophenyl)-2-(2-propenyloxy)ethanone using the Protocol of example 6, stage 3 gives the desired product.

1H NMR (DMSO-D6): δ 3,50 (d, 1H); 3,93 (d, 1H); is 4.03 (d, 2H); further 5.15 (DD, 1H); 5.25-inch (DD, 1H, (DD, 1H); of 5.84 (DDT, 1H); 7,47 (m, 2H); at 7.55 (m, 2H); 8,67 (s, 1H); was 10.82 (s, 1H).

JHMS: (Rt=3,06 min): without ionization.

Stage 4: 4-[4-(4-chlorophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

The interaction of 1.4 g of 4-(4-chlorophenyl)-4-(2-propenyloxy)imidazolidin-2,5-dione using the Protocol of example 6, stage 4 gives the desired product.

1H NMR (DMSO-D6): δ 3,71 (d, 1H); of 4.05 (m, 2H); 4,15 (d, 1H); 5,13 (d, 1H); to 5.21 (d, 1H); to 5.85 (DDT, 1H); 7,53 (d, 2H); to 7.68 (d, 2H); 7,98 (d, 1H); 8,10 (C, H); 8,31 (d, 1H).

JHMS: (Rt=3,41 min): (448/450)-(M-H-).

Stage 5: 4-[4-(4-chlorophenyl)-2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

The interaction of 0.50 g of 4-[4-(4-chlorophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov using the Protocol of example 6, stage 5 gives the desired product.

1H NMR (DMSO-D6): δ 2,87 (s, 3H); 4,10 (m, 2H); 4,18 (d, 1H); however, 4.40 (d, 1H); further 5.15 (d, 1H); to 5.21 (d, 1H); 5,88 (DDT, 1H); rate of 7.54 (m, 4H); 8,00 (d, 1H); to 8.12 (s, 1H); with 8.33 (d, 1H).

JHMS: (Rt=3,57 min): without ionization.

Stage 6: 4[4-(4-chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical

The interaction of 0.6 g of 4-[4-(4-chlorophenyl)-2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov using the Protocol of example 6, stage 6 gives the desired product.

1H NMR (DMSO-D6): δ 2,87 (s, 3H); 4,07 (m, 1H); however, 4.40 (m, 1H); of 5.82 (m, 1H); 7,51 (m, 4H); 8,03 (d, 1H); 8,19 (s, 1H); 8,32 (d, 1H).

JHMS: (Rt=3,13 min): (392/394)-(M-CH2OH-).

Example 8: 4-[4-(4-forfinal)-2,5-dioxo-4-hydroxymethyl-3-(2-PROPYNYL)imidazolidin-1-yl]-2-cryptomathematical

Stage 1: 4-[2,5-dioxo-4-(4-forfinal)-4-[(2-propenyloxy)methyl]-3-(2-PROPYNYL)imidazolidin-1-yl]-2-cryptomathematical

To a solution of 0.42 g of 4-[2,5-dioxo-4-(4-forfinal)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-trifluoromethyl what benzonitrile in 3 ml of DMF added 160 mg of potassium carbonate and 0.2 ml of propargylamine (80% solution in toluene). The mixture is stirred at room t for 4 h in an argon atmosphere. Then add 0.04 ml of propargylamine (80% solution in toluene) and the mixture is stirred for 1 hour at room T., evaporated to dryness, diluted with water and saturated salt solution and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and evaporated.

The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 4/1.

1H NMR (DMSO-D6): δ 3,17 (s, 1H); 4,05-4,12 (m, 2H); 4.25 in-and 4.40 (m, 4H); 5,12 (d, 1H); 5,22 (d, 1H); 5,88 (DDT, 1H); 7,30 (m, 2H); of 7.60 (m, 2H); 8,00 (d, 1H); to 8.12 (s, 1H); with 8.33 (d, 1H).

JHMS: (Rt=3.46 in minutes): without ionization.

Stage 2: 4-[4-(4-forfinal)-2,5-dioxo-4-hydroxymethyl-3-(2-PROPYNYL)imidazolidin-1-yl]-2-cryptomathematical

Dissolved 0.45 g of 4-[2,5-dioxo-4-(4-forfinal)-4-[(2-propenyloxy)methyl]-3-(2-PROPYNYL)imidazolidin-1-yl]-2-triftormetilfosfinov obtained in stage 1, in 5 ml DHM in argon atmosphere. Add 0.2 ml of the complex trevormoran-dimethyl sulfide. The mixture is stirred at room t for 18 hours. Slowly add saturated aqueous sodium bicarbonate solution. The product is extracted with DHM and the organic layer dried over sodium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel, elwira mixture DHM/ethyl acetate 6/1.

1H NMR (DMSO-D6): δ 3,10 (m, 3H); 4,10-and 4.40 (m, 4H); 5,80 (m, H); 7,28 (m, 2H); of 7.60 (m, 2H); with 8.05 (d, 1H); to 8.20 (s, 1H); 8,35 (d, 1H).

JHMS: (Rt=3,07 min): 400-(M-CH2OH-).

Example 9: 4-[4-(3-chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-trifluoromethyl-benzonitrile (method A)

Stage 1: 1-(3-chlorophenyl)-2-hydroxyethane

The interaction of 2 g of 2-bromo-1-(3-chlorophenyl)ethanone using the Protocol of example 6, stage 1 gives the desired product.

1H NMR (DMSO-D6): δ 4,80 (s, 2H); 5,20 (m, 1H); 7,58 (t, 1H); 7,72 (d, 1H); 7,88 (d, 1H); to 7.95 (s, 1H).

JHMS: (Rt=2,30 min): without ionization.

Stage 2: 1-(3-chlorophenyl)-2-(2-propenyloxy)alanon

The interaction of 2.5 g of 1-(3-chlorophenyl)-2-hydroxyethane using the Protocol of example 6, stage 2 gives the desired product.

1H NMR (DMSO-D6): δ 4,07 (m, 2H); 4,88 (s, 2H); by 5.18 (DD, 1H); and 5.30(DD, 1H); of 5.92 (DDT, 1H); 7,58(t, 1H); 7,72 (d, 1H); 7,88 (d, 1H); 7,92 (s, 1H).

Stage 3: 4-(3-chlorophenyl)-4-(2-propenyloxy)imidazolidin-2,5-dione

The interaction of 1.5 g of 1-(3-chlorophenyl)-2-(2-propenyloxy)ethanone using the Protocol of example 6, stage 3 gives the desired product.

1H NMR (DMSO-D6): δ 3,52 (d, 1H); 3,95 (d, 1H); was 4.02 (d, 2H); 5,16 (DD, 1H); 5.25-inch (DD, 1H); to 5.85 (DDT, 1H); 7,44 (m, 2H); 7,52 (m, 1H); to 7.59 (s, 1H); to 8.70 (s, 1H); 10,83 (s, 1H).

JHMS: (Rt=2.57 m min): without ionization.

Stage 4: 4-[4-(3-chlorophenyl)-2,5-dioxo-4-[(2-vinyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

The interaction of 1.0 g of 4-(3-chlorophenyl)-4-(2-propenyloxy)imidazolidin,5-dione using the Protocol of example 6, stage 4 gives the desired product.

1H NMR (DMSO-D6): δ and 3.72 (d, 1H); of 4.05 (m, 2H); 4,18 (d, 1H); 5,13 (d, 1H); to 5.21 (d, 1H); to 5.85 (DDT, 1H); to 7.50 (m, 2H); a 7.62 (m, 1H); of 7.70 (s, 1H); 7,98 (d, 1H); 8,10 (s, 1H); 8,32 (d, 1H); 9,12 (s, 1H).

JHMS: (Rt=3,41 min): (448/450)-(M-H-).

Stage 5: 4-[4-(3-chlorophenyl)-2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

The interaction of 0.66 g of 4-[4-(3-chlorophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov using the Protocol of example 6, stage 5 gives the desired product.

1H NMR (DMSO-D6): δ is 2.88 (s, 3H); 4,10 (m, 2H); 4,20 (d, 1H); was 4.42 (d, 1H); 5,16 (d, 1H); 5,22 (d, 1H); of 5.89 (DDT, 1H); to 7.50 (m, 1H); 7,52(m, 2H); of 7.60(s, 1H); 8,00 (d, 1H); 8,15 (s, 1H), with 8.33 (d, 1H).

JHMS: (Rt=3,57 min, apolar way): without ionization.

Step 6: 4-[4-(3-chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical

The interaction of 0.60 g of 4-[4-(3-chlorophenyl)-2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov using the Protocol of example 6, stage 6 gives the desired product.

1H NMR (MeOD): δ is 3.08 (s, 3H); 4,20 (m, 1H); br4.61 (m, 1H); 7,45 (m, 1H); 7,52 (m, 2H); to 8.14 (m, 2H); of 8.25 (s, 1H).

JHMS: (Rt=3,10 min): (392/394)-(M-CH2OH-).

Examples 10 and 11: (S)-4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical and (R)-4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-phenylimidazole the n-1-yl]-2-cryptomathematical

Two enantiomers of 4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-phenylimidazoline-1-yl]-2-triftormetilfosfinov share chromatography 1.5 g sample of racemic mixture obtained in example 1 on a Chiralcel OD (column LC50 Prochrom), elwira mix 75/25 heptane/isopropanol.

The first eluted enantiomer (S). Upon evaporation of the solvent receive the requested connection.

[a]D=-40,8° (c=1%in EtOH).

HPLC: column Chiralcel OD, 250×4.6 mm, heptane/isopropanol 75/25, flow rate 1 ml/min, Rt: 9,01 minutes

The enantiomer (R) eluted second. Further purification under the same conditions with the subsequent evaporation of the solvent gives the desired connection.

[a]D=+41,1°(c=1%in EtOH).

HPLC: column Chiralcel OD, 250×4.6 mm, heptane/isopropanol 75/25, flow rate 1 ml/min, Rt: 13,24 minutes

Alternative method:

Following the method similar to that described for example 1 and depicted in figure 3, it is possible to carry out cleaning "of the intermediate product n-1", receiving connections from example 10 and 11 after the removal of protection by using column Chiralpak AD® (250×4.6 mm) and a mixture of supercritical CO2/MeCN/iPrOH (90/5/5) at 40°C and 100 bar with the subsequent removal of the protective group by known methods (see reference 10).

Example 12: 4-[2,5-dioxo-3-ethyl-4-hydroxymethyl-4-phenylimidazoline-1-yl]-2-cryptomathematical (method A)

Stage 1: 4-2,5-dioxo-3-ethyl-4-phenyl-4-[(2-propenyloxy)methyl] imidazolidin-1-yl]-2-cryptomathematical

The procedure of example 1, stage 1, applied to a 0.23 g of 4-[2,5-dioxo-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov 0.18 ml of itatani, gives the desired connection.

JHMS: (Rt=3.20 minutes); 444+(MH+).

Stage 2: 4-[2,5-dioxo-3-ethyl-4-hydroxymethyl-4-phenylimidazoline-1-yl]-2-cryptomathematical

0.2 g of 4-[2,5-dioxo-3-ethyl-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov treated with 0.2 ml of the complex trevormoran-dimethyl sulfide as described in example 3, stage 2, receiving the requested connection.

TLC: Fr=0,35 (heptane/ethyl acetate 20/10).

1H NMR (DMSO-D6): δ of 1.05 (t, 3H); 3,32 (square, 2H); 4,22 and 4,40 (2 m, 2H); 5,62 (t, 1H); of 7.4-7.5 (m, 5H); 8,08 (d, 1H); to 8.20 (s, 1H); with 8.33 (d, 1H).

JHMS: (Rt=3,81 min): 372-(M-CH2OH-).

Example 13: 4-[4-(4-cyanophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical (method A)

Stage 1: 4-(2-hydroxyacyl)benzonitrile

A solution of 1 g of 4-(2-bromoacetyl)benzonitrile in acetonitrile (5 ml) and water (10 ml) is treated by microwave irradiation (125°C, 50 min). A similar experiment is carried out five times. The substance of all the tubes is collected, extracted with ethyl ether, dried over magnesium sulfate and concentrated in vacuo, receiving the requested connection.

TLC: Fr=0,15 (ethyl acetate/cyclohexane 30/70).

1H NMR (CDCl3 ): δ 4,94 (s, 2H); a 7.85-7,87 (DD, 2H); 8,05-8,07 (DD, 2H).

JHMS: (Rt=2,40 min): without ionization.

Stage 2: 4-[2-(2-propenyloxy)acetyl]benzonitrile

To a solution of 2.7 g of 4-(2-hydroxyacyl)benzonitrile in allylbromide (15 ml) is added 10.2 g of calcium sulfate and 6.7 g of silver oxide. The mixture is stirred in an argon atmosphere in the dark for 2 hours. The mixture is diluted with AcOEt, filtered on celite, concentrate, and purify on silica gel (ethyl acetate/cyclohexane: from 0/100 to 50/50)to give the desired compound.

TLC: Fr=0,38 (ethyl acetate/cyclohexane 40/60).

1H NMR (CDCl3): δ 4,01 (d, 2H); of 4.57 (s, 2H); 5,13 (d, 1H); 5,22 (s, 1H); 5,73 and 5.86 (m, 1H); to 7.64 (d, 2H); to $ 7.91 (d, 2H).

JHMS: (Rt=3,05 min): without ionization.

Stage 3: 4-[2,5-dioxo-4-[(2-vinyloxy)methyl]imidazolidin-4-yl]benzonitrile

To a solution of 500 mg of 4-[2-(2-propenyloxy)acetyl]benzonitrile (in EtOH (5 ml) and water (5 ml) is added 324 mg of potassium cyanide and 1.67 g of ammonium carbonate. The mixture is refluxed over night at 55°C. the Mixture is extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo, receiving the requested connection.

TLC: Fr=0,16 (ethyl acetate/cyclohexane 30/70).

1H NMR (CD3OD): δ of 3.45 (d, 1H); 3,86 (m, 3H); of 4.95 (d, 1H); of 5.06 (DD, 1H); ceiling of 5.60-5,73 (m, 1H); 7,58 (s, 4H).

JHMS: (Rt=2,77 min): 270-(M-H)-.

Stage 4: 4-[4-(4-cyanophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl] imidazolidin-1-yl]-2-cryptomathematical

the solution of 675 mg of 4-[2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-4-yl]benzonitrile and 622 mg of 4-bromo-2-triftormetilfosfinov in DMAC (2.5 ml) is added 214 mg of copper oxide(I). The mixture is refluxed overnight at 130°C. the Mixture is concentrated and transferred into DHM, washed with 10% aqueous solution of ammonia and saturated salt solution. The organic phase is dried over magnesium sulfate, concentrated in vacuo and purified on silica gel (ethyl acetate/cyclohexane: from 0/100 to 50/50)to give the desired compound.

TLC: Fr=0,48 (ethyl acetate/cyclohexane 50/50).

1H NMR (CDCl3): δ of 3.85 (d, 1H); 4.09 to 4,19 (m, 3H); 5.25 to 5,31 (m, 2H); 5,80-by 5.87 (m, 1H); 6,07 (s, 1H); 7,79-to 7.84 (s, 4H); 7,95 (s, 2H); 8,07 (s, 1H).

JHMS: (Rt=3,29 min): 439-(M-H)-.

Stage 5: 4-[4-(4-cyanophenyl)-2,5-dioxo-3-methyl-4-[(2-propenyloxy) methyl]imidazolidin-1-yl]-2-cryptomathematical

To a solution of 459 mg of 4-[4-(4-cyanophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov obtained in stage 4, in DMF (1.5 ml) is added 173 mg of potassium carbonate and 130 μl of methyliodide. The mixture is stirred for 3 hours at room T., evaporated, washed with saturated salt solution, extracted with ethyl acetate, dried over magnesium sulfate and concentrated, obtaining the desired connection.

TLC: Fr=0,54 (ethyl acetate/cyclohexane 50/50).

1H NMR (CDCl3): δ to 3.09 (s, 3H); 3,95 (d, 1H); to 4.14 (m, 2H); 4,39 (d, 1H); 5,28-of 5.34 (m, 2H); of 5.84-5,91 (m, 1H); EUR 7.57 (d, 2H); 7,80 (d, 2H), 7,95 (s, 2H), 8,10 (s, 1H).

JHMS: (Rt=3,81 min): without ionization.

Step 6: 4-[4-(4-cyanophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-reformational

To a solution of 433 mg of 4-[4-(4-cyanophenyl)-2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov obtained at stage 5, DHM (5 ml) add 600 ál of the complex of boron TRIFLUORIDE-dimethyl sulfide. The mixture is stirred for 8 hours at room T., diluted DHM, washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, concentrated and purified on silica gel (ethyl acetate/cyclohexane: from 0/100 to 50/50)to give the desired compound.

TLC: Fr=0,10 (ethyl acetate/cyclohexane 30/70).

1H NMR (CDCl3): δ 3,14 (s, 3H); 4.16 the (d, 1H); to 4.73 (d, 1H); EUR 7.57 (d, 2H); of 7.82 (d, 2H), 7,93-of 8.00 (m, 2H), 8,13 (s, 1H).

JHMS: (Rt=3,05 min): 383-(M-CH2OH)-.

Example 14: 4-[4-(3-cyanophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical (method A)

Stage 1: 3-(2-hydroxyacyl)benzonitrile

A solution of 776 mg of 3-(2-bromoacetyl)benzonitrile in acetonitrile (5 ml) and water (10 ml) is treated by microwave irradiation (125°C, 50 min). A similar experiment is carried out a second time, using 976 mg of the Substance of all the tubes is collected, extracted with ethyl ether, dried over magnesium sulfate and concentrated in vacuo, receiving the requested connection.

TLC: Fr=0,38 (ethyl acetate/cyclohexane 30/70).

1H NMR (CDCl3): δ 4,94 (s, 2H); 7,71 (t, 1H); to 7.95 (d, 1H); 8,18 (d, 1H); of 8.25 (s, 1H).

Stage 2: 3-[(2-(2-propenyloxy]benzonitrile

To a solution of 1.08 g of 3-(2-hydroxyacyl)benzonitrile in allylbromide (8 ml) are added 4 g of calcium sulfate and 2.6 g of silver oxide. The mixture is stirred in an argon atmosphere and the darkness during the night. The mixture is diluted with ethyl acetate, filtered on celite, concentrate, and purify on silica gel (ethyl acetate/cyclohexane from 0/100 to 30/70)to give the desired compound.

TLC: Fr=0,64 (ethyl acetate/cyclohexane 30/70).

1H NMR (CDCl3): δ 4,18 (d, 2H); to 4.73 (s, 2H); 5,31 (d, 1H); lower than the 5.37 (d, 1H); of 5.92-of 6.02 (m, 1H); 7,66 (t, 1H); of 7.90 (d, 1H); by 8.22 (d, 1H); 8,29 (s, 1H).

JHMS: (Rt=3.04 from min): without ionization.

Stage 3: 3-[2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-4-yl]benzonitrile

To a solution of 450 mg of 3-[(2-(2-propenyloxy)acetyl]benzonitrile in EtOH (5 ml) and water (5 ml) is added 291 mg of potassium cyanide and ammonium carbonate. The mixture is refluxed for one night at 55°C. the Mixture is extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo, receiving the requested connection.

TLC: Fr=0.1 (ethyl acetate/cyclohexane 30/70).

1H NMR (CD3OD): δ 3,70 (d, 1H); 4,10-to 4.14 (m, 3H); 5,23 (d, 1H); 5,33 (d, 1H); of 5.89 is 5.98 (m, 1H); to 7.67 (t, 1H); 7,80 (d, 2H); 7,98-8,02 (m, 1H).

Stage 4: 4-[4-(3-cyanophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

To a solution of 579 mg of 3-[2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-4-yl]benzonitrile and 534 mg of 4-bromo-2-(trifluoromethyl)benzonitrile in DMAC (2.5 m is added 183 mg of copper oxide. The mixture is refluxed overnight at 130°C. the Mixture is concentrated and transferred into DHM, washed with 10% aqueous solution of ammonia and saturated salt solution. The organic phase is dried over magnesium sulfate, concentrated in vacuo and purified on silica gel (ethyl acetate/cyclohexane from 0/100 to 50/50)to give the desired compound.

TLC: Fr=0,3 (ethyl acetate/cyclohexane 50/50).

1H NMR (CDCl3): δ of 3.85 (d, 1H); 4,07-is 4.21 (m, 3H); 5,26 is 5.38 (m, 2H); 5,80-of 5.89 (m, 1H); 6,24 (s, 1H); to 7.59-of 7.70 (m, 1H); 7,80(d, 1H); 7,94-8,19 (m, 5H).

JHMS: (Rt=3,26 min): 439-(M-H)-.

Stage 5: 4-[4-(3-cyanophenyl)-2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

To a solution of 358 mg of 4-[4-(3-cyanophenyl)-2,5-dioxo-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov in DMF (1.5 ml) is added 135 mg of potassium carbonate and 101 μl of methyliodide. The mixture is stirred over night at room temperature, evaporated, washed with saturated salt solution, extracted with ethyl acetate, dried over magnesium sulfate and concentrated, obtaining the desired connection.

TLC: Fr=0,58 (ethyl acetate/cyclohexane 50/50).

1H NMR (CDCl3): δ to 3.09 (s, 3H); 3,95 (d, 1H); to 4.14 (m, 2H); to 4.38 (d, 1H); from 5.29-of 5.34 (m, 2H); of 5.84-5,91 (m, 1H); 7,63-7,79 (m, 4H); of 7.96 (s, 2H); 8,11 (s, 1H).

JHMS: (Rt=3,81 min): without ionization.

Step 6: 4-[4-(3-cyanophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-triptime benzonitrile

Add 328álcomplex trevormoran-dimethyl sulfide to a solution of 354 mg4-[4-(3-cyanophenyl)-2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinovin DHM (5 ml). The mixture is stirred for 6 hours at room temperature, diluted with DHM, washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, concentrated and purified on silica gel (ethyl acetate/cyclohexane from 0/100 to 50/50)to give the desired compound.

TLC: Fr=0,30 (ethyl acetate/cyclohexane 50/50).

1H NMR (CDCl3): δ 3,14 (s, 3H); to 4.17 (m, 1H); 4,71 (d, 1H); 7,65-7,79 (m, 4H); 7,94-8,02 (m, 2H); to 8.14 (s, 1H).

JHMS: (Rt=3.04 from min): 383-(M-CH2OH)-.

Example 15: 4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-(3-triptoreline)imidazolidin-1-yl]-2-trifluoromethyl-benzonitrile (method A)

Stage 1: 1-(3-triptoreline)-2-hydroxyethane

A solution of 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (1 g) in acetonitrile (2.5 ml) and water (10 ml) is treated by microwave irradiation (125°C, 50 min). A similar experiment is repeated five times. The substance of all the tubes is collected, extracted with DHM, dried over magnesium sulfate and concentrated in vacuo, receiving the requested connection.

1H NMR (CDCl3): δ 4,96 (s, 2H); of 7.70 (m, 1H); to 7.93 (d, 1H); to 8.14(d, 1H), they were 8.22 (s, 1H).

Stage 2: 2-[(2-propenyloxy)methyl]-1-(3-triptoreline)alanon

To a solution of 1-(3-tripto who were)-2-hydroxyethane (3,66 g) allylbromide (20 ml) add calcium sulfate (10,9 g) and silver oxide (7,1 g). The mixture is stirred in an argon atmosphere and the dark for 2 hours. The mixture is diluted with ethyl acetate, filtered on celite, concentrate, and purify on silica gel (ethyl acetate/cyclohexane from 0/100 to 15/85)to give the desired compound.

TLC: Fr=0,79 (ethyl acetate/cyclohexane 50/50).

1H NMR (CDCl3): δ 4,20 (m, 2H); 4,78 (s, 2H); and 5.30 (d, 1H); 5,38 (d, 1H); 5,94-of 6.02 (m, 1H); 7,66 (t, 1H); 7,88 (d, 1H); 8,18 (d, 1H), of 8.25 (s, 1H).

JHMS: (Rt=3,53 min): without ionization.

Stage 3: 4-[(2-propenyloxy)methyl]-4-(3-(triptoreline)imidazolidin-2,5-dione

To a solution of 2-[(2-propenyloxy)methyl]-1-(3-triptoreline)ethanone (1,17 g) in EtOH (5 ml) and water (5 ml) is added potassium cyanide (624 mg) and ammonium carbonate (3.2 g). The mixture is refluxed over night at 55°C. the Mixture is extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo, receiving the requested connection.

TLC: Fr=0,45 (ethyl acetate/cyclohexane 50/50).

1H NMR (CDCl3): δ of 3.80 (d, 1H); 4,00-4,10 (m, 3H); 5,20 at 5.27 (m, 2H); 5,77-by 5.87 (m, 1H); 6,77 (s, 1H); EUR 7.57 (t, 1H); to 7.67 (d, 1H); to 7.77-7,88 (m, 2H), 8,59 (s, 1H).

JHMS: (Rt=3,19 min): 313-(M-H)-.

Stage 4: 4-[2,5-dioxo-4-[(2-propenyloxy)methyl]-4-(3-triptoreline)imidazolidin-1-yl]-2-cryptomathematical

To a solution of 4-[(2-propenyloxy)methyl]-4-(3-triptoreline)imidazolidin-2,5-dione (1.45 g) and 4-bromo-2-(trifluoromethyl)benzonitrile (1,15 g) in DMAC (7 ml) is added copper oxide (528 mg). The mixture is refluxed overnight at 130°C. The mixture is concentrated and transferred into ethyl acetate, washed with 10% aqueous solution of ammonia and saturated salt solution. The organic phase is dried over magnesium sulfate, concentrated in vacuo and purified on silica gel (ethyl acetate/cyclohexane from 0/100 to 50/50)to give the desired compound.

TLC: Fr=0,69 (ethyl acetate/cyclohexane 50/50).

1H NMR (CDCl3): δ of 3.84 (d, 1H); 4,10 (m, 2H); 4,20 (d, 1H); the 5.25 and 5.30 (m, 2H); 5,80-of 5.89 (m, 1H); to 6.57 (s, 1H); 7,62-7,66 (t, 1H); 7,74 (d, 1H); to $ 7.91-of 7.96 (m, 4H), of 8.09 (s, 1H).

JHMS: (Rt=3,55 min): 482-(M-H)-.

Stage 5: 4-[2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]-4-(3-triptoreline)imidazolidin-1-yl]-2-cryptomathematical

To a solution of 814 mg of 4-[2,5-dioxo-4-[(2-propenyloxy)methyl]-4-(3-triptoreline)imidazolidin-1-yl]-2-triftormetilfosfinov in DMF (1.5 ml) is added potassium carbonate (279 mg) and methyliodide (420 μl). The mixture is stirred for 5 hours at room temperature, evaporated, washed with saturated salt solution, extracted with ethyl acetate, dried over magnesium sulfate and concentrated, obtaining the desired connection.

TLC: Fr=0,39 (ethyl acetate/cyclohexane 30/70).

1H NMR (CDCl3): δ to 3.09 (s, 3H); 3,98 (d, 1H); 4,14-4,19 (m, 2H); was 4.42 (d, 1H); 5,28-of 5.34 (m, 2H); 5,85-of 5.92 (m, 1H); to 7.64-to 7.68 (m, 3H); of 7.75 (d, 1H); 7,93-of 8.00 (m, 2H), 8,12 (s, 1H).

JHMS: (Rt=4,05 min): without ionization.

Step 6: 4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-(3-triptoreline)imidazolidin-1-yl]-2-triptorelin the nitrile

To a solution of 782 mg4-[4-(3-triptoreline)-2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinovin DHM (5 ml) is added 662 μl of complex trevormoran-dimethyl sulfide. The mixture is stirred for 6 hours at room temperature, diluted with DHM, washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, concentrated and purified on silica gel (ethyl acetate/cyclohexane from 0/100 to 50/50)to give the desired compound.

TLC: Fr=0,45 (ethyl acetate/cyclohexane 50/50).

1H NMR (CDCl3): δ 3,14 (s, 3H); 4,18 (d, 1H); 4.75 in (DD, 1H); 7,62-of 7.69 (m, 3H); 7,76 (d, 1H); to 7.95 (d, 1H); 8,02 (d, 1H); is 8.16 (s, 1H).

JHMS: (Rt=3,10 min): 426-(M-CH2OH)-.

Example 16: 1-(3,4-dichlorophenyl)-4-hydroxymethyl-3-methyl-4-phenylimidazoline-2,5-dione (method A)

Stage 1: 1-phenyl-2-(2-propenyloxy)alanon

This compound is obtained from 2-hydroxy-1-phenylethanone according to the methodology used G.A. Molander and J.A. McKie 1-hydroxybutane-2-Ohe, J. Org.Chcm. (1995), 60, 872-882.

Stage 2: 4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-2,5-dione

Heat 0,775 g of 1-phenyl-2-(2-propenyloxy)ethanone, 0,575 g of potassium cyanide and 1.6 g of ammonium carbonate to 55°C for 3 h in 23 ml of a mixture of ethanol/water 50/50. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic solution was washed with saturated aqueous sodium chloride, then dried over what Ulfat sodium and evaporated, receiving the requested connection.

TLC: Rt=0,42 (silica gel, eluent: heptane-ethyl acetate 50-50).

1H NMR (CD3OD): δ 3,68 (d, 1H); 4,13 (m, 3H); 4,22 (d, 1H); 4.92 in (s, 2H); 5,22 (DD, 1H); of 5.34 (DD, 1H); 5,95 (DDT, 1H); was 7.45 (m, 3H); to 7.64 (d, 2H).

JHMS: (Rt=5,79 min): 288+(MH, MeCN+).

Stage 3: 1-(3,4-dichlorophenyl)-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-2,5-dione

Dissolve 0.7 g of 4-phenyl-2-(propenyloxy)imidazolidin-2,5-dione in 2 ml of DMAC and add 780 mg of 1,2-dichloro-4-yogashala, and then 234 mg of copper oxide(I). The mixture is heated at 160°C for 3 hours. In the room. so the mixture is diluted with 20% aqueous ammonia solution and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 2/1.

1H NMR (DMSO-D6): δ 3,70 (d, 1H); 4,08 (m, 2H); 4,15 (d, 1H); 5.17 to (d, 1H); 5.25 in (d, 1H); 5,88 (DDT, 1H); 7,38-to 7.50 (m, 4H); a 7.62 (d, 2H); to 7.67 (m, 1H); for 7.78 (d, 1H), 9,40 (s, 1H).

JHMS: (Rt=3,44 min): without ionization.

Stage 4: 1-(3,4-dichlorophenyl)-4-hydroxymethyl-3-methyl-4-phenylimidazoline-2,5-dione

To a solution of 0.45 g 5-1-(3,4-dichlorophenyl)-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-2,5-dione in 3 ml of DMF, added 238 mg of potassium carbonate and 0,143 ml of iodomethane. The mixture is stirred at room t for 5 hours, evaporated to dryness, diluted with saturated salt solution and extracted with ethyl acetate. The organic layer sushi is t over sodium sulfate, filtered and evaporated, getting to 0.47 g of yellow oil, which is then dissolved in 5 ml DHM in argon atmosphere. Then add 0.4 ml of the complex trevormoran-dimethyl sulfide. The mixture is stirred at room t for 5 hours. Slowly add saturated aqueous sodium bicarbonate solution. The mixture is extracted with DHM and the organic layer dried over sodium sulfate, filtered and evaporated. The crude product is purified by crystallization from a mixture of DGM/ethyl ether.

1H NMR (MeOD): δ to 3.02 (s, 3H); 4,20 (d, 1H); to 4.62 (d, 1H); 7,43-EUR 7.57 (m, 5H); to 7.68 (d, 1H); 7,92 (d, 1H); to 7.75 (m, 1H).

JHMS: (Rt=3,13 min): without ionization.

General procedure for examples 17 to 19 (method A)

Stage 1

Dissolve 0,415 g of 4-[2,5-dioxo-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov in 40 ml of DMF with the appropriate alkylhalogenide and 163 mg of potassium carbonate. The mixture is stirred at room t for 5 hours, evaporated to dryness, diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and the solvent is evaporated. The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 70/30.

Stage 2

0.3 ml of the complex trevormoran-dimethyl sulfide in 10 ml of dichloromethane are added to a solution of the compounds obtained in stage 1 and dissolved in 15 ml dichloromethane (respectively, 0.32 g of N-isopropyl,0.4 g of N-cyanomethyl and 0.4 g of N-propargyl). The mixture is stirred at room t for 6 hours, poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 70/30.

Example 17: 4-[2,5-dioxo-4-hydroxymethyl-3-(1-methylethyl)-4-phenylimidazoline-1-yl]-2-cryptomathematical

Stage 1: 4-[2,5-dioxo-3-(1-methylethyl)-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

TLC: Fr=0,65 (heptane/ethyl acetate 50/50).

1H NMR (CDCl3): δ of 1.41 (d, 3H); 1.50 in (d, 3H); 3,37 (dt, 1H); 4,12 (d, 1H); 4,13 (s, 2H); was 4.42 (d, 1H); 5.25 in (d, 1H); 5,32 (d, 1H); by 5.87 (DDT, 1H); 7,35 (m, 2H); of 7.48 (m, 3H); to 7.93 (d, 1H); 8,01 (d, 1H); 8,15 (m, 1H).

JHMS: (Rt=3,71 min): 457+(M+).

Stage 2: 4-[2,5-dioxo-4-hydroxymethyl-3-(1-methylethyl)-4-phenylimidazoline-1-yl]-2-cryptomathematical

TLC: Fr=0,45 (heptane/ethyl acetate 50/50).

1H NMR (CDCl3): δ of 1.41 (d, 3H); of 1.53 (d, 3H); 3.40 in (dt, 1H); 4,30 (d, 1H); 4.72 in (d, 1H); 7,37 (m, 2H); of 7.48 (m, 3H); to 7.93 (d, 1H); of 8.06 (d, 1H); to 8.20 (broad s, 1H).

JHMS: (Rt=3,37 min); 386-(M-CH2OH-).

Example 18: 4-[2,5-dioxo-3-cyanomethyl-4-hydroxymethyl-4-phenylimidazoline-1-yl}-2-cryptomathematical

Stage 1: 4-[3-cyanomethyl-2,5-dioxo-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

TLC: Fr0,25 (heptane/ethyl acetate 50/50).

1H NMR (CDCl3): δ 4.09 to (d, 1H); 4,20 (m, 3H); 4,47 (d, 1H); 4,60 (d, 1H); from 5.29 (d, 1H); 5,33 (d, 1H); of 5.92 (DDT, 1H); 7,38 (m, 2H); 7,53 (m, 3H); 7,98 (broad s, 2H); 8,11 (broad s, 1H).

JHMS: (Rt=3,39 min): without ionization.

Stage 2: 4-[2,5-dioxo-3-cyanomethyl-4-hydroxymethyl-4-phenylimidazoline-1-yl]-2-cryptomathematical

TLC: Fr=0,35 (heptane/ethyl acetate 50/50).

1H NMR (CDCl3): δ 4,10 (d, 1H); to 4.46 (d, 1H); 4,69 (d, 1H); of 4.77 (d, 1H); of 7.36 (m, 2H); 7,53 (m, 3H); 7,98 (d, 1H); 8,0l(d, 1H); to 8.12 (broad s, 1H).

JHMS: (Rt=3,12 min): 383-(M-CH2OH-).

Example 19: 4-[2,5-dioxo-4-hydroxymethyl-4-phenyl-3-(2-PROPYNYL)imidazolidin-1-yl]-2-cryptomathematical

Stage 1: 4-[2,5-dioxo-4-phenyl-4-[(2-propenyloxy)methyl]-3-(2-PROPYNYL)imidazolidin-1-yl]-2-cryptomathematical

TLC: Fr=0,65 (heptane/ethyl acetate 50/50).

1H NMR (CDCl3): δ of 2.27 (m, 1H); 4,06 (DD, 1H); to 4.14 (m, 2H); 4,22 (d, 1H); however, 4.40 (DD, 1H); to 4.46 (d, 1H); 5,26 (d, 1H); 5,31 (d, 1H); 5,91 (DDT, 1H); 7,41 (m, 2H); 7,49 (m, 3H); 7,94 (d, 1H); 8,01 (DD, 1H); to 8.14 (broad s, 1H).

JHMS: (Rt=3,45 min): without ionization.

Stage 2: 4-[2,5-dioxo-4-hydroxymethyl-4-phenyl-3-(2-PROPYNYL)imidazolidin-1-yl]-2-cryptomathematical

TLC: Fr=0,40 (heptane/ethyl acetate 50/50).

1H NMR (CDCl3): δ 2,48 (m, 1H); 3,83 (DD, 1H); 4,48 (d, 1H); to 4.73 (d, 1H); to 4.81 (DD, 1H); 7,46 (m, 2H); 7,51 (m, 3H); to 7.95 (d, 1H); 8,03 (d, 1H); 8,18 (broad s, 1H).

JHMS: (Rt=3,16 min): 382-(M-CH2OH-).

Example 20: 4-[2,5-dioxo-4-hydroxymethyl-4-phenylimidazoline-yl]-2-trifluoromethyl (method A)

Stage 1: 4-[2,5-dioxo-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

To a solution of 0.47 g of 4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-2,5-dione in 30 ml of DMF added 0.28 g of copper oxide(I) and 0.81 g of 4-bromo-2-triftormetilfosfinov. The mixture is heated at 135°C for 20 h, then it is evaporated to dryness. The crude product is diluted with 20% aqueous ammonia solution and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 70/30.

TLC: Fr=0,30 (heptane/ethyl acetate 70/30).

1H NMR (CDCl3): δ 3,86 (d, 1H); 4,14 (broad s, 2H); 4,27 (d, 1H); 5,28 (d, 1H); 5,32 (d, 1H); of 5.89 (DDT, 1H); 7,52 (m, 3H); of 7.70 (m, 2h); 7,98 (m, 2H); to 8.14 (m, 1H).

JHMS: (Rt=6,91 min): 414-(M-H-)

Stage 2: 4-[2,5-dioxo-4-hydroxymethyl-4-phenylimidazoline-1-yl]-2-cryptomathematical

To a solution of 0.18 g of 4-[2,5-dioxo-4-phenyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov in 15 ml DHM add 0.2 ml of the complex trevormoran-dimethyl sulfide in 10 ml of dichloromethane. The mixture is stirred at room t for 6 hours, poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by the method of chromatog is the her on silica gel, elwira a mixture of heptane/ethyl acetate 70/30.

TLC: Fr 0,25 (heptane/ethyl acetate 50/50).

1H NMR (CDCl3): δ 3,99 (d, 1H); was 4.42 (d, 1H); 7,11 (broad s, 1H); 7,49 (m, 3H); to 7.64 (m, 2H); 7,94 (m, 2H); 8,10 (broad s, 1H).

JHMS: (Rt=3,02 min): 344-(M-CH2OH-).

Example 21: 4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-(3-were)imidazolidin-1-yl]-2-cryptomathematical (method A)

Stage 1: 2-bromo-1-(3-were)alanon

To a solution of 1-(3-were)ethanone(2 g) in ethyl ether (20 ml) is added bromine (726 μl) at 0°C. the Mixture is treated with an aqueous sodium bicarbonate solution, extracted with ethyl ether, dried over magnesium sulfate, concentrated and purified on silica gel (ethyl acetate/cyclohexane 0/100)to give the desired compound.

TLC: Fr=0,42 (ethyl acetate/cyclohexane 10/90).

1H NMR (CDCl3): δ 2,47 (s, 3H); of 4.49 (s, 2H); 7,40-7,47 (m, 2H); 7,81-to $ 7.91 (m, 2H).

JHMS: (Rt=3,42 min): without ionization.

Stage 2: 2-hydroxy-1-(3-were)alanon

A solution of 2-bromo-1-(3-were)ethanone (1 g) in acetonitrile (2.5 ml) and water (13 ml) is treated by microwave irradiation (125°C, 50 min). A similar experiment is repeated three times. The substance of all the tubes is collected, extracted with DHM, dried over magnesium sulfate and concentrated in vacuo, receiving the requested connection.

TLC: Fr=0,15 (ethyl acetate/cyclohexane 10/90).

1H NMR (CDCl3): δ 2,47 (s, 3H); 4,90 (2H); 7,41-7,49 (m, 2H); 7,74 for 7.78 (m, 2H).

Stage 3 2-[(2-propenyloxy)methyl]-1-(3-were)alanon

To a solution of 2-hydroxy-1-(3-were)ethanone (1,95 g) allylbromide (10 ml) add calcium sulfate (7.9 g) and silver oxide (5,1 g). The mixture is stirred in an argon atmosphere and the dark for 2 hours. The mixture is diluted with ethyl acetate, filtered on celite, concentrate, and purify on silica gel (ethyl acetate/cyclohexane from 0/100 to 15/85)to give the desired compound.

TLC: Fr=0,54 (ethyl acetate/cyclohexane 30/70).

1H NMR (CDCl3): δ of 2.45 (s, 3H); 4,20 (d, 2H); rate 4.79 (s, 2H); from 5.29 (d, 1H); lower than the 5.37 (d, 1H); 5,96-6,04 (m, 1H); 7,37 was 7.45 (m, 2H); 7,75-7,79 (m, 2H).

JHMS: (Rt=3,30 min): without ionization.

Stage 4: 4-[(2-propenyloxy)methyl]-4-(3-were)imidazolidin-2,5-dione

To a solution of 2-[(propenyloxy)methyl]-1-(3-were)ethanone (690 mg) in ethanol (5 ml) and water (5 ml) is added potassium cyanide (472 mg) and ammonium carbonate (2,44 g). The mixture is refluxed over night at 55°C. the Mixture is extracted with ethyl acetate, dried over magnesium sulfate and concentrated in vacuo, receiving the requested connection.

1H NMR (CDCl3): δ is 2.41 (s, 3H); of 3.78 (d, 1H); 4,06-4.09 to (m, 3H); 5,22-and 5.30 (m, 2H); 5,81-5,90 (m, 1H); 5,94 (s, 1H); 7,21-7,39 (m, 4H); to 7.61 (s, 1H).

JHMS: (Rt=2,97 min): without ionization.

Stage 5: 4-[2,5-dioxo-4-(3-were)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

To a solution of 4-[(2-propenyloxy)methyl-4-(3-were)imidazolidin-2,5-dione (899 mg) and 4-bromo-2-(trifluoromethyl)benzonitrile (863 mg) in DMAC (5 ml) is added copper oxide(I) (395 mg). The mixture is refluxed overnight at 130°C. the Mixture is concentrated and transferred into ethyl acetate, washed with 10% aqueous solution of ammonia and saturated salt solution. The organic phase is dried over magnesium sulfate, concentrated in vacuo and purified on silica gel (ethyl acetate/cyclohexane from 0/100 to 50/50)to give the desired compound.

TLC: Fr=0,30 (ethyl acetate/cyclohexane 30/70).

1H NMR (CDCl3): δ of 2.44 (s, 3H); of 3.80 (d, 1H); 4,10 (m, 2H); 4,22 (d, 1H); 5,23-and 5.30 (m, 2H); of 5.83-5,90 (m, 1H); 6,37 (s, 1H); 7,26 was 7.45 (m, 4H); 7,93-7,98 (s, 2H); 8,11 (s, 1H).

JHMS: (Rt=3,43 min): 428-(M-H)-.

Step 6: 4-[2,5-dioxo-3-methyl-4-(3-were)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-cryptomathematical

To a solution of 4-[2,5-dioxo-4-(3-were)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov (829 mg) in DMF (1.5 ml) is added potassium carbonate (320 mg) and methyliodide (480 µl). The mixture is stirred for 3 hours at room T., evaporated, washed with saturated salt solution, extracted with ethyl acetate, dried over MgSO4and concentrate, receiving the requested connection.

TLC: Fr=0,43 (ethyl acetate/cyclohexane 30/70).

1H NMR (CDCl3): δ 2,43 (s, 3H); 3.04 from (s, 3H); of 3.97 (d, 1H); to 4.14 (m, 2H); was 4.42 (d, 1H); 5.25-in of 5.34 (m, 2H); 5,85-5,91 (m, 1H); 7,17 (m, 2H); 7,26-7,28 (m, 1H); to 7.93 (d, 2H); 8,01 (d, 1H); 8,15 (s, 1H).

JHMS: (Rt=4,01 min): without ionization.

Stage 7: 4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-(3-were)imidazo the one-1-yl]-2-cryptomathematical

To a solution of 856 mg of 4-[2,5-dioxo-3-methyl-4-(3-were)-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov in DHM (5 ml) add complex trevormoran-dimethyl sulfide (812 μl). The mixture is stirred for 4 hours at room T., diluted DHM, washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, concentrated and purified on silica gel (ethyl acetate/cyclohexane from 0/100 to 50/50)to give the desired compound.

TLC: Fr=0,76 (ethyl acetate/cyclohexane: 50/50).

1H NMR (CDCl3): δ of 2.44 (s, 3H); to 3.09 (s, 3H); 4,17 (d, 1H); 4.72 in (d, 1H); 7,17 (m, 2H); 7,28 (m, 1H); 7,39 (m, 1H); to 7.93 (d, 1H); 8,03 (d, 1H); 8,18 (s, 1H).

JHMS: (Rt=3,19 min): 372-(M-CH2OH)-.

Example 22: 4-[4-(2-chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical

The interaction of 0.80 g of 4-[4-(2-chlorophenyl)-2,5-dioxo-3-methyl-4-[(2-propenyloxy)methyl]imidazolidin-1-yl]-2-triftormetilfosfinov using the Protocol described in example 6, stage 6, gives the desired connection.

1H NMR (DMSO-D6): δ 2,69 (s, 3H); 4.25 in (m, 1H); to 4.46 (m, 1H); 5,90 (t, 1H); to 7.50 (m, 3H); 7,58 (m, 2H); with 8.05 (m, 2H), 8,35 (d, 1H).

JHMS: (Rt=3,47 min): (392/394)-(M-CH2OH-).

Example 23: [1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl hydrosulfate

A solution of 0.39 g of 4-[3-methyl-4-hydroxymethyl-2,5-dioxo-4-phenylimidazoline-1-yl]-2-triftormetilfosfinov is of 0.48 g of a complex of a sulfur trioxide-pyridine in 20 ml of pyridine is refluxed for 18 hours, then evaporated to dryness. The crude product is purified by chromatography on silica gel, elwira mixture DHM/methanol/acetic acid/water 90/10/1/1.

TLC: Fr=0,25 (DHM/methanol/acetic acid/water 90/10/1/1).

1H NMR (CD3OD): δ 3,09 (NCH3); 4,69 (d, 1H); to 5.03 (d, 1H); rate of 7.54 (m, 5H); 8,13 (m, 2H); of 8.25 (s, 1H).

JHMS: (Rt=3,52 min): 468-(M-H-).

Example 24: [1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl dihydrophosphate

Stage 1: [1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl diethylphosphate

A solution of 0.4 g of 4-[3-methyl-4-hydroxymethyl-2,5-dioxo-4-phenylimidazoline-1-yl]-2-triftormetilfosfinov in 2 ml of pyridine and 0.2 ml of diethylphosphate stirred for 3 hours at room T. in an argon atmosphere. The mixture was quenched with 2M aqueous hydrochloric acid and extracted with diethyl ether and ethyl acetate. The crude product is purified by chromatography on silica gel, elwira mixture DHM/ethyl acetate 4/1.

TLC: Fr=0,7 (4/1 DHM/ethyl acetate).

1H NMR (CD3OD): δ 1,31 (square, 6H); 3,03 (s, 3H); 4,15 (m, 4H); a 4.83 and 5,07 (2m, 2H); 7,45-of 7.55 (m, 5H); of 8.06 (m, 1H); 8,15 (m, 2H).

JHMS: (Rt=3,76 min): 526+(MH+).

Stage 2: [1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl dihydrophosphate

In an argon atmosphere was added 1 ml of bromotrimethylsilane to a solution of 0.39 g of 1-(4-cyano-3-triptoreline)-2,5-di the CSR-3-methyl-4-phenylimidazole-4-yl]methyl diethylphosphate in 10 ml DHM, cooled at 0°C. the Reaction mixture is stirred for 1 hour at 0°C followed by 18 h at room T. the Solvent is evaporated, then dissolve the residue in a mixture of water and ethanol. The solvent is evaporated and this process repeated twice. The crude product is purified by chromatography on silica gel, elwira mixture DHM/methanol/acetic acid/water 85/15/1/1 and receiving 0.25 g of a white solid. After washing with a mixture of diethyl ether/pentane get the desired connection.

1H NMR (DMSO-D6): δ 2,90 (s, 3H); 4,58 and 4,70 (m, 2H); 7,49 (m, 5H); 8,04 (d, 1H); to 8.20 (s, 1H); 8,35 (d, 1H).

JHMS: (Rt=2,46 min): 468-(M-H-).

Example 25: [1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methoxy-3-methyl-1-oxobutyl-2-amine chloride

Stage 1: [1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl ester (2S)-2-[(1,1-dimethylmethoxy)carbylamine]-3-methylbutanoic acid

A solution of 0.3 g of 4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-triftormetilfosfinov, 0,217 g of (2S)-2-[(1,1-dimethylmethoxy)carbylamine]-3-methylbutanoic acid, 0,122 g of 4-dimethylaminopyridine and 0.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide in 50 ml of dichloromethane is stirred for 18 h, then poured into water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filter the t and evaporated. The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 70/30, and receiving the requested connection.

TLC: Fr=0,20 (heptane/ethyl acetate 70/30).

JHMS: (Rt=4,07 min): 489+(M-tBuOCO+H+).

Stage 2: [1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methoxy-3-methyl-1-oxobutyl-2-amine chloride

Add 2 ml triperoxonane acid to a solution of 0.43 g of [1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl ester (2S)-2-[(1,1-dimethylmethoxy)carbylamine]-3-methylbutanoic acid in 20 ml of dichloromethane. The mixture is stirred at 25°C for 2 hours, then the solvent is evaporated to dryness. The crude product was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated.

The crude product is dissolved in 100 ml of a mixture of dichloromethane/ethyl ether (5/95) and add 0.4 ml of 2M solution of hydrogen chloride in ethyl ether. After filtration receive the requested connection.

TLC: Fr=0,2 (dichloromethane/methanol 95/5).

1H NMR (CD3OD): δ 1.06 a (m, 6H); to 2.25 (m, 1H); of 3.07 (d, 3H); of 4.12 (m, 1H); 4.75 in (DD, 1H); 4,88 (t, 1H); 7,58 (m, 5H); 8,19 (m, 2H); compared to 8.26 (m, 1H).

JHMS: (Rt=2,8 min): 489+(M+H+).

Example 26: 4-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methoxy-4-oxobutanoic the I acid

To a solution of 0.20 g of 4-[3-methyl-4-hydroxymethyl-2,5-dioxo-4-phenylimidazoline-1-yl]-2-triftormetilfosfinov in 3 ml of pyridine added 6 mg of dimethylaminopyridine and 0,052 g of succinic anhydride. The mixture is stirred for 12 hours, then evaporated to dryness. The crude product is washed with water and extracted with DHM. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel, elwira with a mixture of cyclohexane/ethyl acetate 50/50, and receiving the requested connection.

TLC: Fr=0,17 (cyclohexane/ethyl acetate 50/50).

1H NMR (CDCl3): δ 2,67-of 2.72 (m, 4H); to 3.02 (s, 3H); to 4.92 (d, 1H); to 5.03 (d, 1H); 7,39 (m, 2H); 7,53 (m, 3H); of 7.96 (d, 1H); 8,04 (DD, 1H); 8,18 (d, 1H).

JHMS: (Rt=3,49 min): 358-(M-H-CH2O-C4H4O3).

Example 27: (S)-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyldihydromorphine

Stage 1: (S)-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]otildeotildesad

A solution of 1.2 g (S)-4-[3-methyl-4-hydroxymethyl-2,5-dioxo-4-phenylimidazoline-1-yl]-2-triftormetilfosfinov in 6 ml of pyridine and 0.6 ml of diethylphosphate stirred for 48 hours at room temperature in argon atmosphere. The mixture was quenched with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The crude product is purified by chromatography on silica gel, elwira mixture is Yu 1/1 heptane/ethyl acetate.

TLC: Fr=0,12 (1/1 heptane/ethyl acetate).

1H NMR (CDCl3): δ of 1.45 (m, 6H); 1.75 of (s, 1H); 3,10 (s, 3H); 4,13 (m, 4H); 4,65 (square, 1H); 5,02 (square, 1H); 7,37 (m, 2H); 7,51 (m, 3H); to 7.95 (d, 1H); 8.0 a (DD, 1H); 8,13 (c, 1H).

JHMS: (Rt=4,66 min): 526+(MH+).

[a]D=-44,8° (c=1%in EtOH).

Stage 2: (S)-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl dihydrophosphate

In argon atmosphere, add 2.5 ml of bromotrimethylsilane to a solution of 0.80 g (S)-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl diethylphosphate in 25 ml DHM, cooled at 0°C. the Reaction mixture is stirred for 1 hour at 0°C followed by 18 h at room temperature. The solvent is evaporated, then the residue is dissolved in a mixture of water and methanol. The solvent is evaporated and this process repeated twice. The crude product is purified by chromatography on silica gel, elwira a mixture of dichloromethane/methanol/acetic acid/water from 90/10/1/1 to 85/15/2/2, receiving the requested connection.

TLC: Fr=0,12 (dichloromethane/methanol/acetic acid/water 85/15/2/2).

1H NMR (CD3OD): δ 2,00 (m, 2H); to 3.09 (m, 2H); 3,37 (s, 3H); 4,51 (d, 1H); 4,91 (d peak water, 1H); 7,53 (m, 5H); 816 (m, 2H); of 8.27 (m, 1H).

JHMS: (Rt=2,50 min): 470+(M+H+).

[a]D=-47,6° (c=1,05%, EtOH).

Example 28: (S)-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methoxy-4-oxobutanoic acid

To dissolve the u of 0.60 g of (S)-4-[3-methyl-4-hydroxymethyl-2,5-dioxo-4-phenylimidazoline-1-yl]-2-triftormetilfosfinov in 24 ml of pyridine added 19 mg dimethylaminopyridine and 1.54 g of succinic anhydride. The mixture was stirred at 110°C for 7 h, then evaporated to dryness. The crude product is washed with water and extracted with dichloromethane. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 50/50, and receiving the requested connection.

TLC: Fr=0,17 (cyclohexane/ethyl acetate 50/50).

1H NMR (CDCl3): δ 2,67-to 2.74 (m, 4H); to 3.02 (s, 3H); to 4.92 (d, 1H); to 5.03 (d, 1H); 7,38 (m, 2H); 7,52 (m, 3H); of 7.96 (d, 1H); 8,04 (DD, 1H); 8,18 (d, 1H).

JHMS: (Rt=3,22 min): 358-(M-H-CH2O-C4H4O3).

Example 29: (S)-((S)-1-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,5-dioxo-4-phenylimidazole-4-yl)methyl-3-methylbutanoate-2-ammonium chloride

Stage 1: (S)-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl ester (2S)-2-[(1,1-dimethylmethoxy)carbylamine]-3-methylbutanoic acid

A solution of 0.45 g (S)-4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-triftormetilfosfinov, 0.33 g of (2S)-2-[(1,1-dimethylmethoxy)carbylamine]-3-methylbutanoic acid, 0,185 g of 4-dimethylaminopyridine and 0.45 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 70 ml of dichloromethane is stirred for 1 hour, then poured into water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified m is Todd chromatography on silica gel, elwira a mixture of heptane/ethyl acetate 70/30, and receiving the requested connection.

TLC: Fr=0,20 (heptane/ethyl acetate 70/30).

1H NMR (CDCl3): δ of 0.89 and 0.97 (2D, 6H); of 1.46 (s, 9H); 2.05 is (m, 1H); to 3.02 (s, 3H); 4,22 (m, 1H); is 4.93 (m, 2H); 5,04 (m, 1H); 7,38 (m, 2H); 7,52 (m, 3H); of 7.96 (d, 1H); 8,04 (d, 1H); 8,15 (s, 1H).

JHMS: (Rt=3,90 min): 489+(M-tBuOCO+H+).

[a]D=-54,7° (c=1,25%, EtOH).

Stage 2: (S)-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methoxy-3-methyl-1-oxobutyl-2-amine chloride

Add 3 ml triperoxonane acid to a solution of 0.65 g (S)-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl ester (2S)-2-[(1,1-dimethylmethoxy)carbylamine]-3-methylbutanoic acid in 30 ml dichloromethane. The mixture is stirred at room temperature for 5 hours, add 20 ml of toluene, and then the solvent is evaporated to dryness. The crude product was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated.

The crude product is dissolved in 120 ml of a mixture of dichloromethane/ethyl ether (10/90) and add 0.75 ml of 2M solution of hydrogen chloride in ethyl ether. After filtration receive the requested connection.

TLC: Fr=0,2 (dichloromethane/methanol 95/5).

1H NMR (CD3OD): δ 1.07 and 1,10 (2D, 6H); and 2.26 (m, 1H); of 3.07(s, 3H); 4,11 (d, 1H); 5,22 and are 5.36 (2D, 2H); 7,58 (m, 5H); 8,19 (AB, 2H); of 8.25 (s, 1H).

[a]D=-46,7° (c=1,08%, EtOH).

Example 30: 4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-phenylimidazoline-1-yl]-2-methoxybenzonitrile

Stage 1: 4-[2,5-dioxo-4-hydroxymethyl-4-phenylimidazoline-1-yl]-2-methoxybenzonitrile

A solution of 384 mg of 4-cyano-3-methoxyphenylalanine (obtained according to WO 2007/137874) in 8 ml of dioxane are added to a solution of 200 mg of 2-hydroxymethyl-2-phenylglycine (obtained according to literature procedures) in an aqueous solution of 1.8 ml of 1 n sodium hydroxide in 2 ml of water. The mixture is stirred at room temperature overnight, acidified by adding 3 ml of 12 N. HCl, and heated at 110°C for 2 hours. Then the solution is treated with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, dried over magnesium sulfate, filtered, evaporated and purified on silica gel, elwira a mixture of heptane/ethyl acetate 60/40 and receiving the expected product.

TLC: Fr=0,30 (heptane/ethyl acetate 50/50).

1H NMR (CDCl3): δ 3,98 (s, 3H); 4.06 and 4,40 (2D, 2H); 6,07 (broad s, 1H); 7.23 percent (m, 2H); 7,51 (m, 3H); 7,66 (m, 3H).

JHMS: (Rt=5,44 min): 306-(M-CH2OH)-.

Stage 2: 4-[2,5-dioxo-4-hydroxymethyl-1-methyl-4-phenylimidazoline-1-yl]-2-methoxybenzonitrile

Added 173 mg of potassium carbonate and 86 μl of methyliodide to a solution of 141 mg of 4-[2,5-dioxo-4-hydroxymethyl-4-phenylimidazoline-1-yl]-2-methoxybenzonitrile in 2 ml of DMF. The mixture is stirred for n is Chi at room temperature, is evaporated to dryness. The residue is transferred into water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered, evaporated and chromatographic on silica gel, elwira a mixture of heptane/ethyl acetate 70/30 and receiving the expected product.

1H NMR (CDCl3): δ to 3.09 (s, 3H); of 3.97 (s, 3H); 4,17 and 4,72 (2D, 2H); 7,27 (m, 2H); 7,40 (m, 2H); to 7.50 (m, 3H); to 7.64 (m, 1H).

JHMS: (Rt=5,67 min): without ionization.

Example 31: (S)-1-(3,4-dichlorophenyl)-4-hydroxymethyl-3-methyl-4-phenylimidazoline-2,5-dione

Stage 1: (S)-1-(3,4-dichlorophenyl)-4-hydroxymethyl-4-phenylimidazoline-2,5-dione

Dissolve 217 mg (S)-2-hydroxymethyl-2-phenylglycine (obtained according to A. Olma, Polish J. Chem., 70, (1996), 1442-1447) in 5 ml of 0.5 N. aqueous sodium hydroxide. Added slowly over 10 min 300 mg of 3,4-dichlorophenylisocyanate dissolved in 5 ml of dioxane, the mixture is then stirred for 1 hour, the pH is about 7-7,5. Add 3 ml of 0.5 N. aqueous sodium hydroxide to obtain an alkaline pH, then slowly add another 300 mg of 3,4-dichlorophenylisocyanate dissolved in 5 ml of dioxane. The mixture is stirred for 1 hour at room temperature, then add 12 N. hydrochloric acid until acidic pH and the mixture is heated for 1 hour at boiling temperature under reflux. The dioxane is removed by evaporation in vacuo, extracted the aqueous phase with ethyl acetate. The extracts are washed with saturated what astora salt, dried over magnesium sulfate and evaporated to dryness. The residue is purified on silica gel, elwira with a gradient mixture of heptane to pure ethyl acetate and receiving the expected product.

[a]D=margin of 13.3° (c=1,02%, MeOH).

Stage 2: (S)-1-(3,4-dichlorophenyl)-4-hydroxymethyl-3-methyl-4-phenylimidazoline-2,5-dione

Dissolve 150 mg of (S)-1-(3,4-dichlorophenyl)-4-hydroxymethyl-4-phenylimidazoline-2,5-dione in 5 ml of dimethylformamide, then add 165 mg of potassium carbonate and then 137 ál dimethylsulfate. The mixture is stirred over night at room temperature, then transferred into a mixture of water and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The extracts are washed with saturated salt solution, dried over magnesium sulfate and evaporated to dryness. The residue is purified over silica gel, elwira with a gradient mixture of heptane to pure ethyl acetate and receiving the expected product.

1H NMR (CDCl3): δ 3.04 from (s, 3H); 4,11 and 4,65 (2D, 2H); 7,37 (m, 3H); 7,51 (m, 4H); 7,66 (d, 1H).

JHMS: (Rt=3,16 min): 364/366+(MH+); 333/335-(M-CH2OH)-.

[a]D=-38,5° (c=0,925%, EtOH).

Table 1
Typical compounds according to the invention
IDStructureName Races-please take. MM
14-[2,5-Dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical389,3
24-[2,5-Dioxo-4-(1-hydroxypropyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical
isomer A
417,4
34-[2,5-Dioxo-4-(1-hydroxypropyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical
isomer B
417,4
44-[2,5-Dioxo-4-(1-hydroxyethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical
isomer A
403,4

54-[2,5-Dioxo-4-(1-hydroxyethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical
isomer B
403,4
6 4-[2,5-Dioxo-4-(4-forfinal)-4-(hydroxymethyl)-3-methylimidazolidine-1-yl]-2-cryptomathematical407,3
74-[4-(4-Chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical423,8
84-[2,5-Dioxo-4-(4-forfinal)-4-hydroxymethyl-3-(2-PROPYNYL)imidazolidin-1-yl]-2-cryptomathematicalthat amount to 431,3

94-[4-(3-Chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical423,8
10(S)-4-[2,5-Dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical389,3
11(R)-4-[2,5-Dioxo-4-(is hydroxymethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical 389,3
124-[2,5-Dioxo-3-ethyl-4-(hydroxymethyl)-4-phenylimidazoline-1-yl]-2-cryptomathematical403,4

134-[4-(4-Cyanophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical414,3
144-[4-(3-Cyanophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical414,3
154-[2,5-Dioxo-4-hydroxymethyl-3-methyl-4-(3-triptoreline)imidazolidin-1-yl]-2-cryptomathematical457,3
161-(3,4-Dichlorophenyl)-4-hydroxymethyl-3-methyl-4-phenylimidazoline-2,5-dione365,2
17 4-[2,5-Dioxo-4-(hydroxymethyl)-3-(1-methylethyl)-4-phenylimidazoline-1-yl]-2-cryptomathematical417,4

184-[3-Cyanomethyl-2,5-dioxo-4-(hydroxymethyl)-4-phenylimidazoline-1-yl]-2-cryptomathematical414,3
194-[2,5-Dioxo-4-(hydroxymethyl)-4-phenyl-3-(1-PROPYNYL)imidazolidin-1-yl]-2-cryptomathematical413,4
204-[2,5-Dioxo-4-hydroxymethyl-4-phenylimidazoline-1-yl]-2-cryptomathematical375,3
214-[2,5-Dioxo-4-hydroxymethyl-3-methyl-4-(3-were)imidazolidin-1-yl]-2-cryptomathematical403,4
224-[4-(2-Chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methyl-imidazo the one-1-yl]-2-cryptomathematical 423,8

23[1-(4-Cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl hydrosulfate469,06
24[1-(4-Cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl dihydrophosphate469,31
25(2S)-1-[1-(4-Cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methoxy-3-methyl-1-oxobutyl-2-amine chloride488,47
264-[1-(4-Cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methoxy-4-oxobutanoic acid489,41

27(S)-(1-(4-Cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,5-dioxo-4-phenylimidazole-4-yl)meth is l dihydrophosphate 469,31
28(S)-4-((1-(4-Cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,5-dioxo-4-phenylimidazole-4-yl)methoxy)-4-oxobutanoic acid489,41
29(S)-((S)-1-(4-Cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,5-dioxo-4-phenylimidazole-4-yl)methyl-3-methylbutanoate-2-ammonium chloride488,47
304-[2,5-Dioxo-4-hydroxymethyl-3-methyl-4-phenylimidazoline-1-yl]-2-methoxybenzonitrile351,37

31(S)-1-(3,4-Dichlorophenyl)-4-hydroxymethyl-3-methyl-4-phenylimidazoline-2,5-dione365,22

Biological examples

The effectiveness of these compounds according to the invention can be demonstrated in tests in vitro development after simultaneous and stable expression of human androgennogo receptor (hAR) and the reporter gene is ar transcriptional control responsive elements (ARE) androgen receptor (AR) in the cells of the host. This test includes the identification of pure or partial agonists, which mimic the effects of natural hormones such as DHT (dihydrotestosterone), in this case, or, on the other hand, antagonists that inhibit.

For this transactivational test plasmids encoding the reporter gene, and human androgenic receptor (hAR) are administered together by transfection into the cell line HeLa. Reporter plasmid contains the luciferase cDNA under control ARE contained in the promoter sequences of the gene probasin (3xpbAREminicoll-luciferase/pGL3-puro). The reporter gene expression is an indication of the transcriptional activity of hAR. It also encodes a protein that allows expressing his cells to resist treatment puromycin. A plasmid encoding hAR, contains the cDNA of the receptor hAR under the control of the promoter of the cytomegalovirus (CMV). It also encodes a protein that allows expressing his cells to resist treatment with neomycin. The cell treatment with increasing amounts of potentially agonistic compounds increases reporter gene expression. On the other hand, for detection of antagonists tested increasing doses of the investigated compounds in the presence of increasing concentrations of DHT. The reporter gene expression, which is constant for each dose DHT decreases when overzeese concentration of test compounds.

1 - study the functional efficiency

1.1Construction of plasmids

1.1 (a) Designing puromycin-resistant plasmids 3xpbAREminicoll-luciferase/pGL3

The first stage includes an introduction to the basic vector pGL3 (Promega) minimal promoter gene collagenase above the gene encoding the luciferase. Synthesized two oligonucleotide (coll-semantic and coll-anti). They allow you to enter the cleavage sites of restriction enzymes SacI (underlined one feature of the following sequences) and BglII (double underlined below in the following sequence), respectively, at the ends of the 5' and 3' sequences between positions -42 and +46 (bold in the following sequences) described promoter sequence [P Angel and others, 1987 Mol. Cell. Biol., 7: 2256-2266]. After hybridization and cloned between the SacI sites (position 8) and BglII (position 37) "pGL3 basic" plasmids receive plasmid "minicoll-luciferase/pGL3". Oligonucleotide sequences "coll-semantic" and "coll-anti" are as follows:

coll-sense (SEQ ID No: 1):

5' CACTGTGTCGACGCGTGCAAGGACTCTATATATACAGAGGGAGCTTCCTAGCTGGGATATTGGAGCAGCAAGAGGCTGGGAAGCCATCACTTACCTTGCACTGA 3'

coll-anti (SEQ ID No: 2):

3'GATCTCAGTGCAAGGTAAGTGATGGCTTCCCAGCCTCTTGCTGCTCCAATATCCCAGCTAGGAAGCTCCCTCTGTATATATAGAGTCCTTGCACGCGTCGACACAGTGAGCT 5'

The second stage includes multimerization (3 times) responsive element androgen receptor, soderjaschegosya the promoter probasin (pbARE) (in bold in the following sequence) (F. Claessensand other1996 J. Biol. Chem. 271: 19013-19016), and putting it between sites kpni restriction sites and Ecl136II-plasmid "minicoll luciferase/pGL3". Synthesize two of the oligonucleotide (coll-semantic and coll-anti). They allow the introduction of the cleavage sites of restriction enzymes kpni restriction sites (underlined one feature of the following sequences) and a blunt end (highlighted two features of the following sequences at the ends of the 5' and 3', respectively. After hybridization get a DNA fragment that can be cloned between the Kpnl sites (position 1) and Ecl136II (position 8) plasmids "minicoll-luciferase/pGL3", generating, thus, plasmid "3xpbAREminicoll-luciferase/pGL3". Oligonucleotide sequences "coll-semantic" and "3xpbARE-anti" are as follows:

3xpbARE-sense (SEQ ID No: 3):

5' CAAAGAGCTCTAGCTTAATAGGTTCTTGGAGTACTTTACGTGCTTAATAGGTTCTTGGAGTACT TTACGTGCTTAATAGGTTCTTGGAGTACTTT 3'

3xpbARE-anti (SEQ ID No: 4);

3' AAAGTACTCCAAGAACCTATTAAGCACGTAAAGTACTCCAAGAACCTATTAAGCACGTAAAGTA CTCCAAGAACCTATTAAGCTAGAGCTCTTTGGTAC 5'

The third stage involves the introduction puromycin-resistant gene in the plasmid "3xpbAREminicoll-luciferase/pGL3". Konstruktsii [promoter-puromycin-resistant gene sequence of the SV40 polyadenylation] (fragment 1-1396, library of genes U07648) subcloning using PCR amplification based on plasmids "pPUR" (Clontech) using two oligonucleotide (pPUR-semantic and pPUR-anti), allowing you to enter the site of the BamHI cleavage. A fragment of 1550 base pairs, obtained by the Les PCR (30 cycles, 30 sec at 94°C, 30 sec at 55°C, 1.5 min at 72°C), is estimated by BamHI, and then cloned on a single BamHI site of the plasmid 3xpbAREminicoll-luciferase/pGL3, giving, thus, puromycin resistant plasmid 3xpbAREminicoll-luciferase/pGL3. Oligonucleotide sequences "coll-semantic" and "coll-anti" are as follows:

pPUR-sense (SEQ ID No: 5): 5' TAAGGATCCGCTGTGGAATGTGTGTCAGTT 3'

pPUR-anti (SEQ ID No: 6): 3' GACGGATCCAGACATGATAAGATACATTGA 5'

1.1b Construction of plasmids "pcDNA3-hAR"

The sequence encoding hAR cDNA clone between sites EcoRIand XbaI vectorpcDNA3.1(+) (Invitrogen), based on the vector psg5-hAR (provided by Professor P. Chambon, IGBMC, Illkirch, France). This plasmid contains the sequence described Tilley WD, etc. [Tilley WD and others, 1989, Proc Natl Acad Sci USA. 86:327-31; Library of genes J04150].

1.2The creation of stable cell lines HALP

For this test receive HeLa cells from American Type Culture Collection (Rockville, MD) and cultured in DMEM containing 4.5 g/l glucose, supplemented with Glutamax, nonessential amino acids and 10% fetal calf serum (SVF; Dominique Dutscher).

The day before transfection were seeded in Petri dishes million cells in DMEM not containing phenol red, supplemented with Glutamax and SVF (5%) without steroids. Cells transferout through 4 µg puromycin-resistant plasmids pcDNA3-hAR and 3xpbAREminicoll-luciferase/pGL3 using reagent "lipofectamine plus (Invitrogen), following the recom is presented to suppliers. The day after transfection were seeded cells with different densities (from 10000 to 100000 cells per Petri dish). Two days after transfection transfetsirovannyh cells collected in DMEM not containing phenol red, supplemented with Glutamax and SVF (5%) without steroids containing 400 μg/ml G418 (Invitrogen) and 150 ng/ml puromycin (Sigma). Culture medium update weekly until the resistant clones. Resistant clones are separated and amplified prior to study their functional response.

The study of functional reaction carried out as follows: cells were seeded (80,000 cells per well, 48 holes on the tablet) for 24 h before the stimulation phase in DMEM containing 4.5 g/l glucose, supplemented with Glutamax, nonessential amino acids and SVF (5%) without steroids. On the day of stimulation sowing medium is replaced by DMEM containing no phenol red, supplemented with Glutamax and SVF (5%) without steroids containing DHT in the concentration range from 1 PM to 1 μm. The cells are put in contact with the compounds for 18 h at 37°C. Then the medium is removed, cells are subjected to lysis and determine luciferase activity using a reagent system for determining the activity of luciferase" (Promega) according to manufacturer's instructions. Induced luminescence detected on the meter type TopCount (Perkin-Elmer). Clone (HALP2)stored for screening the new research, shows the curve of the transcription reaction, similar to the curve obtained after transient transfection of the same vectors in the HcLa cells.

1.3The study of functional responses

The study of functional reactions carried out on 96-well plates. Cells HALP2 seeded (20,000 cells per well) in culture medium (DMEM with phenol red, 1% Pen-Strep, 1% nonessential amino acids, 10% fetal bovine serum, 400 μg/ml of geneticin and 0.150 μg/ml puromycin) on day 1. After 24 hours incubation at 37°C, 5% CO2, high humidity (day 2) Wednesday, delete, and update research medium (DMEM not containing phenol red, supplemented with 1% Pen-Strep, 1% non-essential amino acids and 5% fetal bovine serum without steroids). After another 24 h of incubation at 37°C, 5% CO2, high humidity (day 3) Wednesday update again before the stimulation phase.

Stimulation includes the intersection of the range of concentrations of DHT (0,329 PM to 640 nm), with a range of concentrations of the investigated compounds (from 6.4 nm to 4 μm). The cells are put in contact with the compounds for 24 h at 37°C, 5% CO2, high humidity. Later in the day 4 remove the environment and lead in contact with the cells reagent for determination of luciferase activity in accordance with the manufacturer's instructions (SteadyLite, Perkin-Elmer). Induced luminescence detected at scity the surrounding device Envision (Perkin-Elmer).

Agonism characterized by the value EC50in other words, the concentration of the tested compound that induces 50% of the maximum agonistic effect observed in the presence of the compounds. Antagonism is characterized by a value of KSchildin other words, the concentration of the tested compound that increases EC50DHT (dihydrotestosterone) in 2 times. This concentration is determined by well-known Schild regression.

Determining the relative agonism/antagonistic compounds produced by comparing the maximum activation obtained in the presence of the specified connection and activation obtained using only DHT (100%).

Table 2
Definition agonism and antagonism of the compounds according to the invention
Semiquantitative rating:
EC50(nm)KSchild
(nm)
% Effect on DHT (100%)
0.01 to 10 nm:****0.01 to 10 nm:++++41-50%§§§§
11-100 nm:***11-100 nm:+++21-40%§§§
101-500 nm:**101-500 nm:++6-20%§§
501-1000 nm:*501-1000 nm:+0-5%§
N/A: not applicable

IDEC50 (nm)KSchild
(nm)
% Effect relative-but DHT (100%)Classification
1****++++§§§Mixed agonist/antagonist
2N/A+++§Antagonist
3N/A +++§Antagonist
4N/A++++§Antagonist
5N/A+++§Antagonist
6***+++§§§Mixed agonist/antagonist
7**++++§§§Mixed agonist/antagonist
8**+++§§Mixed agonist/antagonist
9****++++§§§§Mixed agonist/antagonist
10***+++§§§Mixed agonist/antagonist
11N/A+§Antagonist
12****+++§§§Mixed agonist/antagonist
13N/ANot available§Antagonist
14**+++§§§Mixed agonist/antagonist
15**++++§§§§Mixed agonist/antagonist
16**+++§§Mixed agonist/antagonist
17**+++§§§§Mixed agonist/antagonist
18*N/Athe§ Mixed agonist/antagonist
19**+++§§Mixed agonist/antagonist
20N/A+++§Antagonist
21*++§§Mixed
agonist/antagonist
23Not availableNot availableNot availablenot available
24****+++§§§Mixed agonist/antagonist
25***++§§§Mixed agonist/antagonist
26***+++§§§Mixed agonist/antagonist
/p>

2. Characterization in animal models

2.1Adapted model test of Hershberger

In vivo activity of the compounds according to the invention can be demonstrated on an adapted model test of Hershberger as follows.

Selective modulation of the activity androgennogo receptor research on models castrated immature young rats. This model, which is widely acknowledged to assess the anabolic effects of androgen compounds on the muscles and the prostate, described by Hershberger and others, 1953 Proc. Soc. Expt. Biol. Med., 83: 175.

The method is based on measuring the well-known effects of androgens on muscle growth and accessory male sex organs of animals and men. Effects of castration are manifested in the form of rapid involution and atrophy of the prostate, seminal vesicles and muscles, levator anus (levator ani). This effect can be fully compensated by exogenous administration of androgen, in particular testosterone. Thus, this model is used to determine the ability of the investigated molecules can save a lot of accessory sex organs and muscles in immature castrated rats and, consequently, their androgenous efficiency.

Immature young rats Sprague Dawley (4-5 weeks of age) weighing approximately 140-160 g (Charles River, Les Oncins, FRANCE) distributed randomly on different gr is pam and contain in an environment at 22±2°C with a cycle of the alternating day/night for 12 hours and access to food and drink without restrictions.

On day 0 (within seven days prior to first treatment) rats weighed individually, then anaesthetize, introducing intraperitoneal dose of ketamine/xylazine (85/15 mg/kg, approximately 2 ml/kg). Next, each animal was placed in a sterile area and disinfect the abdomen and the scrotum using Betadine and 70% alcohol. In the case of control animals exposed blindness (ORX), remove the testicles, producing an incision in the middle of the scrotum. Then impose a sterile suture, tying up a piece of tissue over the egg prior to surgical excision of each testicle. Animals from groups that are subject to treatment with investigational compounds, operate in the same way. In the case of intact control animals (SHAM) testes extract in a similar way and delicately placed in their original position. Then sew up the place surgery using sterile suture thread, and the place disinfected again, causing the Betadine. Next, each animal is kept sterile pillow to Wake-up before returning to the cage. Animals kept in the conditions at 22±2°C with a cycle of the alternating day/night for 12 hours and access to food and drink without restrictions. Animals treated with the substances study, starting from day 7 after surgery and up to day 10 prior to the killing (day 11).

Rats are divided into groups and treated daily is about 7 to 10 day conditions defined below.

The control group SHAM: medium (PEG400/DMSO/water 79/1/20) administered orally.

The control group ORX: medium (PEG400/DMSO/water 79/1/20) administered orally.

Subjected to the treatment group ORX: the compounds administered individually administered orally in the form of a suspension in the above medium at a dose of 10 mg/kg

After treatment for 4 consecutive days animals are decapitate, using the guillotine. Removed and weighed separately muscles, levator anus, and ventral prostate. For macexpertencoding data comparison the mass of each body have been standardized and expressed in milligrams per 100 g weight of the animal (W). For each body record the average value of the standardized weights for the control group ORX by determining at 0% and record the average value of standardized mass control group SHAM by definition at 100%. The effectiveness of each product expressed as a percentage and calculated using the following formula:

(Wtreatment-WORX)/(WSHAM-WORX)×100

Subsequent ANOVA test used for statistical analysis to identify differences between groups.

Table 3
Test data of Hershberger for selected compounds is ia according to the invention.
A semiquantitative estimate
0,5-25%*
25-50%**
50-75%***
75-100%****

ExampleThe study dose (mg/kg)Anabolic activity,
%
Androgena activity, % (prostate)
630***
710**0
910****
1010*****
1130****
1210*******
13 10**
1410******
1510**0
1610*****
1710*******
1810*****
1910******
2110*0

3. Determination of the absolute bioavailability

For rapid screening imidazolidinone derived on the basis of their absolute bioavailability explore limited pharmacokinetic profile with only four time points of sampling after administration of oral and intravenous method on rats Sprague Dawley as follows: a dose of investigational compounds of Perera is Ino (10 mg/kg) and intravenous (3 mg/kg) animal groups, includes 3 male rats Sprague Dawley. The oral dose administered in the form of a solution in EtOH/PEG400/H2O (1/79/20 about./about.) through the esophageal probe (2 mg/ml, 5 ml/kg) and intravenous dose injected into the tail vein as a solution in DMSO/PEG400/H2O (1/65/34 about./about.) bolus (3 mg/ml; 1 ml/kg). Before oral dose animals are deprived of food (water, without limitation, at least 16 h before the study and at 6 hours after injection.

Blood is withdrawn from retroorbital sinus in polypropylene tubes (Li-heparinate) at +4°C in the following sampling: through 0,083, of 0.25, 1 and 3 h after intravenous injection and at 0.25, 1, 3 and 6 hours after oral dose. Three (3) animals taken a blood sample in each moment of time; for each animal taken a blood sample four times. After centrifugation at 5000 rpm and +4°C for 10 min collect plasma in polypropylene tubes and stored frozen at -20°C until investigations. Plasma samples are examined by LC-MS/MS with a lower limit of quantitation of 1 to 10 ng/ml depending on the connection (plasma volume: 100 μl).

Method LC-MS/MS for the quantitative determination in heparinised plasma was developed for each tested compound. Sample preparation involves the precipitation of plasma proteins with methanol and filtered by centrifugation su is inatant filter on tablets Captiva 96 deep-hole 0.2 μm. To a methanol phase supernatant water is added to the research method liquid chromatography (Pursuit 5 C18 20×2.0 mm VARIAN, loop 2 ál, gradient mixture of water/methanol (90/10 to 0/100) for the 1.7 min) and tandem mass spectrometry (API4000) with ionization sputtering at high pressure, the registration of negative ions and application monitoring selected reactions. The method includes 8 standard and 3 quality control level with the lower limit of quantitation, corresponding to the first standard level.

Exposure determined by applying compartmental model (WinNonLin 2.1), and the absolute bioavailability (F) is calculated as follows:

[AUC(0-6h) oral * 3 mg/kg]/AUC(0-3 hours) IV 10 mg/kg] and expressed in percent.

Table 4
The determination of the biological availability of typical compounds according to the invention
Semiquantitative rating:
>90%###
50-90%##
0-49%#

IDBioavailability
1##
3##
4#
5###
6##
7###
8###
10###
12##

4. Determination of the absolute bioavailability of selected compounds according to the invention in rats and dogs

The absolute bioavailability of drugs after oral administration of doses corresponding ester prodrugs research on rats Sprague Dawley as follows: each prodrug administered orally (10 mg/kg, a dose equivalent to 8 mg/kg medicine) and medicine administered intravenously (3 mg/kg) animals groups of 3 male rats Sprague Dawley. The oral dose is administered as a solution in EtOH/PEG400/H2O (1/79/20;./about.) through the esophageal probe (2 mg/ml; 5 ml/kg) and intravenous dose is administered as a solution in DMSO/PEG400/H2O (1/65/34;./about.) bolus into the tail vein (0.6 mg/ml; 5 ml/kg). Before oral dose animals is ishut food (water, without limitation, at least 16 h before the study and at 6 hours after injection.

Blood is taken using a catheter inserted into the jugular vein and collected into polypropylene tubes (Li-heparinate) at +4°C at the following times: via 0,05, 0,25, 0,5, 1, 3, 5 and 8 hours after intravenous injection and after 0,25, 0,5, 1, 3, 5, 8 and 24 hours after oral dose. To prevent ex vivo cleavage of the prodrug with the formation of the drug to the test tubes for blood collection add some volume PMSF (5 mg/ml phenylmethylsulfonyl in ethanol solution), corresponding to 10% of the volume of selected blood. Three (3) animals taken blood samples in a certain time. After centrifugation at 5000 rpm for 3 min at +4°C collect plasma in polypropylene tubes and stored until investigations frozen at -20°C.

Dogs investigate the absolute bioavailability of drugs after oral dose with the corresponding ester prodrugs as follows: a dose of each prodrug oral (dose equivalent to 10 mg/kg of the drug and the dose of the drug administered intravenously (3 mg/kg) 3 males greyhounds. The oral dose administered in powder form, which is filled gelatin capsule, and intravenous dose administered to the head of Vienna as a solution in DMSO/PEG400/H2(1/65/34; about./about.) bolus (3 mg/ml; 1 ml/kg). Before oral dose animals are deprived of food (water, without limitation, at least 12 h before the study and at 4 hours after injection.

Blood is taken via direct venipuncture jugular vein of each of three dogs and collected into polypropylene tubes (Li-heparinate) at +4°C at the following times: via 0,083, 0,167, 0,25, 0,5, 1, 2, 4, 8, 10 and 24 hours after intravenous injection and after 0,25, 0,5, 1, 2, 4, 6, 8, 10 and 24 hours after oral dose. As in the plasma of dogs does not occur ex vivo cleavage of the prodrug with the formation of drugs in test tubes for blood collection do not add esterase inhibitors. After centrifugation at 5000 rpm for 3 min at +4°C collect plasma in polypropylene tubes and stored until investigations frozen at -20°C.

Drug level is determined in the plasma samples of rats by LC-MS/MS with a lower limit of quantitation of 1 ng/ml (plasma volume: 25 µl). Sample preparation involves the precipitation of plasma proteins with methanol and filtered by centrifugation supernatant by filtration tablets Captiva with deep holes of 0.2 μm. To a methanol phase supernatant water is added prior to analysis by liquid chromatography (Pursuit 5 C18 20×2.0 mm VARIAN, loop 2 ál, gradient mixture of water/methanol (90/10 to 0/100) 1,7 min.) with tandem mass spectrometry (API4000) with ionization sputtering at high pressure, registration of negative ions and application monitoring selected reactions. The method includes 8 standard and 3 quality control level with the lower limit of quantitation, corresponding to the first standard level.

Exposure determined by applying compartmental model (WinNonLin 5.2), and the absolute bioavailability (F) is calculated as follows:

[AUC(0-z) oral * 3 mg/kg]/AUC(0-z) IV 8 or 10 mg/kg] and expressed in percent.

Table 5
Determination of the absolute bioavailability of selected compounds according to the invention
>90%####
50-90%###
20-49%##
<20%#

IDBioavailability (rat)Bioavailability (dogs)
27####
28### ###

5. In-vivo experiments

5.1 Glucocorticoid-induced loss of muscle mass (rats).

In this model examined the effect of the compounds according to the invention for the loss of muscle mass induced by dexamethasone (Kun Maand others,2003). Male rats Sprague Dawley 8 weeks of age treated with daily 0.3 mg/kg of dexamethasone by subcutaneous injection for 15 days. Rats are divided into several groups: SHAM (no treatment, n=8), control (medium, n=8), andrological (3 mg/kg/day, subcutaneously, n=8) and test the connection (selected range of oral doses, n=8). After 15 days of treatment produce gastrocnemius muscle, weigh and determine muscle function in the anterior tibial muscle (Hourde and others, 2009).

5.2 TNF-induced cachexia (mouse)

In this model (Dario Coletti and others, 2005) induce receiving tumor necrosis factor α (TNF) via electroporation DNA with the gene expression of TNF into the tibial muscle of mice. Chronic exposure to TNF triggers debilitating muscle reminiscence cachexia. Male mice divided into several groups: SHAM, control, nandrolone decanoate and G100192. At the end of processing produce gastrocnemius muscle and the soleus muscle, weigh and determine muscle function in the soleus muscle (Hourdeand others,2009).

5.3 Model immobilization (mouse)

Unloading of the skeleton calls the AET loss of bone and muscle mass. The effects of the compounds according to the invention for unloading of the skeleton exploring, applying the suspension is introduced into the tail, within 14 days (Rolandand other, 2005). Male mice divided into several groups: without entering a suspension, the introduction of the suspension into the tail, the introduction of the suspension into the tail with the processing of the investigated compound and introducing the suspension into the tail processing mantraonline.com. At the end of the experiment allocate the soleus muscle and the gastrocnemius muscle, weigh and determine muscle function in the soleus muscle (Hourdeand others,2009).

5.4 Model orchidectomy (rat)

Orchidectomy more updates bones and muscle mass fat. This model examined the effect of the compounds according to the invention on the structure of the muscles (the ratio of lean and fat mass) and the update of bones (Hourdeand others., 2009). Male rats Sprague Dalwey 8 weeks of age are divided into several groups: intact rats (SHAM)rats with remote testicles processed within 2 months the media, mantraonline.com or investigational compound. At the end of the experiment investigating the correlation of lean and fat mass and renewal of bones, calf identify, weigh and determine muscle function in the soleus muscle (Hourdeand others.,2009).

All publications, including cited in the description of the patents and patent applications, but not limited to, included ZV is camping in the form of links, as if each individual publication were specifically and individually indicated that she incorporated herein by reference in its entirety.

On the basis of the preceding description specialists in this field will come to mind various modifications and changes in the composition and methods according to this invention. It is assumed that all such modifications falling within the scope of the attached claims included in it.

It should be understood that such factors as the ability of various compounds to penetrate the differential cells, may contribute to the differences between the activity of the compounds in in vitro biochemical and cellular studies.

At least some of the chemical names of the compounds according to the invention, which are listed and defined in this application, can be obtained automatically using commercially available software for assigning chemical names, and cannot independently confirm. Typical programs that perform this function, include the program values Lexichem supplied Open Eye Software, Inc., and the program Autonom Software, supplied by MDL, Inc. In the case where a specified chemical name and shows the structure of a different, depicts the structure of regulate.

Shown here chemical structure obtained using ChemDraw® and ISIS®/DRW. Any open valence, appearing on the carbon atoms, oxygen or nitrogen in the listed structures, indicates the presence of a hydrogen atom. If the structure has a chiral center, but does not show the specific stereochemistry for chiral center, the structure covers both enantiomers associated with chiral structure.

LINKS:

1. Kaufman JM and Vermeulen A. Endocr Rev. 2005, 26, 833-76.

2. The decline of androgen levels in elderly men and its clinical and therapeutic implications.

Liu PY, et al. J. Clin. Endocrinol. Metab. 2004, 89, 4789-96.

Clinical review, 171: The rationale, efficacy and safety of androgen therapy in older men: future research and current practice recommendations.

3. Davison SL and Davis SR. J. Steroid Biochem. Mol. Biol. 2003, 85, 363-366. Androgens in women.

4. Mohler et al. Expert Opin. Ther. Patents 2005, 15 (11), 1565-1585.

5. EP-A-0966447.

6. EP-A-0572191.

7. WO 2007/137874.

8. Bundgard, H. " Design of Prodrugs 1985, Elsevier, Amsterdam.

9. Remington's Pharmaceutical Sciences, 17th edition. 1985, Mack Publishing Company, Easton, Pennsylvania.

10. Greene, T.W. and Wuts, P.G.M.Protecting Groopsin Organic Synthesis, Second Edition, 1991, Wiley, New York.

11. Molander, G.A. and McKie, J.A. J. Org.Chem. 1995, 60, 872-882.

12. Angel, P.et al., Mol. Cell. Biol. 1987, 7: 2256-2266.

13. Claessens, F. et al., J. Biol. Chem. 1996, 271: 19013-19016.

14. Tilley, WDet al., Proc. Natl. Acad. Sci USA 1989, 86: 327-31. Gen library J04150.

15. Hershberger et al., Proc. Soc. Expt. Biol. Med. 1953, 83: 175.

16. Kun Ma, Con Mallidis, Shalender Bhasin, Vahid Mahabadi, Jorge Arfaza, Nestor Gonzalez-Cadavid, Jose Arias and Behrouz Salehian Am J Physiol Endocrinol Metab. 2003, 285: E363-E371.

Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expression.

17. C. Hourde, C. Jagerschmidt, P. Clement-Lacroix, A. Vignaud P. Ammann, G. S. Butler-Browne and A. Ferry. Acta Physiol. 2009, 195: 471-482. Androgen replacement therapy improves function in male rat muscles independently of hypertrophy and activation of the Akt/mTOR pathway.

18. Dario Coletti, Viviana Moresi, Sergio Adamo, Mario Molinaro and David Sassoon. Genesis 2005, 43: 120-128.

Tumor Necrosis Factor-α Gene Transfer Dosage Cachexia and Inhibits Muscle Regeneration.

19. Roland M, Hanson AM, Cannon CM, Stodieck LS, Ferguson VL. Biomed Sci Instrum. 2005, 41: 128-34.

Exercise prevention of unloading-induced bone and muscle loss in adult mice.

1. The compound of formula Ib

where X represents O;
R1represents H; or
R1selected from C1-C6the alkyl and C3-C6the quinil, where alkyl optionally may be substituted with cyano;
R2aselected from H, P(O)(OH)2and C(O)(CH2)n1C(O)OH; or
R2aselected from-C(O)-C1-C6of alkyl, which is substituted by amino;
n1 is 1 or 2;
each R2band R2cindependently selected from H and C1-C6of alkyl;
R3arepresents H, halogen atom or cyano;
each R3bindependently represents a halogen atom or cyano; or
each R3bindependently represents a C1-C6alkyl, optionally substituted by three halogen atoms;
each R4aand R4bindependently represents H or a halogen atom; or
each R4aand R4bselected from C1-C6the alkyl and C1-C6alkoxy, where the alkyl is substituted by three halogen atoms;
R4c means halogen atom or cyano; and
m1 is 0 or 1;
or its pharmaceutically acceptable salt and solvate, or a solvate of pharmaceutically acceptable salts.

2. The compound or its pharmaceutically acceptable salt according to claim 1, where X represents O.

3. The compound or its pharmaceutically acceptable salt according to claim 1 or 2, where R2bmeans H, Me or Et.

4. The compound or its pharmaceutically acceptable salt according to claim 1 where R2cmeans H, Me or Et.

5. The compound or its pharmaceutically acceptable salt according to claim 1, where R2arepresents H.

6. The compound or its pharmaceutically acceptable salt according to claim 1, where R2arepresents P(O)(OH)2.

7. The compound or its pharmaceutically acceptable salt according to claim 1, where R2arepresents C(O)(CH2)n1C(O)OH; and n1 is 1 or 2.

8. The compound or its pharmaceutically acceptable salt according to claim 1, where R1represents Me, Et, i-Pr, or n-Pr.

9. The compound or its pharmaceutically acceptable salt according to claim 1, where the compound corresponds to the formula II

where R3a, R3b, R4a, R4b, R4cand m1 are the same as in item 1.

10. The compound or its pharmaceutically acceptable salt according to claim 1, where R4crepresents cyano or halogen atom.

11. The compound or its pharmaceutically acceptable salt according to claim 1, where R4brepresents the t a H, halogen atom or C1-C6alkyl, where the alkyl is substituted by three halogen atoms.

12. The compound or its pharmaceutically acceptable salt according to claim 1, where the compound corresponds to formula Va, Vb, Vc or Vd:

and where R3athe same as in claim 1; and
R3crepresents H, halogen atom or cyano; or
R3crepresents a C1-C6alkyl, optionally substituted by three halogen atoms.

13. The compound or its pharmaceutically acceptable salt according to clause 12, where R3arepresents H, halogen atom or cyano; and R3crepresents H.

14. The compound or its pharmaceutically acceptable salt according to clause 12, where R3arepresents H; and R3crepresents H, a halogen atom, a C1-C6alkyl, optionally substituted by three halogen atoms, or cyano.

15. The compound or its pharmaceutically acceptable salt according to claim 1, where the compound is selected from the following:
4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical;
4-[2,5-dioxo-4-(1-hydroxypropyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical;
4-[2,5-dioxo-4-(1-hydroxyethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical;
4-[2,5-dioxo-4-(4-forfinal)-4-(hydroxymethyl)-3-methylimidazolidine-1-yl]-2-cryptomathematical;
4-[4-(4-chlorophenyl)-2,5-is ioxo-4-hydroxymethyl-3-methyl-imidazolidin-1-yl]-2-cryptomathematical;
4-[2,5-dioxo-4-(4-forfinal)-4-hydroxymethyl-3-(2-PROPYNYL)imidazolidin-1-yl]-2-cryptomathematical;
4-[4-(3-chlorophenyl)-2,5-dioxo-4-hydroxymethyl-3-methyl-imidazolidin-1-yl]-2-cryptomathematical;
(S)-4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical;
(R)-4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazoline-1-yl]-2-cryptomathematical;
4-[2,5-dioxo-3-ethyl-4-(hydroxymethyl)-4-phenylimidazoline-1-yl]-2-cryptomathematical;
4-[4-(4-cyanophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical;
4-[4-(3-cyanophenyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical;
4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-(3-triptoreline)imidazolidin-1-yl]-2-cryptomathematical;
1-(3,4-dichlorophenyl)-4-hydroxymethyl-3-methyl-4-phenylimidazoline-2,5-dione;
4-[2,5-dioxo-4-(hydroxymethyl)-3-(1-methylethyl)-4-phenylimidazoline-1-yl]-2-cryptomathematical;
4-[3-cyanomethyl-2,5-dioxo-4-(hydroxymethyl)-4-phenylimidazoline-1-yl]-2-cryptomathematical;
4-[2,5-dioxo-4-(hydroxymethyl)-4-phenyl-3-(1-PROPYNYL)imidazolidin-1-yl]-2-cryptomathematical;
4-[2,5-dioxo-4-hydroxymethyl-4-phenylimidazoline-1-yl]-2-cryptomathematical;
4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-(3-were)imidazolidin-1-yl]-2-cryptomathematical;
4-[4-(2-chloro who enyl)-2,5-dioxo-4-hydroxymethyl-3-methylimidazolidine-1-yl]-2-cryptomathematical;
[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methyl dihydrophosphate;
(2S)-1-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methoxy-3-methyl-1-oxobutyl-2-ammonium chloride;
4-[1-(4-cyano-3-triptoreline)-2,5-dioxo-3-methyl-4-phenylimidazole-4-yl]methoxy-4-oxobutanoic acid;
(S)-(1-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,5-dioxo-4-phenylimidazole-4-yl)methyl dihydrophosphate;
(S)-4-((1-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,5-dioxo-4-phenylimidazole-4-yl)methoxy)-4-oxobutanoic acid;
(S)-((S)-1-(4-cyano-3-(trifluoromethyl)phenyl)-3-methyl-2,5-dioxo-4-phenylimidazole-4-yl)methyl-3-methylbutanoate-2-ammonium chloride;
4-[2,5-dioxo-4-hydroxymethyl-3-methyl-4-phenylimidazoline-1-yl]-2-methoxybenzonitrile and
(S)-1-(3,4-dichlorophenyl)-4-hydroxymethyl-3-methyl-4-phenylimidazoline-2,5-dione.

16. Pharmaceutical composition for modulation of the activity of androgen receptors containing a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to claim 1.

17. The use of compound or pharmaceutically acceptable salt according to claim 1 for the treatment or prevention of conditions caused by or inherent in the changing levels of circulating androgens in mammals.

18. The use of compound or its pharmaceutically acceptable salt according to claim 1 for the treatment or pros who ACTICE state, characterized by low activity of androgen receptors.

19. The use of compound or its pharmaceutically acceptable salt according to claim 1, where the specified compound is an agonist or mixed agonist/antagonist of the androgen receptor, for the treatment or prevention of osteoporosis, sarcopenia, reduced libido and/or sexual dysfunction.

20. The use of compound or its pharmaceutically acceptable salt according to claim 1, where the specified compound is an antagonist or mixed agonist/antagonist of the androgen receptor, for the treatment or prevention of androgen-dependent tumors, such as prostate cancer or hyperplasia.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - pharmaceutically acceptable salts of (S)-N-[4-(1-adamantyl)benzoyl]-α-amino acids of general formula (1) , where A+ denotes an ion of an alkali metal, ammonia and N+(C1-4alkyl)4, R2 provided that R1 denotes a hydrogen atom, radicals -CH3, -CH(CH3)2, -CH2CH(CH3)2, -CH(CH3)CH2CH3, CH2-CH2-SH, -CH2-CH2-S-CH3, R1 and R2 together denote a biradical -CH2-CH2-CH2-, closed in the pyrrolidine ring, as well as a method of producing said compounds.

EFFECT: improved method of producing the said compounds.

23 cl, 7 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: present invention relates to new imidazole derivatives of general formula I , where R1 is C1-C10alkyl or C3-C10cycloalkyl, each possibly and independently substituted with 1 substitute selected from C3-C10cycloalkyl or aryl or a heteroaryl group, possibly substituted with one or two halogens; aryl or heteroaryl; R2 is C1-C10alkoxy or C1-C10thioalkyl; R3 is C1-C10alkoxy, possibly substituted with one C1-C10alkoxy or nitrile, where the said alkoxy group can be cyclic or can contain one O heteroatom; R4 is C1-C10alkyl; C2-C10alkenyl; C1-C10alkoxy or C3-C10cycloalkyl, each possibly and independently substituted with 1 or 2 substitutes selected from C1-C10alkoxy, C3-C10cycloalkyl, carboxylic ester, or with one or two aryl or heteroaryl groups, possibly substituted with one substitute selected from C1-C10alkyl, C3-C10cycloalkyl, nitro or halogen; aryl or heteroaryl, each possibly and independently substituted with 1-3 substitutes selected from C1-C10alkyl, C3-C10cycloalkyl, C1-C10alkoxy, phenoxy, thiophenyl, halogen, nitro, nitrile or aryl group, possibly substituted with one halogen; where up to three hydrogen atoms of the alkyl group can be substituted with fluorine atoms; where the said cycloalkyl can independently have one or two carbon atoms substituted with O or N; where the said aryl denotes an aromatic ring having 6 to 10 carbon atoms, including mono- and bicyclic compounds; and where the said heteroaryl denotes an aromatic ring having 3 to 10 carbon atoms, including mono- and bicyclic compounds in which one to three ring atoms are oxygen, nitrogen or sulphur atoms; except compounds given in paragraph 1. The invention also pertains to use of the said compounds for making a medicinal agent, a treatment and prevention method, a compound of formula II (values of radicals are given in the formula of invention).

EFFECT: new imidazole derivatives having positive allosteric modulator effect on GABAB receptor are obtained.

30 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (III): in racemic form, in enantiometic form or in form of any combination of these forms, in which Het represents a five-member heterocycle containing 2 heteroatoms, where general formula (III) corresponds to only one of the following formulae , , in which: n = 1, A is biphenyl or cyclohexylphenyl, B is a hydrogen atom, R1 and R2 each independently represents a hydrogen atom, X is NR3, where R3 is a hydrogen atom, and Ω is a NR46R47 radical, where R46 is a -COOR51 radical, where R51 is alkyl, cycloalkyl, cycloalkylalkyl or alkoxyalkyl and R47 is a hydrogen atom, and a salt of such a compound, as well as to a pharmaceutical composition based on the said compounds. Formula (III) compounds can be used to prepare a medicinal agent for inhibiting monoamine oxidase and/or lipid peroxidation, and/or as sodium channel modulators.

EFFECT: obtaining a medicinal agent for treating or preventing pain and neuropathic pain.

12 cl, 349 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

The invention relates to new substituted phenylimidazoline, to a method for their production and to their use in pharmaceutical compositions

The invention relates to a series of new derivatives of imidazole, which are antagonists of angiotensin II (hereinafter referred to as A-II/ and can then be used for the treatment and prevention of diseases caused by hypertension and for the treatment or prevention of cardiovascular diseases

The invention relates to compounds of imidazole

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely 12-imidazolyl-1-dodecantole or its pharmaceutically acceptable salts.

EFFECT: what is prepared is a new imidazole derivative effective in treating, including malignant pathological conditions.

4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to a fluorine-containing organosulphur compound of formula (I) and a composition based on said compound, which can be used in arthropod pest control: where m equals 0; n equals 0, 1 or 2; A is pyrazolyl, isoxazolyl, imidazolyl, oxazolyl or thiazolyl, optionally substituted with a group E1; R1 is C1-4 alkyl, a cyano group, a halogen atom or a hydrogen atom; R2 is C1-4 alkyl, a halogen atom or a hydrogen atom; Q is C1-5 haloalkyl containing at least one fluorine atom or a fluorine atom; group E1 is selected from halogen, tert-butyl, trifluromethyl, pentafluoroethyl, ethynyl, propargyl, propargyloxy, cyano, trifluoromethyl, trifluromethane thionyl and trifluoromethane sulphonyl.

EFFECT: efficient agent for arthropod pest control.

5 cl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention claims substituted O-[ω-(azol-1-yl)alkyl]-N-phenylthiocarbamates of formula I: where Z=CH, N, R=H, Alk, AlkO, Hal etc., m=1, 2, 3, n=0-5, obtained by acylation of ω-(azol-1-yl)alkanols of formula II by substituted phenylisothiocyanates in polar aprotonic solvents in the presence if tertiary amines. Invention allows for more efficient suppression of phytopathogenic fungi in vitro than by such reference material as triadimefon, due to application of fungicide composition including substituted O-[ω-(azol-1-yl)alkyl]-phenylthiocarbamates I, such as O-(imidazole-1-ylmethyl)-N-(2-methyl-phenyl)thiocarbamates.

EFFECT: efficient suppression of phytopatogenic fungi growth.

4 cl, 5 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula I R1 represents phenyl, possibly substituted with phenyl or heterocyclic group, or heterocyclic group, possibly substituted with phenyl, where said heterocyclic group represents mono- or bicyclic ring, containing 4-12 atoms, of which at least one atom is selected from nitrogen, sulfur or oxygen, each phenyl or heterocyclic group possibly being substituted with one or more than one of the following groups: C1-6alkyl group; phenylC1-6alkyl, alkyl, phenyl or alkylphenyl group is possibly substituted with one or more than one from Rb; halogen; -ORa; -OSO2Rd; -SO2Rd; -SORd; -SO2ORa; where Ra represents H, C1-6alkyl group, phenyl or phenylC1-6alkyl group; where R represents halogeno, -OH, -OC1-4alkyl, Ophenyl, -OC1-4alkylphenyl, and Rd represents C1-4alkyl; group -(CH2)m-T-(CH2)n-U-(CH2)p- is bound either in third, or in fourth position in phenyl ring, as shown with figures in formula I, and represents group selected from one or more than one of the following: O(CH2)2, O(CH2)3, NC(O)NR4(CH2)2, CH2S(O2)NR5(CH2)2, CH2N(R6)C(O)CH2, (CH2)2N(R6)C(O)(CH2)2, C(O)NR7CH2, C(O)NR7(CH2)2 and CH2N(R6)C(O)CH2O; V represents O, NR8 or single bond; q represents 1, 2 or 3; W represents O, S or single bond; R2 represents halogeno or C1-4alkoxyl group; r represents 0, 1, 2 or 3; s represents 0; and R6 independently represent H or C1-10alkyl group; R4, R5, R7 and R8 represent hydrogen atom; and to their pharmaceutically acceptable salts.

EFFECT: increase of composition efficiency.

12 cl, 31 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of imidazolyl derivative of the general formula (I) wherein each Ra and Rb represents independently (C1-C6)-alkyl, (C1-C6)-alkoxyalkyl, optionally substituted aryl or heteroaryl, or wherein Ra and Rb form in common additional homocyclic or heterocyclic system comprising one or some rings; each Ra' and Rb' represents hydrogen atom, or they in common form a carbon-carbon double bond wherein indicated carbon-carbon double bond is optionally part of aromatic system; Rc represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C1-C6)-alkoxyalkyl or halogen atom; Rd represents hydrogen atom or (C1-C4)-alkyl; Re represents hydrogen atom or (C1-C4)-alkyl; m = 1 or 2; R1 represents hydrogen atom or (C1-C4)-alkyl, and its salts after addition of acid and wherein compound of the general formula (II) wherein values Ra, Ra', Rb, and Rb' are given above is subjected for interaction with compound of the formula (III) wherein R represents hydrogen atom, (C1-C4)-alkyl group optionally substituted with hydroxy-group, or optionally substituted aryl group; each R', R'', R''' and R'''' represents independently hydrogen atom or (C1-C4)-alkyl group followed by interaction with compound of the formula (IV) wherein R, Rd and Re have values given above and the following optional interaction with the corresponding acid. Proposed method shows high effectiveness for synthesis of ondansetron and cilansetron.

EFFECT: improved method of synthesis.

10 cl, 10 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for synthesis of 2-imidazolylpropane-2-sulfoacid. Invention describes a method for synthesis of 2-imidazolylpropane-2-sulfoacid that involves dissolving imidazole in a solvent, such as lower alcohols or acetone, bubbling gaseous sulfurous anhydride in its at temperature 200C, not above, for 20-25 min in the mass ratio imidazole : sulfurous anhydride = 1:1 and addition of propanone-2 in the mass ratio imidazole : propanone-2 : water = 1:1:1. Method provides preparing the end product of high purity (99.2-99.8%) with the high yield (89-92%) and to exclude using a solvent prohibited by Pharmacological committee of Russian Federation. Synthesized compound possesses bacteriostatic, immunostimulating, anti-aggregating and de-aggregating activity with respect to platelets and enhancing contracting activity of skeletal muscles.

EFFECT: improved method of synthesis, valuable medicinal properties of compound.

3 ex

FIELD: organic chemistry, fungicides.

SUBSTANCE: invention describes substituted 1-(pyridinyl-2)-2-azolylethanols of the general formula (I): wherein R means hydrogen atom, direct or branched alkyl with 1 to 8 carbon atoms, cycloalkyl with from 3 to 8 carbon atoms; X means nitrogen atom or CH-group. Also, invention relates to a method for synthesis of these compounds and a fungicide composition that contains compound of the formula (I). Invention provides expanding assortment of fungicides for carrying out the effective control of harmful fungi.

EFFECT: valuable fungicide properties of compounds and composition.

5 cl, 1 tbl, 7 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

The invention relates to the chemistry of heterocyclic compounds, namely to substituted 1-(pyridinyl-3)-2-azolylmethyl General formula I

where R means a hydrogen atom, an unbranched or branched alkyl with a number of carbon atoms of from one to eight, cycloalkyl with the number of carbon atoms from three to eight, cycloalkenyl with the total number of atoms from four to ten, alkylsilanes with the total number of atoms from four to ten, X denotes a nitrogen atom or CH group, which possess fungicidal activity and can be used as agricultural, industrial, medical or veterinary fungicides

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely obstetrics and gynaecology, and may be used for treating early miscarriage in females with primary hyperprolactinemia. That is ensured by prescribing a sparing regimen combined with the administration of dufaston. It is added with prescribing the preparation dostinex 0.125 mg - 0.250 mg at bedtime to a pregnant woman 1-2 times a week to the 10-12th week of pregnancy.

EFFECT: method provides higher clinical effectiveness, reduced side effects and complications.

3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to stable metastin derivatives, having excellent biological activity. The disclosed metastin derivatives improve stability, gelation tendency is reduced, pharmacokinetics are also improved, and an excellent cancer metastasis suppressing activity or a cancer growth suppressing activity is exhibited.

EFFECT: metastin derivatives of the present invention also have a gonadotropic hormone secretion suppressing activity and sex hormone secretion suppressing activity.

5 cl, 4 tbl, 18 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely gynaecology, and is applicable for the purpose of prevention of hormone resistance in endometrial hyperplasia. That is ensured by prescribing a depot synthetic analogue of gonadotrophin releasing hormone by 1 injection on the 1st-2nd day of menstrual cycle once every 28 days. Nine injections in all. It is combined with an oestrogen-gestagen drug by 1 tablet a day starting with the 14th day after the second injection of the gonadotrophin releasing hormone analogue and up to the 28th day after the ninth injection.

EFFECT: method enables prevention of hormone resistance in endometrial hyperplasia.

3 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine, namely to gynecology, and can be used for syndrome of ovary hyperstimulation, as well as for its prevention in a subject who is under treatment against infertility with gonadotropic hormone. For this purpose composition, which contains quinagolide in pharmaceutically acceptable carrier, is introduced to patient.

EFFECT: introduction of quinagolide, in contrast to other dophamine agonists, ensures high therapeutic efficiency in considerably smaller doses and is quickly excreted from organism, which reduces risk of toxicity for mother and fetus.

16 cl, 3 tbl, 6 ex, 2 dwg

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