Biphenyl derivatives, their using, cosmetic composition and its using, pharmaceutical composition

FIELD: organic chemistry, medicine, cosmetics, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 means radical of the following formulae: (a) or (b) wherein R2 and R3 are similar or different and mean hydrogen atom, alkyl with 10-12 carbon atoms, aryl, radical -OR7; X means a binding fragment of the following formula: -(CH2)m-(Z)n-(CO)p-(W)q- wherein a binding fragment can be read from the left to the right or inversely; R4 means alkyl with 1-12 carbon atoms, aryl, aralkyl, heteroaryl or 9-fluorenylmethyl; Y means radical -CH2 or sulfur atom; R5 means hydroxyl, alkoxyl with 1-6 carbon atoms, radical -NH-OH or radical -N(R8)(R9); R6 means alkyl with 1-12 carbon atoms, radical -OR10 or radical -(CH2)r-COR11; R7 means hydrogen tom or aralkyl; Z means oxygen atom or radical -NR12; W means oxygen atom, radical -NR13 or radical -CH2; m, n, p and q are similar or different and can mean 0 or 1 under condition that the sum (m + n + p + q) = 2 or above, and when p = 0 then n or q = 0; R8 means hydrogen atom; R9 means hydrogen atom or aryl; r means 0 or 1; R10 means alkyl with 1-12 carbon atoms; R11 means hydroxyl or radical -OR14; R12 means hydrogen atom or alkyl with 1-12 carbon atoms; R13 means hydrogen atom or alkyl with 1-12 carbon atoms; R14 means alkyl with 1-12 carbon atoms; and optical and geometric isomers of abovementioned compounds of the formula (I), and their salts also. These compounds are useful as activating agents of receptors of type PPAR-γ in pharmaceutical compositions designated for using in medicine, in particular, in dermatology, in treatment of cardiovascular diseases and related to immunity of diseases and/or diseases associated with lipid metabolism, and in cosmetic compositions also.

EFFECT: valuable properties of compounds and compositions.

19 cl, 1 tbl, 2 dwg, 37 ex

 

The invention relates to new and valuable industrial products, constituting a new class barometrically compounds which are activators of receptor subtype γactivating the proliferation of peroxisomes (PPARγ). It relates also to a method for their production and their use in pharmaceutical compositions intended for therapeutic use or in veterinary medicine or in cosmetic compositions.

The activity of the PPAR receptor type has been the subject of numerous studies. You can cite as example the publication "Differential Expression of Peroxisome Proliferator-Activated Receptor Subtypes During the Differentiation of Human Keratinocytes", Michel Rivier, etc., J. Invest. Dermatol.,111, 1116-1121 (1998), which contains a large number of bibliographic references relating to the PPAR receptor type. You can also call for information: "The PPARs: From orphan receptors to Drug Discovery" Timothy M. Willson, Peter J. Brown, Daniel D. Sternbach and Brad R. Henke, J. Med. Chem.,43, 527-550 (2000).

The PPAR receptors activate transcription by binding to elements in DNA sequences called response elements proliferation peroxisomes (PPRE), in the form of heterodimer with receptors X retinoids (called RXR).

Identified and described three subtypes of the human PPAR: PPARα, PPARγ and PPARδ (or NUC1). PPARα is expressed mainly in the liver, whereas PPARδ is ubiquitary.

PPAR&x003B3; is the most studied of the three subtypes. A set of published work indicates a critical role of PPARγ in the regulation of differentiation of adipocytes, where it is intensively expressed. He also plays a key role in systemic lipid homeostasis.

In the international patent application WO-96/33724, in particular, describes the selective against PPARγ compounds such as prostaglandin-J2 or-D2, are active potential connections in the case of treatment of obesity and diabetes.

In addition, in the application for French patent 98/02894 the applicant has already described the use of compounds of activators of PPARγ for the preparation of pharmaceutical compositions, and the composition is intended for the treatment of skin disorders related to an anomaly of differentsirovat epidermal cells.

One of the purposes of the invention is to propose a new class of compounds - activators of PPARγ.

Thus, the present invention relates to compounds that meet the following General formula (I):

in which:

- R1means a radical of the following formulae (a) and (b):

and Y, R5and R6have the following values;

- R2and R3identical or different, denote a hydrogen atom, alkyl with 1-12 carbon atoms, aryl, atom g is lagena, radical OR7simple polyether radical, a nitro-group or amino group which may be optionally substituted by one or more alkyl radicals with 1 to 12 carbon atoms, and R7has the following value;

- X means-binding fragment has the following structure:

-(CH2)m-(Z)n-(CO)p-(W)q-and above-binding fragment can be read from left to right or Vice versa, and Z, W, m, n, p, q have the following values;

- R4denotes alkyl with 1-12 carbon atoms, aryl, aralkyl, heteroaryl or 9-fluorenylmethyl;

- Y represents a radical CH2or sulfur atom;

- R5means hydroxyl, alkoxy with 1-6 carbon atoms, a radical NH-OH or a radical N(R8)(R9), and R8and R9have the following values;

- R6denotes alkyl with 1-12 carbon atoms, the radical OR10the radical SR10or the radical (CH2)r-COR11and r, R10and R11have the following values;

- R7means a hydrogen atom, alkyl with 1-12 carbon atoms or aralkyl;

Z means oxygen atom, a sulfur atom or a radical NR12and R12has the following value;

- W means an oxygen atom, a sulfur atom, a radical NR13or the radical CH2and R13has the following value;

- , n, p, q, same or different, can take the values 0 or 1,

bearing in mind that the sum (m+n+p+q) is higher or equal to 2 and when p is 0, then n or q is 0;

- R8means a hydrogen atom or alkyl with 1-12 carbon atoms;

- R9means a hydrogen atom, alkyl with 1-12 carbon atoms or aryl;

- r means 0 or 1;

- R10denotes alkyl with 1-12 carbon atoms, aryl or aralkyl;

- R11means hydroxyl, radical OR14or a radical N(R15)(R16);

- R12means a hydrogen atom or alkyl with 1-12 carbon atoms;

- R13means a hydrogen atom or alkyl with 1-12 carbon atoms;

- R14denotes alkyl with 1-12 carbon atoms, aryl or aralkyl;

- R15means a hydrogen atom or alkyl with 1-12 carbon atoms;

- R16means a hydrogen atom, alkyl with 1-12 carbon atoms, aryl, aralkyl or heteroalkyl;

and to salts of compounds of formula (I), when R1carboxyl group, as well as optical and geometrical isomers of the above compounds of formula (I).

When the compounds according to the invention are in the form of a salt, it is preferably a salt of alkali or alkaline earth metal or zinc salts or organic amine.

According to the present invention under an alkyl with 1-12 carbon atoms understand radical containing 12 carbon atoms, and preferably methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, octyl, decyl or dodecyl.

Under ordinary polyester moiety understand simple polyester radical with 1-6 carbon atoms, interrupted by at least one oxygen atom, such as methoxyethoxy, ethoxyethoxy or methoxyethoxyethoxy.

Under the halogen atom understand fluorine atom, chlorine or bromine.

Under arcoxia with 1-6 carbon atoms understand radical containing from one to six carbon atoms, such as methoxy, ethoxy, isopropoxy-, tert-butoxy or hexyloxy.

Under the aryl understand phenyl which may be mono - or Disaese a halogen atom, the radical CF3, alkyl with 1-12 carbon atoms, alkoxyl with 1-6 carbon atoms, a nitrogroup, simple polyether radical, a hydroxyl may be protected by acetyl, benzoyl or amino group, possibly protected by acetyl, benzoyl or possibly substituted by at least one alkyl with 1-12 carbon atoms.

Under aralkyl understand benzyl or phenethyl, which may be mono - or Disaese a halogen atom, the radical CF3, alkyl with 1-12 carbon atoms, hydroxyl, alkoxyl with 1-6 carbon atoms, a nitrogroup, simple polyether radical, a hydroxyl may be protected by acetyl, benzoyl or an amino group may, Conn is authorized by acetyl, the benzoyl or possibly substituted by at least one alkyl with 1-12 carbon atoms.

Under heteroaryl understand pyridyl, furyl, thienyl, isoxazolyl, possibly substituted by at least one halogen atom, alkyl with 1-12 carbon atoms, alkoxyl with 1-6 carbon atoms, a nitrogroup, simple polyether radical, a hydroxyl may be protected by acetyl, benzoyl or amino group may be protected by acetyl, benzoyl or possibly substituted by at least one alkyl with 1-12 carbon atoms.

Of the compounds of the above formula (I)included in the scope of the present invention, include, in particular, the following (individually or in a mixture):

- N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzamide;

- 2-methyl-3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)propionic acid;

-(S)-2-ethoxy-3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)propionic acid;

- onomatology ester 2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonic acid;

- dimethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonate;

- methyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonamate;

- 5-{3'-[(methylpyridin-2-ylamino)methyl]biphenyl-4-ylmethyl}thiazolidine-2,4-dione;

- N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]ansamed;

- N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-ethylbenzamide;

- N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-pentylbenzene;

- tert-butyl-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamate;

- tert-butyl-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]ethylcarbamate;

- tert-butyl-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]propylgallate;

- N-fluoren-9-ylmethyl-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamate;

- N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-2,2,N-trimethylpropane;

- N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylacrylamide;

- N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnonanoic;

- N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-3-phenylpropionamide;

- 1-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-3-phenylacetone;

- N-[4'-(2-carbamoylethyl)biphenyl-3-ylmethyl]-N-methylbenzamide;

- N-methyl-N-[4'-(2-phenylcarbamoyloxy)biphenyl-3-ylmethyl]benzamide;

- N-[4'-(2-hydroxycarbamoyl)biphenyl-3-ylmethyl]-N-methylbenzamide;

- 2-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-yl]-N-methyl-N-phenylacetamide;

- 1-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-1-methyl-3-phenylacetone;

- ethyl-3-{3'-[(benzoylamino)methyl]biphenyl-4-yl}-2-methylpropionate;

- monoamide N-Ki-the Roxy-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonic acid;

- N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-propylbenzamide;

- tert-butyl-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-yl]carbamate;

- monoamide 2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonic acid;

- N-benzyl-N-methyl-4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-carboxamide;

- N-benzyl-4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-carboxamide;

- N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-metalmechanic;

- N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-yl]-2-phenylacetamide;

- N-octyl-4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-carboxamide;

- N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylheptane;

- N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-3,4-diethoxy-N-methylbenzamide.

According to the present invention preferred compounds of formula (I) are those which have at least one of the following characteristics:

- R1means a radical of the formula (a) or a radical of formula (b), where R5means hydroxyl and R6means radical OR10;

- X means connecting the fragment of the structure-CH2-N(R12)-CO-, read from left to right or Vice versa.

The object of the present invention are also methods for obtaining compounds of formula (I), in particular according to the reaction schemes, presents the output in figures 1 and 2.

Derivatives of formula (Ia) can be obtained (figure 1) from derivatives (Ic) by hydrogenation in the presence of palladium-on-coal in a solvent such as dioxane, ethyl acetate, dimethylformamide or ethyl alcohol.

Derivatives of formula (Ia) can also be obtained (figure 1) derived from thiazolidin-2,4-dione (6):

when Q means -(CH2)m-ZH, by reaction with allelochemical formula Cl-CO-(W)q-R4in the presence of a base such as triethylamine, in a solvent such as tetrahydrofuran or dichloromethane, or by reaction with an isocyanate of the formula O=C=N-R4;

when Q means -(CH2)m-COOH by reaction in an anhydrous medium, in an organic solvent, preferably in tetrahydrofuran or dichloromethane, in the presence of tertiary amine (e.g. triethylamine or pyridine), an activated form of the carboxylic group, for example, carboxylic acid, amino, hydroxyl derivative, or tilenum derived formulas HW-R4.

Derivatives of the formula (6) can be obtained (figure 1) derived from formula (5) by hydrogenation in the presence of palladium-on-coal in a solvent such as dioxane, ethyl acetate, dimethylformamide or ethyl alcohol.

Compounds of formulas (5) and (Ic) can be respectively obtained (figure 1) from compounds of formulas (3) and (8) by re who work with 2.4-thiazolidinedione in the presence of piperidineacetate in an alcohol solvent, such as ethanol or toluene. Compounds of the formulas (3) and (8) can be respectively obtained (figure 1) from galoidoproizvodnykh formulas (1) and (7), preferably iodine or bromine derivatives by reactions combination reactions with Suzuki Bronevoy acid of the formula (2). This reaction is carried out in the presence of a catalyst based on palladium, as, for example, tetrakis(triphenylphosphine)palladium, according to the conditions described N.Miyaura and others, Synthetic Communications,11(7), 513-519 (1981).

Boranova derivatives of the formula (2) can be obtained from the appropriate galoidoproizvodnykh (preferably iodine or bromine derivatives), first by protecting the aldehyde group in the form of an acetal, followed by transformation in litiisoderzhashchego derivative, reaction with trimethylboron and hydrolysis.

Derivatives of formula (Ib) can be obtained (figure 2) of the aldehyde derivative of formula (9) according to the reaction type Horner with lithium or patripassianism phosphonate of the formula (10), followed by hydrogenation in the presence of palladium-on-coal and saponification of ester to acid.

Derivatives of formula (Id) can be obtained (figure 2) through a series of reactions under the conditions described S.Doulut etc., J. Med. Chem.,36, 1369-1379 (1993).

Derivatives of formula (Ie) can be obtained (figure 2) through a series of reactions under the conditions described H.Shinkai etc., J. Med. Chem.,41, 1927-1933 (1998).

Derivatives of formula (If) mouthbut obtained (figure 2) through a series of reactions in terms described B.Hulin etc., J. Med. Chem.,39, 3897-3907 (1996).

When R1includes a carboxyl group, compounds obtained by protecting R1the protective group of the alkyl type with 1-12 carbon atoms, allyl, benzyl or tert-Putilkovo type. The transition to a free form can be made:

in the case of protective alkyl group with 1-12 carbon atoms with sodium hydroxide or lithium hydroxide in an alcohol solvent such as methanol, or tetrahydrofuran;

in the case of allyl protective group using a catalyst, such as certain transition metal complexes, in the presence of a secondary amine, such as morpholine;

- in the case of the benzyl protective group by dibenzylamine in the presence of hydrogen using a catalyst such as palladium-on-coal;

in case the protective group is tert-Putilkovo type - using trimethylsilane.

Compounds according to the invention have the properties of activated receptors type PPARγ.

Under activator receptor type PPARγ understand according to the invention is any compound concentration of 1 μm in test development, such as described Kliewer and others, Nature,358, 771-774 (1992), shows the percentage of activation of PPARγat least 20%, calculated with respect to the standard connection, SB 219994, to enable the interested PPARγ 100%.

Preferably the activator receptor type PPARγ shows the percentage of activation is higher or equal to 40% and preferably higher than or equal to 70%.

Preferably the activator receptor type PPARγ is specific, i.e. it is the ratio of percent activated receptor type PPARγ the percentage activation of PPARα (calculated with respect to the standard connection, Wy 14643, activating PPARα 100%) is higher or equal to 3. This ratio is preferably greater than or equal to 5 and more preferably greater than or equal to 10.

Affinity derivatives to human PPAR receptor PPARγ it was also determined in the test for binding by comparing with the fixation of the standard agonist, tritium-labeled BRL 49653. For separating the ligand bound to the receptor, from free ligand was used the method of adsorption on hydroxylapatite gel. The human receptor PPARγ was obtained from insect cells Sf9 infected with recombinant baculovirus. The results are expressed as the values of Kd (nmol), which represents the dissociation constant at equilibrium, we obtain for each connection. Under ligand of PPARγ understand any connection according to the invention, having a Kd value below 10000 nmol. Compounds according to the invention preferably have a value Kd 1000 nmol and mainly below 100 nmol.

The object of the present invention is a medicinal product, which are compounds of formula (I)described above.

Compounds according to the invention are particularly well suited in the following areas of treatment:

1) for treating dermatological diseases associated with disorders of keratinization affecting differentiation and proliferation, in particular for the treatment of ordinary, youth, polymorphic, pink acne; nodular-cystic, nodular acne; senile acne, secondary acne such as solar, drug or occupational acne;

2) for treating other types of disorders of keratinization, in particular ichthyosis, idiotphone States, disease Daria, Palmar-plantar keratoderma, leukoplakia and makoplasty States, skin Stripping or Stripping of the mucosa (oral lichen);

3) for treating other dermatological diseases with inflammatory immunoallergic component, with or without violation of disorders of cell proliferation, especially all forms of psoriasis, whether it is a cutaneous, mucosal or ungual, and even psoriatic rheumatism, or cutaneous atopy, such as eczema, respiratory atopy or gingival hypertrophy;

4) for treating all dermal or epidermal of proliferate as dobrokachestven the data and malignant viral or non-viral, such as ordinary simple warts, flat warts and resembling a wart epidermodysplasia, oral or Floridia papillomatosis, lymphoma T, and proliferate, which can be provoked by ultraviolet rays, in particular, in the case of basic - and speckletone of epithelium, as well as any pre-cancerous skin lesions, such as keratoacanthoma;

5) for treating other dermatological disorders such as immune dermatoses, such as lupus erythematosus, bullous immune diseases and collagen diseases such as scleroderma;

6) in the treatment of dermatological or General diseases with an immunological component;

7) in the treatment of skin disorders caused by being under the influence of ultraviolet radiation, as well as to restore or fight against skin aging, whether it is photo-induced or age or to reduce pigmentations and actinic keratoses, or any pathologies associated with age or actinic aging, such as xerosis;

8) to fight against violations of fat options, such as acne affected Hyperborea or simple seborrhoea;

9) for the prevention or treatment of impaired wound healing or to prevent or recover scars n the skin when it is stretched;

10) in the treatment of pigmentation disorders such as hyperpigmentation, melasma, hypopigmentation or vitiligo;

11) in the treatment of lipid metabolism disorders, such as obesity, hyperlipidemia, or non-insulin-dependent diabetes;

12) in the treatment of inflammatory diseases such as arthritis;

13) in the treatment or prevention of cancerous or precancerous conditions;

14) in the prevention or treatment of alopecia of various origins, in particular, alopecia, resulting from chemotherapy or irradiation;

15) in the treatment of immune system disorders, such as asthma, diabetes type I, multiple sclerosis, or other selective dysfunctions related to the immune system;

16) in the treatment of diseases of the cardiovascular system such as arteriosclerosis or hypertension.

The object of the present invention is also a pharmaceutical or cosmetic composition comprising in a physiologically acceptable medium at least one compound of formula (I), such as the above.

The object of the present invention is also the use of compounds of formula (I) to obtain a composition intended for the treatment of the above diseases, in particular for regulating and/or restoring the metabolism of skin lipids.

The composition according invented the Y. you can enter enterline, parenterally, locally or ocular. The pharmaceutical composition is preferably packaged in a form suitable for the application of a local path.

Introduced by enteral composition, in particular pharmaceutical composition, may be in the form of tablets, gelatin capsules, pills, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipid or polymeric visicol that allows for controlled release. Injected parenterally, the composition may be in the form of solutions or suspensions for perfusion or for injection.

Compounds according to the invention is usually administered in a daily dose of about 0.001 to 100 mg/kg body weight and for 1-3 reception.

Compounds are used systematically in a concentration of usually from 0.001% to 10%, preferably from 0.01% to 1% by weight of the composition.

Introduced by local pharmaceutical composition according to the invention is intended in particular for the treatment of skin and mucous membranes and may be in the form of ointments, creams, jelly, lipstick, powders, impregnated swabs, solutions, gels, sprays, lotions or suspensions. It can also be in the form of microspheres or nanospheres or lipid or polymeric visicol or polymeric patches and hydrogels allowing controlled release. This enter the traveler by local composition can be in anhydrous form, in aqueous form or in the form of an emulsion.

Connections use a local path in a concentration of usually from 0.001% to 10%, preferably from 0.01% to 1%, by weight of the composition.

The compounds of formula (I) according to the invention also find application in cosmetics, in particular for the hygiene of the body and for hair care, and in particular for regulating and/or restoring the metabolism of skin lipids. In comparison with the known from the prior art products, these compounds of formula (I) have the advantage that they have, in addition to other valuable properties, anti-inflammatory and soothing properties, which makes the connection less irritating and therefore better tolerated.

The object of the invention is therefore also used in the cosmetic composition comprising in a physiologically acceptable medium at least one compound of formula (I) for body hygiene, or for hair care.

Cosmetic composition according to the invention, including cosmetic acceptable carrier, at least one compound of formula (I) or one of its optical or geometric isomers or one of its salts, may be, in particular, in the form of a cream, a milk, a lotion, a gel, microspheres or nanospheres or lipid or polymeric visicol, soap or shampoo.

The concentration of the compound form is s (I) in the cosmetic composition is 0.001-3% by weight of the composition.

The composition described above, can additionally contain inert or even pharmacodynamically active additives or combinations of these additives, and in particular: wetting; depigmenting components such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients additives; moisturizing ingredients like glycerin, PEG-400, thiomorpholine and its derivatives or urea; protivoseborainey or protivougrevoe additives, such as S-carboxymethylcysteine, S-benzylcyanide, their salts or their derivatives, or benzoyl peroxide; antifungal agents such as ketoconazole or polymethylene-4,5-isothiazolinone-3; antibacterial agents; carotenoids and, in particular, β-carotene; antipsoriatics components, such as anthralin and its derivatives; eicosa-5,8,11,14-terrainia acid and eicosa-5,8,11-tarinoita acid, their esters and amides, and, finally, the retinoids. The compounds of formula (I) can also be combined with vitamin D or its derivatives, corticosteroids, preventing the formation of free radicals components, α-hydroxy - or α-keto acid or their derivatives, or blockers of ion channels.

These compositions can also contain agents that enhance the taste, preservatives such as esters of p-hydroxybenzoic acid, stabilizers, humidity regulators, regulatory pH, the osmotic pressure modifiers, emulsifiers, filters, UV-a and UV-B, antioxidants, such as α-tocopherol, butylhydroxyanisole or equivalent.

Of course, the specialist must choose a possible connection or potential connection to be added to these compositions, so that they do not worsen or do not materially impair the valuable properties, in accordance with the present invention.

Below are given as an illustration and is not limiting of the scope of protection of the present invention, several examples of active compounds of the formula (I) according to the invention, and the results of determination of biological activity of such compounds and various concrete compositions based on these compounds.

Example 1

N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzamide

(a) tert-Butyl(3-bromobenzyl)carbamate

Into the flask in a stream of nitrogen injected 15 g (67 mmol) of 3-bromobenzimidazole, and 9.4 ml (67 mmol) of triethylamine and 150 ml of dichloromethane. At room temperature add small portions of 15.5 ml (67 mmol) of di-tert-BUTYLCARBAMATE and stirred for three hours. Reaction medium was poured into ice water, extracted with dichloromethane, the organic phase is decanted, dried over magnesium sulfate, the issue is more. Obtain 19.3 g (100%) of the expected product.

(b) tert-Butyl(3-bromobenzyl)-N-methylcarbamate

Into the flask in a stream of nitrogen injected 19.3 g (67 mmol) of tert-butyl(3-bromobenzyl)carbamate and 200 ml of tetrahydrofuran. Add small portions of 3 g (74 mmol) of sodium hydride (60%in oil) and stirred until the gas evolution stops. Then add 4.6 ml (74 mmol) under the conditions and stirred for one hour. The reaction medium is poured into a mixture of ice water, extracted with ethyl acetate, the organic phase is decanted, dried over magnesium sulfate, and evaporated. Gain of 20.4 g (100%) of the expected product.

(C) (3-Bromobenzyl)methylamine

Into the flask in a stream of nitrogen introduced to 20.2 g (67 mmol) of tert-butyl(3-bromobenzyl)-N-methylcarbamate in 100 ml of dichloromethane and added 26 ml (335 mmol) triperoxonane acid. Stirred at room temperature for eight hours and the reaction medium was hydrolized with a saturated solution of potassium carbonate. Extracted with dichloromethane, the organic phase is decanted, washed with water, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira a mixture of dichloromethane and methanol (in the ratio 50:50). After evaporation of the solvents get 9 g (67%) of the expected product.

(d) N-(3-Bromobenzyl)-N-methylbenzamide

Into the flask in a stream of nitrogen is lead 9 g (45 mmol) (3-bromobenzyl)methylamine, 90 ml of tetrahydrofuran and 6.9 ml (50 mmol) of triethylamine. Added dropwise to 5.7 ml (50 mmol) of benzoyl chloride and stirred for one hour. The reaction medium is poured into water, extracted with dichloromethane, the organic phase is decanted, washed with water, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira a mixture of ethyl acetate and heptane (in the ratio 15:85). After evaporation of the solvents gain of 13.7 g (64%) of the expected product.

(e) N-(4'-formylphenyl-3-ylmethyl)-N-methylbenzamide

In a three-neck flask and the atmosphere of argon injected 8,78 g (of 28.9 mmol) of N-(3-bromobenzyl)-N-methylbenzamide, 8.7 g (58 mmol) 4-formylbenzeneboronic acid and 125 ml of toluene. Added dropwise 36 ml of a 2M aqueous solution of potassium carbonate, the reaction medium Tegaserod using argon and add 1 g tetranitropentaerithrite(0)chloride and heated at a temperature of 90°C for 24 hours. The reaction medium is poured into water, extracted with dichloromethane, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (in the ratio 50:50).

After evaporation of the solvents to obtain 7.2 g (75%) of the expected product.

(f) N-[4'-(2,4-Dioxothiazolidine-5-yl is danmeter)biphenyl-3-ylmethyl]-N-methylbenzamide

Into the flask in a stream of nitrogen injected 1.55 g (4.6 mmol) of N-(4'-formylphenyl-3-ylmethyl)-N-methylbenzamide, 610 mg (4.6 mmol) of 2,4-thiazolidinedione, 137 mg piperidineacetate and 60 ml of toluene. Refluxed for five hours and separating the water formed by the nozzle Dean-stark. The reaction medium is cooled, the precipitated precipitate is filtered off and clean it on a column of silica using an eluting mixture of heptane and ethyl acetate (ratio 70:30). After evaporation of the solvents to obtain 1.4 g (70%) of the expected product.

(g) N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzamide

In a three-neck flask injected 1.4 g (3.3 mmol) of N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methylbenzamide, 30 ml of dimethylformamide and 25 ml of ethyl acetate. Reaction medium Tegaserod injected 1.4 g of 10%palladium-on-coal and hydronaut at atmospheric pressure and at a temperature of 60°C. the Reaction medium is filtered, evaporated and the resulting residue purified by chromatography on a column of silica, elwira a mixture of dichloromethane and methanol (in the ratio 99:1). After evaporation of the solvents receive 300 mg (21%) of N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzamide with a melting point of 70-71°C.

Example 2

5-{3'-[(Methylpyridin-2-ylamino)methyl]biphenyl-4-ylmethyl}thiazolidine-2,-dione

(a) (3-Bromobenzyl)methylpyridin-2-ylamine

Into the flask in a stream of nitrogen injected 1.5 g (7.5 mmol) (3-bromobenzyl)of methylamine and 15 ml of 2-herperidin. Refluxed for 8 hours, the reaction medium is evaporated to dryness. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 80:20). After evaporation of the solvents get 1 g (50%) of the expected product.

(b) 3'-[(Methylpyridin-2-ylamino)methyl]biphenyl-4-carbaldehyde

Similar to example 1(e) the method by reaction 475 mg (1.7 mmol) (3-bromobenzyl)methylpyridin-2-ylamine with 386 mg (2.6 mmol) 4-formylbenzeneboronic acid obtain 310 mg (60%) of the expected product.

(C) 5-{3'-[(Methylpyridin-2-ylamino)methyl]biphenyl-4-ylmethylene}thiazolidin-2,4-dione

Similar to example 1(f) the method by reaction of 610 mg (of 1.85 mmol) of 3'-[(methylpyridin-2-ylamino)methyl]biphenyl-4-carbaldehyde with 216 mg (of 1.85 mmol) of 2,4-thiazolidinedione obtain 640 mg (81%) of the expected product.

(d) 5-{3'-[(Methylpyridin-2-ylamino)methyl]biphenyl-4-ylmethyl}thiazolidine-2,4-dione

Similar to example 1(g) the method of 310 mg (0.77 mmol) of 5-{3'-[(methylpyridin-2-ylamino)methyl]biphenyl-4-ylmethylene}thiazolidin-2,4-dione receive 80 mg (26%) 5-{3'-[(methylpyridin-2-ylamino)methyl]biphenyl-4-ylmethyl}thiazolidine-2,4-dione with a melting point 135-136°C.

Example 3

N-[4'-(24-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]benzamide

(a) N-(3-Bromobenzyl)benzamid

Similar to example 1(d) the method by the reaction of 7 g (of 31.6 mmol) 3-bromobenzylamine with 4 ml (34.6 mmol) of benzoyl chloride gain of 9.1 g (100%) of the expected product.

(b) N-(4'-Formylphenyl-3-ylmethyl)benzamide

Similar to example 1(e) the method by reaction of 2 g (6,9 mmol) of N-(3-bromobenzyl)benzamide with 1.6 g (10.3 mmol) of 4-formylbenzeneboronic acid obtain 1.4 g (65%) of the expected product.

(C) N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]benzamide

Similar to example 1(f) the method by reaction of 1 g (3.2 mmol) of N-(4'-formylphenyl-3-ylmethyl)benzamide with 370 mg (3.2 mmol) of 2,4-thiazolidinedione obtain 1.22 g (93%) of the expected product.

(d) N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]benzamide

Similar to example 1(g) methods of 600 mg (1,45 mmol) N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]benzamide receive 200 mg (33%) of N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]benzamide with a melting point 225-226°C.

Example 4

Ethyl-3-{3'-[(benzoylamino)methyl]biphenyl-4-yl}-2-methylpropionate

(a) Ethyl(E)-2-methyl-3-(3'-{[(1-phenylethanol)amino]methyl}biphenyl-4-yl)acrylate

In a three-neck flask in a stream of nitrogen injected 440 mg (11 mmol) of sodium hydride (80%in oil) and 10 ml of tetrahydrofuran. Add dropwise a solution of 2.2 ml of triethyl-2-phosphonopropionic in 10 ml of tetrahydrofuran and then a solution of 3 g (9.1 mmol) of N-(4'-formylphenyl-3-ylmethyl)-N-methylbenzamide (obtained according to example 1(e)) and stirred at room temperature for 3 hours. The reaction medium is poured into water, extracted with dichloromethane, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 70:30). After evaporation of the solvents receive 3 g (80%) of ethyl(E)-2-methyl-3-(3'-{[(1-phenylethanol)amino]methyl}biphenyl-4-yl)acrylate in the form of oil.

(b) Ethyl-3-{3'-[(benzoylamino)methyl]biphenyl-4-yl}-2-methylpropionate

In a three-neck flask injected 2.2 g (5.3 mmol) of ethyl(E)-2-methyl-3-(3'-{[(1-phenylethanol)amino]methyl}biphenyl-4-yl)acrylate and 100 ml of ethyl acetate. Reaction medium Tegaserod administered 450 mg of 10%palladium-on-coal and hydronaut at atmospheric pressure for two hours. Reaction medium was filtered, evaporated and the resulting residue purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 80:20). After evaporation of the solvents to obtain 1.45 g (64%) of ethyl-3-{3'-[(benzoylamino)methyl]biphenyl-4-yl}-2-methylpropionate in the form of oil.

Example 5

2-Methyl-3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)propionic acid

Into the flask is administered 1,25 g (3 mmol) of ethyl-3-{3'-[(benzoylamino)methyl]biphenyl-4-yl}-2-methylpropionate, 3 ml 10h. the sodium hydroxide solution, 32 ml of tetrahydrofuran and 2 ml of methanol. Boil the t under reflux for 8 hours, the reaction medium is poured into water, extracted with dichloromethane, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 60:40). Receive 900 mg (90%) of 2-methyl-3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)propionic acid with a melting point 60-61°C.

Example 6

N-[4'-(2-Carbamoylethyl)biphenyl-3-ylmethyl]-N-methylbenzamide

(a) 3-(3'-{[Methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)propionate

By reaction of 1.6 g (4.1 mmol) of 2-methyl-3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)propionic acid with 390 μl (4.5 mmol) of oxalicacid in dichloromethane after evaporation obtain 1.7 g (100%) 3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)propionitrile.

(b) N-[4'-(2-Carbamoylethyl)biphenyl-3-ylmethyl]-N-methylbenzamide

By reaction of a solution of 1.7 g (4.1 mmol) of 3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)Propionaldehyde in 5 ml of tetrahydrofuran, 10 ml of ammonium hydroxide after purification by chromatography on a column of silica receive 200 mg (32%) of N-[4'-(2-carbamoylethyl)biphenyl-3-ylmethyl]-N-methylbenzamide with a melting point 47-48°C.

Example 7

N-Methyl-N-[4'-(2-phenylcarbamoyloxy)biphenyl-3-ylmethyl]benzamide

By reaction RA is down 637 mg (1.6 mmol) of 3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)Propionaldehyde in 5 ml of tetrahydrofuran with 146 μl (1.6 mmol) of benzylamine in the presence of 250 μl (1.8 mmol) of triethylamine after purification by chromatography on a column of silica obtain 370 mg (50%) N-methyl-N-[4'-(2-phenylcarbamoyloxy)biphenyl-3-ylmethyl]benzamide with a melting point of 68-69°C.

Example 8

N-[4'-(2-Hydroxycarbamoyl)biphenyl-3-ylmethyl]-N-methylbenzamide

By reaction of a solution of 669 mg (1,65 mmol) 3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)propionitrile in 6 ml of tetrahydrofuran with 243 mg (1,65 mmol) of O-(tert-butyldimethylsilyl)hydroxylamine in the presence of 250 μl (1.8 mmol) of triethylamine, and then removing the protective group using 530 μl of 1N. solution tetrabutylammonium in tetrahydrofuran after purification by chromatography on a column of silica obtain 350 mg (42%) of N-[4'-(2-hydroxycarbamoyl)biphenyl-3-ylmethyl]-N-methylbenzamide with a melting point 65-66°C.

Example 9

1-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-3-prilocaine

(a) 1-(4'-Bromobiphenyl-3-ylmethyl)-3-prilocaine

Into the flask enter 2.9 g (14.5 mmol) of 3-bromobenzylamine, 90 ml of dichloromethane and added dropwise at 1.73 ml (16 mmol) of phenylisocyanate. Stirred at room temperature for eight hours, the reaction medium is poured into water, extracted with dichloromethane, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira mixture hept is on and ethyl acetate (ratio 70:30). Obtain 3.7 g (80%) of the expected product.

(b) 1-(4'-Formylphenyl-3-ylmethyl)-3-prilocaine

Similar to example 1(e) the method by reaction of 2.5 g (8.2 mmol) of 1-(4'-bromobiphenyl-3-ylmethyl)-3-phenylacetone with 1.8 g (12.3 mmol) of 4-formylbenzeneboronic acid obtain 2.1 g (77%) of the expected compound.

(C) 1-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-3-prilocaine

Similar to example 1(f) the method by reaction of 2.1 g (6.4 mmol) of 1-(4'-formylphenyl-3-ylmethyl)-3-phenylacetone with 750 mg (6.4 mmol) of 2,4-thiazolidinedione get 1,43 g (53%) of the expected compound.

(d) 1-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-3-prilocaine

Similar to example 1(g) the method of 1,43 g (3.3 mmol) of 1-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-3-phenylacetone receive 300 mg (21%) of 1-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-3-phenylacetone with a melting point of 70-71°C.

Example 10

1-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-1-methyl-3-prilocaine

(a)tert-Butyl(4'-formylphenyl-3-ylmethyl)methylcarbamate

Similar to example 1(e) the method by reaction of 13.7 g (45 mmol) of tert-butyl(3-bromobenzyl)-N-methylcarbamate (obtained according to example 1(b)) with 10 g (67 mmol) 4-formylbenzeneboronic acid get 11 g (76%) of the expected product.

(b) tert-Butyl[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ILM is Teal]methylcarbamate

Similar to example 1(f) the method by reaction of 8 g (25 mmol) of tert-butyl(4'-formylphenyl-3-ylmethyl)methylcarbamate with 2.9 g (25 mmol) of 2,4-thiazolidinedione obtain 8.6 g of the expected product.

(C) 5-(3'-Methylaminomethyl-4-ylidenemethyl)thiazolidin-2,4-dione

Into the flask is administered 2 g (4.7 mmol) of tert-butyl[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]methylcarbamate and 20 ml dichloromethane. Add 2.2 ml (28,2 mmol) triperoxonane acid and stirred at room temperature for four hours. The reaction medium is poured into the containing hydrogen water, extracted with dichloromethane, the organic phase is decanted, dried over magnesium sulfate, and evaporated. Obtain 1.3 g (85%) of the expected product.

(d) 1-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-1-methyl-3-prilocaine

For a similar example 9(a) the method by reaction of 300 mg (0.9 mmol) of 5-(3'-methylaminomethyl-4-ylmethylene)thiazolidine-2,4-dione with 190 μl (1.8 mmol) of phenylisocyanate receive 450 mg (98%) of the expected product.

(e) 1-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-1-methyl-3-prilocaine

Similar to example 1(g) the method of 450 mg (0.8 mmol) of 1-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-1-methyl-3-phenylacetone receive 100 mg (28%) of 1-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-1-methyl-3-phenylacetone with temperature p is Alenia 70-71° C.

Example 11

tert-Butyl[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamate

Similar to example 1(g) the methodology of 500 mg (1.2 mmol) of tert-butyl[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]methylcarbamate (obtained according to example 10(b)) receive 250 mg (49%) of tert-butyl[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamate with a melting point 45-46°C.

Example 12

N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnonanoic

(a) N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methylnonanoic

Similar to example 1(d) the method by reaction of 500 mg (0.9 mmol) of 5-(3'-methylaminomethyl-4-ylmethylene)thiazolidine-2,4-dione with 330 μl (1.8 mmol) of nonrailroad obtain 350 mg (66%) of the expected product.

(b) N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylnonanoic

Similar to example 1(g) the method of 330 mg (0.7 mmol) of N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methylmaleimide receive 70 mg (21%) of N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylmaleimide.

Example 13

(S)-2-Ethoxy-3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)propionic acid

(a) N-{4'-[(1R,2S)-3-((S)-4-Benzyl-2-oxoacridine-3-yl)-2-ethoxy-1-hydroxy-3-oxopropyl]biphenyl-3-ylmethyl}-N-methylbenzamide

In a three-neck flask in an argon atmosphere BB is out of 1.76 g (6.7 mmol) of (S)-4-benzyl-3-(2-ethoxyethanol)oxazolidin-2-she and 15 ml of dichloromethane. At a temperature of 0°With added dropwise sequentially 7.3 ml (8 mmol) dibutylnitrosamine and 1.3 ml (8 mmol) of diisopropylethylamine and stirred for one hour. At a temperature of -78° add a solution of 2 g (6 mmol) of N-(4'-formylphenyl-3-ylmethyl)-N-methylbenzamide (obtained according to example 1(e)) in 25 ml dichloromethane and stirred for one hour. Leave the temperature to rise to 0°and treated using a buffer solution with a pH of 7 (16 ml) in 45 ml of methanol, then with hydrogen peroxide solution (16 ml) in 45 ml of methanol and stirred for one hour at a temperature of 0°C. the Reaction medium is poured into water, extracted with dichloromethane, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 60:40). Obtain 1.7 g (48%) of N-{4'-[(1R,2S)-3-((S)-4-benzyl-2-oxoacridine-3-yl)-2-ethoxy-1-hydroxy-3-oxopropyl]biphenyl-3-ylmethyl}-N-methylbenzamide.

(b) N-{4'-[(S)-3-((S)-4-Benzyl-2-oxoacridine-3-yl)-2-ethoxy-3-oxopropyl]biphenyl-3-ylmethyl}-N-methylbenzamide

In a three-neck flask in a stream of nitrogen injected 320 μl (2.6 mmol) of epirate of boron TRIFLUORIDE and 5 ml dichloromethane. At a temperature of 0°With added dropwise to 800 ml (5 mmol) of trimethylsilane, then malen is Kimi portions 380 mg (0.64 mmol) of N-{4'-[(1R,2S)-3-((S)-4-benzyl-2-oxoacridine-3-yl)-2-ethoxy-1-hydroxy-3-oxopropyl]biphenyl-3-ylmethyl}-N-methylbenzamide. After standing for one hour at room temperature, heated at a temperature of 50°C for 20 hours. The reaction medium is poured into water, extracted with ethyl acetate, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 70:30). Get 280 mg (76%) of the expected product.

(s) (S)-2-Ethoxy-3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)propionic acid

Into the flask is administered 600 mg (1 mmol) N-{4'-[(S)-3-((S)-4-benzyl-2-oxoacridine-3-yl)-2-ethoxy-3-oxopropyl]biphenyl-3-ylmethyl}-N-methylbenzamide and 10 ml of tetrahydrofuran. At a temperature of 0°add to 4.2 ml (2 mmol) of 0.5 M aqueous solution of lithium hydroxide and stirred for one hour. The reaction medium is poured into water, acidified to pH 1, extracted with ethyl acetate, the organic phase is decanted, dried over magnesium sulfate, and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (in the ratio 50:50). Receive 200 mg (47%) of (S)-2-ethoxy-3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)propionic acid with a melting point 53-54°C.

Example 14

Monomethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)is the responsibility of the t

(a) Diethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethylene)malonate

In a three-neck flask in a stream of nitrogen injected 0,58 g (1.8 mmol) of N-(4'-formylphenyl-3-ylmethyl)-N-methylbenzamide (obtained as described in example 1(e)), 10 ml of toluene, 0.3 ml (1.8 mmol) of diethylmalonate and 50 mg (0.35 mmol) of piperidineacetate. Refluxed for 6 hours, separating the water formed by the nozzle Dean-stark. The reaction medium is cooled, extracted with ethyl acetate, washed with water. The organic phase is decanted, dried over magnesium sulfate, and evaporated. The crude product is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (75:25 ratio). After evaporation of the solvents to obtain 0.7 g (84%) of the expected product.

(b) Diethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonate

In a three-neck flask in a stream of nitrogen injected 0.7 g (1.5 mmol) of diethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethylene)malonate, 7 ml of tetrahydrofuran and 1 ml of methanol. Reaction medium Tegaserod, enter 80 mg of 5%palladium-on-coal and hydronaut at atmospheric pressure at room temperature for 20 hours. The reaction medium is filtered through celite, evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl is the Etat (in the ratio 80:20). After evaporation of the solvents to obtain 0.45 g (63%) of the desired product.

(C) Monomethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonate

The flask 0.4 g (0.85 mmol) of diethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethylene)malonate, 5 ml of methanol and 0.1 g of potassium carbonate. Stirred at room temperature for 18 hours, acidified to pH 3 with sulfuric acid and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 70:30). After evaporation of the solvents to obtain 0.16 g (44%) of the expected product with a melting point 67°C.

Example 15

Dimethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonate

(a) Dimethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethylene)malonate

In a three-neck flask in a stream of nitrogen injected 1.4 g (of 4.25 mmol) of N-(4'-formylphenyl-3-ylmethyl)-N-methylbenzamide (obtained as described in example 1(e)), 20 ml of toluene, 0.56 g (of 4.25 mmol) diethylmalonate and 125 mg (0.85 mmol) of piperidineacetate. Refluxed for 6 hours, separating the water formed by the nozzle Dean-stark. The reaction medium is cooled, extracted with ethyl acetate, washed with water. The body is ical phase is decanted, dried over magnesium sulfate, and evaporated. The crude product is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 70:30). After evaporation of the solvents to obtain 1.4 g (75%) of the expected product.

(b) Dimethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonate

In a three-neck flask in a stream of nitrogen injected 1.3 g (2.9 mmol) of dimethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethylene)malonate, 10 ml of dioxane and 2 ml of methanol. Reaction medium Tegaserod, enter 80 mg of 5%palladium-on-coal and hydronaut at atmospheric pressure at room temperature for 8 hours. The reaction medium is filtered through celite, evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 60:40). After evaporation of the solvents get 1 g (78%) of the expected product in the form of oil.

Example 16

Methyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonamate

(a) Dimethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethylene)malonate

In a three-neck flask in a stream of nitrogen injected 1.54 g (of 4.25 mmol) of N-(4'-formylphenyl-3-ylmethyl)-N-methylbenzamide (obtained as described in example 1(e)), 20 ml of toluene, 0.56 g (of 4.25 mmol) diethylmalonate and 123 mg (0.85 mmol) of piperidineacetate. Boil reverse the fridge for 5 hours, separating the water formed by the nozzle Dean-stark. The reaction medium is cooled, extracted with ethyl acetate, washed with water. The organic phase is separated, dried over magnesium sulfate, and evaporated. The crude product is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 70:30). After evaporation of the solvents to obtain 1.4 g (75%) of the expected product.

(b) Dimethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonate

In a three-neck flask in a stream of nitrogen injected 1.3 g (2.9 mmol) of dimethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethylene)malonate, 10 ml of dioxane and 2 ml of methanol. Added 76 mg of 5%palladium-on-charcoal, hydronaut at atmospheric pressure for 8 hours. The reaction medium is filtered through celite, evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 60:40). Get 1 g (78%) of the expected product.

(c) Monomethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonate

Into the flask enter 0,92 g (2 mmol) of dimethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonate, 4 ml of tetrahydrofuran and 8 ml of methanol. At a temperature of 0°With added dropwise to 0.24 ml (2.1 mmol) of 35%aqueous sodium hydroxide solution. Mix in to use the e 18 hours, the reaction medium is poured into water, acidified to pH 4-5 with 1N. hydrochloric acid, extracted with ethyl acetate. After decanting, the organic phase is dried over magnesium sulfate, filtered, evaporated. Get 0,82 g (92%) of the expected product.

(d) Methyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonamate

In a three-neck flask in a stream of nitrogen injected 0,78 g (1.8 mmol) monomethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonate, 8 ml dichloromethane. At a temperature of 0°With added dropwise to 0.18 ml (2 mmol) of oxalicacid, then stirred for 4 hours. The reaction medium is evaporated to dryness, the residue bring in 2 ml acetone and 1 ml of 32%aqueous ammonium hydroxide solution. Stirred at room temperature for 2 hours, the reaction environment contribute in water, acidified to pH 5, extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, evaporated. The obtained residue is washed with a mixture of heptane and diethyl ether (in the ratio 50:50). Obtain 0.4 g (52%) of the expected product with a melting point 62°C.

Example 17

N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-ethylbenzamide

(a) N-(3-Bromobenzyl)benzamid

In a three-neck flask in a stream of nitrogen injected 7 g (of 31.6 mmol) 3-bromobenzylamine, 100 ml of tetrahydrofuran, and 9.6 ml (69,2 mmol) of triethylamine. Add Kaplan ml (34.6 mmol) of benzoyl chloride and stirred at room temperature for 1 hour. The reaction medium is extracted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered, evaporated. Gain of 9.2 g (100%) of the desired product.

(b) N-(4'-Formylphenyl-3-ylmethyl)benzamide

Similar to example 1(e) the method by reaction of 7.4 g (25,4 mmol) of N-(3-bromobenzyl)benzamide with 5.7 g (38,2 mmol) 4-formylbenzeneboronic acid get 4 g (50%) of the expected product.

(C) N-(4'-[1,3]Dioxolane-2-iluvenis-3-ylmethyl)benzamide

In a three-neck flask in a stream of nitrogen injected 3.2 g (10 mmol) of N-(4'-formylphenyl-3-ylmethyl)benzamide, 50 ml of toluene and 2.8 ml (50 mmol) of ethylene glycol and 38 mg (0.2 mmol) of p-toluenesulfonic acid. The reaction medium is refluxed for 3 hours and the water formed is separated by the nozzle Dean-stark. Extracted with dichloromethane, washed with water, the organic phase is decanted. The organic phase is dried over magnesium sulfate, filtered, evaporated. Obtain 3.7 g (100%) of the expected product.

(d) N-(4'-[1,3]Dioxolane-2-iluvenis-3-ylmethyl)-N-ethylbenzamide

In a three-neck flask in a stream of nitrogen injected with 0.6 g (1.7 mmol) of N-(4'-[1,3]dioxolane-2-iluvenis-3-ylmethyl)benzamide, 5 ml of tetrahydrofuran and 206 mg (of 1.85 mmol) of potassium tert-butylate. Added dropwise 0.3 ml (3.7 mmol) of iodata. Stirred at room temperature for 3 hours, extracted with ethyl acetate, washed with water, dried over sulfate is Agnes, filtered and evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 70:30). Obtain 0.4 g (64%) of the desired product.

(e) N-Ethyl-N-(4'-formylphenyl-3-ylmethyl)benzamide

Into the flask is injected 0.4 g (1 mmol) of N-(4'-[1,3]dioxolane-2-iluvenis-3-ylmethyl)-N-ethylbenzamide, 5 ml of methanol, 2 g of silicon dioxide and a few drops of sulfuric acid. Stirred at room temperature for 24 hours. The reaction medium is poured into water, extracted with dichloromethane, the organic phase is decanted, dried over magnesium sulfate, and evaporated. Obtain 0.32 g (91%) of the expected product.

(f) N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-ethylbenzamide

Similar to example 1(f) the method by reaction of 0.3 g (0.9 mmol) of N-ethyl-N-(4'-formylphenyl-3-ylmethyl)benzamide with 0.1 g (0.9 mmol) of 2,4-thiazolidinedione obtain 0.34 g (88%) of the expected product.

(g) N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-ethylbenzamide

Similar to example 1(g) methods of 0.3 g (0.7 mmol) of N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-ethylbenzamide in 10 ml of tetrahydrofuran obtain 0.15 g (50%) N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-ethylbenzamide with a melting point 157°C.

Example 18

N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-p is etilbenzene

(a) N-(4'-[1,3]Dioxolane-2-iluvenis-3-ylmethyl)-N-pentylbenzene

Similar to example 17(d) method of 1 g (2.8 mmol) of N-(4'-[1,3]dioxolane-2-iluvenis-3-ylmethyl)benzamide and 2.4 ml (to 18.3 mmol) iodopentane obtain 0.6 g (50%) of N-(4'-[1,3]dioxolane-2-iluvenis-3-ylmethyl)-N-pentylbenzene.

(b) N-(4'-Formylphenyl-3-ylmethyl)-N-pentylbenzene

Similar to example 17(e) method of 0.55 g (1.2 mmol) of N-(4'-[1,3]dioxolane-2-iluvenis-3-ylmethyl)-N-pentylbenzene obtain 0.4 g (82%) of N-(4'-formylphenyl-3-ylmethyl)-N-pentylbenzene.

(C) N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-pentylbenzene

Similar to example 1(f) the method by reaction of 0.32 g (0.8 mmol) of N-(4'-formylphenyl-3-ylmethyl)-N-pentylbenzene with 0.1 g (0.8 mmol) of 2,4-thiazolidinedione obtain 0.35 g (87%) of the expected product.

(d) N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-pentylbenzene

Similar to example 1(g) the method of 0.33 g (0.7 mmol) of N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-pentylbenzene in 10 ml of ethyl acetate and 10 ml of ethanol 0,22 g (65%) of N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-pentylbenzene with a melting point 57°C.

Example 19

tert-Butyl[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]ethylcarbamate

(a) tert-Butyl(3-bromobenzyl)ethylcarbamate

Similar to example 17(d) method of 3 g (10.5 mmol) of tert-is util-(3-bromo-benzyl)carbamate (obtained, as indicated in example 1(a)) and 4.2 ml (52,5 mmol) iodata obtain 3.2 g (97%) of the expected product.

(b) tert-Butyl ethyl-(4'-formylphenyl-3-ylmethyl)carbamate

Similar to example 1(e) the method by reaction of 3.2 g (10 mmol) of tert-butyl(3-bromobenzyl)ethylcarbamate with 2.3 g (15 mmol) 4-formylbenzeneboronic acid obtain 1.4 g (41%) of the expected product.

(C) tert-Butyl[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]ethylcarbamate

Similar to example 1(f) the method by reaction of 1.35 g (4 mmol) of tert-butyl ethyl-(4'-formylphenyl-3-ylmethyl)carbamate from 0.47 g (4 mmol) of 2,4-thiazolidinedione obtain 1.6 g (92%) of the expected product.

(d) tert-Butyl[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]ethylcarbamate

Similar to example 1(g) methods of 0.5 g (1.15 mmol) of tert-butyl[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]ethylcarbamate in 5 ml of ethyl acetate to obtain 0.1 g (20%) of the expected product with a melting point 103°C.

Example 20

tert-Butyl[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]propellernet

(a) tert-Butyl[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]carbamate

Similar to example 1(f) the method by reaction of 7.4 g (24 mmol) of tert-butyl(4'-formylphenyl-3-ylmethyl)carbamate (obtained as described in example 1(e) of tert-butyl(3-bromobenzyl)carbamate) with 2.8 g (24 mmol) of 2,4-thiazolidine is to get 9 g (95%) of the expected product.

(b) tert-Butyl[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]propellernet

Similar to example 17(d) method of 0.7 g (1.7 mmol) of tert-butyl[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]carbamate and 0.35 ml (3.8 mmol) of 1-bromopropane obtain 0.6 g (78%) of the expected product.

(C) tert-Butyl[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]propellernet

Similar to example 1(g) the method of 0.6 g (1.3 mmol) of tert-butyl[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]propylgallate in 7 ml of ethyl acetate and 7 ml of dimethylformamide receive 50 mg (10%) of the expected product.

Example 21

N-Fluoren-9-ylmethyl-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamate

(a) N-Fluoren-9-ylmethyl-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]methylcarbamate

Into the flask is injected 0.5 g (0.9 mmol) of 5-(3'-methylaminomethyl-4-ylmethylene)thiazolidine-2,4-dione in 12 ml of 10%aqueous sodium carbonate solution. At a temperature of 0°With added dropwise a solution of 0.24 g N-fluoren-9-iletileri in 5 ml of dioxane. Stirred at a temperature of from 0°C to room temperature for 4 hours. Reaction medium contribute in the water and after acidification to pH 4 extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, evaporated. Get 0,49 g (100%) of the expected product.

(b) N-FL the Oren-9-ylmethyl-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamate

Similar to example 1(g) methods of 0.5 g (0.9 mmol) N-fluoren-9-ylmethyl-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]methylcarbamate in 10 ml of dioxane obtain 0.2 g (40%) of the expected product with a melting point 94°C.

Example 22

N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-2,2,N-trimethylpropane

(a) N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-2,2,N-trimethylpropane

Similar to example 1(d) the method by reaction of 0.5 g (0.9 mmol) of 5-(3'-methylaminomethyl-4-ylmethylene)thiazolidine-2,4-dione with 0.3 ml (2.3 mmol) of 2,2-dimethylpropanamide obtain 0.24 g (65%) of the expected product.

(b) N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-2,2,N-trimethylpropane

Similar to example 1(g) the method of 0.24 g (0.6 mmol) N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-2,2,N-trimethylpropane in 20 ml of tetrahydrofuran receive 0.1 g (40%) of the expected product with a melting point 78°C.

Example 23

N-Octyl-4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-carboxamide

(a) Ethyl-4'-formylphenyl-3-carboxylate

Similar to example 1(e) the method by reaction of 12.6 ml (79 mmol) of ethyl-3-bromobenzoate with 15 g (100 mmol) 4-formylbenzeneboronic acid get 12 g (60%) of the expected product.

(b) Ethyl-4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-carboxylate

On analogues of the Noi to example 1(f) the method by reaction of 11.7 g (46 mmol) of ethyl-4'-formylphenyl-3-carboxylate from 5.4 g (46 mmol) of 2,4-thiazolidinedione get 13 g (83%) of the expected product.

(C) 4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-carboxylic acid

Into the flask enter of 12.6 g (37 mmol) of ethyl-4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-carboxylate, 150 ml of tetrahydrofuran, 15 ml of methanol, a few drops of water and 7.4 g (186 mmol) of sodium hydroxide in pastilles. Refluxed for 18 hours. Reaction medium contribute in water, acidified to pH 2, extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, evaporated. Obtain 11.4 g (94%) of the expected product.

(d) N-Octyl-4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-carboxamide

In a three-neck flask in a stream of nitrogen introduced 1 g (3.1 mmol) of 4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-carboxylic acid, 15 ml of dimethylformamide, and 0.46 g (3.4 mmol) of 1-hydroxybenzotriazole and 0.5 ml (3.1 mmol) of n-octylamine. At a temperature of 0°With portions add 0,59 g (3.4 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Stirred for three days with increasing temperature. The reaction medium is poured into water and extracted with ethyl acetate, dried over magnesium sulfate, filtered, evaporated. Obtain 0.45 g (33%) of the expected product.

(e) N-Octyl-4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-carboxamide

In the reactor in a stream of nitrogen injected with 0.15 g (0.35 mmol) of N-octyl-4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-carboxamide, 20 ml dim teleformula and 150 mg of 10%palladium-on-charcoal grill. The environment is heated to a temperature of 80°and hydronaut at a pressure of 3 ATM for 5 hours. The reaction medium is filtered through celite. The filtrate bring into water, extracted with ethyl acetate and rinsed with water. The organic phase is dried over magnesium sulfate, filtered, evaporated. The remainder chromatographic on a column of silica, elwira with a mixture of heptane and ethyl acetate (ratio 30:70). Get 0.1 g (65%) of the expected product with a melting point 137-138°C.

Example 24

N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-3-phenylpropionamide

(a) N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methyl-3-phenylpropionamide

Similar to example 1(d) the method by reaction of 0.5 g (0.9 mmol) of 5-(3'-methylaminomethyl-4-ylmethylene)thiazolidine-2,4-dione from 0.35 ml (2.3 mmol) of 3-phenylpropionylamino get 0,22 g (54%) of the expected product.

(b) N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-3-phenylpropionamide

Similar to example 1(g) the method of 0.21 g (0.45 mmol) of N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methyl-3-phenylpropionamide in 15 ml of tetrahydrofuran obtain 95 mg (45%) of the expected product with a melting point of 325°C.

Example 25

2-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-yl]-N-methyl-N-phenylacetamide

(a) 2-(3-Bromophenyl)-N-methyl-N-phenylacetamide

In t is eagerly flask in a stream of nitrogen injected 6 g (28 mmol) (3-bromophenyl)acetic acid in 50 ml of dichloromethane. At a temperature of 0°With added dropwise to 2.7 ml (28 mmol) of oxalicacid, then stirred at room temperature for 18 hours. The reaction medium is evaporated to dryness, the residue bring in 10 ml of tetrahydrofuran and added dropwise to a mixture of 3.2 g (28 mmol) of N-methylaniline, 50 ml of tetrahydrofuran and 4.6 ml (33 mmol) of triethylamine. The reaction medium is stirred at room temperature overnight, bring in water and extracted with ethyl acetate. After decanting, the organic phase is dried over magnesium sulfate, filtered, evaporated. Obtain 5.7 g (67%) of the expected product with a melting point of 60°C.

(b) 2-(4'-Acetylbiphenyl-3-yl)-N-methyl-N-phenylacetamide

Similar to example 1(e) the method by reaction of 2.9 g (9.5 mmol) of 2-(3-bromophenyl)-N-methyl-N-phenylacetamide with 2.2 g (of 14.2 mmol) 4-formylbenzeneboronic acid get 2.25 g (95%) of the expected product.

(C) 2-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-yl]-N-methyl-N-phenylacetamide

Similar to example 1(f) the method by reaction of 1 g (4 mmol) of 2-(4'-acetylbiphenyl-3-yl)-N-methyl-N-phenylacetamide with and 0.46 g (4 mmol) of 2,4-thiazolidinedione obtain 1.2 g (71%) of the expected product.

(d) 2-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-yl]-N-methyl-N-phenylacetamide

Similar to example 1(g) methods of 1.1 g (2.6 mmol) of 2-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-yl]-N-methyl-N-phenylacetamide 20 ml of ethyl acetate and 20 ml of ethanol 0.66 g (60%) of the expected product with a melting point 158° C.

Example 26

N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-propylbenzamide

(a) tert-Butyl(3-bromobenzyl)propellernet

Similar to example 17(d) method of 3 g (10.5 mmol) of tert-butyl(3-bromobenzyl)carbamate, and 1.15 ml (11.5 mmol) of iodopropane get to 3.35 g (97%) of the expected product.

(b) (3-Bromobenzyl)Propylamine

For a similar example 10(C) method of 2 g (6 mmol) of tert-butyl(3-bromobenzyl)propellerblade obtain 1.3 g (92%) of the expected product.

(C) N-(3-Bromobenzyl)-N-propylbenzamide

Similar to example 1(d) the method by reaction of 1.3 g (5.6 mmol) (3-bromobenzyl)Propylamine with 0.7 ml (6.2 mmol) of benzoyl chloride obtain 1.4 g (74%) of the expected product.

(d) N-(4'-Formylphenyl-3-ylmethyl)-N-propylbenzamide

Similar to example 1(e) the method by reaction of 1.4 g (4.2 mmol) of N-(3-bromobenzyl)-N-propylbenzamide from 0.94 g (6.2 mmol) of 4-formylbenzeneboronic acid get 0,78 g (53%) of the expected product.

(e) N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-propylbenzamide

Similar to example 1(f) the method by reaction of 0.58 g (1.6 mmol) of N-(4'-formylphenyl-3-ylmethyl)-N-propylbenzamide from 0.19 g (1.6 mmol) of 2,4-thiazolidinedione gain of 0.53 g (72%) of the expected product with a melting point 250-251°C.

Example 27

tert-Butyl[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-yl]carbamate

(a) tert-Butyl(3-bromphen the l)carbamate

In a three-neck flask in a stream of nitrogen injected 19 ml 3-bromoaniline in 300 ml of tetrahydrofuran. Added in several portions of 8.4 g (209 mmol) of sodium hydride (60%in oil) and stirred until the gas evolution stops. Then added dropwise 38 g (of 174.5 mmol) di-tert-BUTYLCARBAMATE. Refluxed for 36 hours. The reaction environment contribute into water, extracted with ethyl acetate. After decanting, the organic phase is dried over magnesium sulfate, filtered, evaporated. Get 43 g (92%) of the expected product.

(b) tert-Butyl(4'-formylphenyl-3-yl)carbamate

Similar to example 1(e) the method by reaction 19.3 g (71 mmol) of tert-butyl(3-bromophenyl)carbamate with 16 g (107 mmol) 4-formylbenzeneboronic acid get 21 g (63%) of the expected product.

(C) tert-Butyl[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-yl]carbamate

Similar to example 1(f) the method by reaction of 9.5 g (32 mmol) of tert-butyl(4'-formylphenyl-3-yl)carbamate from 3.8 g (32 mmol) of 2,4-thiazolidinedione obtain 12.7 g (91%) of the expected product.

(d) tert-Butyl[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-yl]carbamate

Similar to example 1(g) the method of 0.7 g (1.8 mmol) of tert-butyl[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-yl]carbamate in 10 ml of dioxane obtain 0.7 g (60%) of the expected product with a melting point 158°C.

Example 28

N-[4'-(2,4-Diocletian is lidin-5-ylmethyl)biphenyl-3-ylmethyl]-3,4-diethoxy-N-methylbenzamide

(a) N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-3,4-diethoxy-N-methylbenzamide

Similar to example 1(d) the method by reaction of 0.5 g (0.9 mmol) of 5-(3'-methylaminomethyl-4-ylmethylene)thiazolidine-2,4-dione with 0.52 g (2.3 mmol) of 3,4-diethoxybenzoic get 0,37 g (80%) of the expected product.

(b) N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-3,4-diethoxy-N-methylbenzamide

Similar to example 1(g) the method of 0.36 g (0.7 mmol) of N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-3,4-diethoxy-N-methylbenzamide in 15 ml of methanol obtain 0.15 g (40%) of the expected product with a melting point 66°C.

Example 29

Monoamide 2-(3'-{[Methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonic acid

0.18 g (0.4 mmol) of Methyl 2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonamate obtained according to example 16(d), introducing 2 ml of methanol, 2 ml of tetrahydrofuran and 0.25 ml (0.5 mmol) of 2n. an aqueous solution of sodium hydroxide. The reaction medium is stirred at room temperature for 36 hours, acidified to pH 3 with hydrochloric acid, extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, evaporated. Obtain 0.08 g (46%) of the expected product with a melting point 117°C.

Example 30

N-Benzyl-N-methyl-4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-carboxamid the

(a) N-Benzyl-N-methyl-4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-carboxamide

In a three-neck flask in a stream of nitrogen injected 0.5 g (1.54 mmol) of 4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-carboxylic acid obtained according to example 23(C), 5 ml of dimethylformamide, to 0.23 g (1.7 mmol) of 1-hydroxybenzotriazole and 0.2 ml (1.5 mmol) of benzylmethylamine. At a temperature of 0°With portions add 0.35 g (1.7 mmol) of dicyclohexylcarbodiimide. Stirred for 18 hours at the temperature. The reaction environment contribute to water and extracted with ethyl acetate, dried over magnesium sulfate, filtered, evaporated. The obtained residue was washed with dichloromethane, and filtered. Obtain 0.4 g (61%) of the expected product.

(b) N-Benzyl-N-methyl-4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-carboxamide

Similar to example 1(g) the method of 0.4 g (0.9 mmol) of N-benzyl-N-methyl-4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-carboxamide in 5 ml of dioxane obtain 0.17 g (43%) of the expected product with a melting point 66°C.

Example 31

N-Benzyl-4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-carboxamide

(a) N-Benzyl-4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-carboxamide

In a three-neck flask in a stream of nitrogen injected with 0.6 g (of 1.84 mmol) of 4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-carboxylic acid obtained according to example 23(C), 5 ml of dimethylformamide, 0.34 g(2.5 mmol) of 1-hydroxybenzotriazole and 0.25 ml (2.3 mmol) of benzylamine. At a temperature of 0°With portions added to 0.48 g (2.5 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. Stirred for 24 hours with increasing temperature. The reaction environment contribute to water and extracted with ethyl acetate, dried over magnesium sulfate, filtered, evaporated. The obtained residue was washed with dichloromethane, and filtered. Get 0,46 g (60%) of the expected product.

(b) N-Benzyl-4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-carboxamide

Similar to example 1(g) method of of 0.43 g (1 mmol) N-benzyl-4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-carboxamide in 7 ml of dimethylformamide receive 0.1 g (23%) of the expected product with a melting point 148°C.

Example 32

N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-metalmechanic

(a) N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-metalmechanic

Similar to example 1(d) the method by reaction of 1 g (1.8 mmol) of 5-(3'-methylaminomethyl-4-ylidenemethyl)thiazolidin-2,4-dione obtained according to example 10(C), from 0.41 ml (2 mmol) of decanoylamino obtain 0.5 g (60%) of the expected compound.

(b) N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-metalmechanic

Similar to example 1(g) the method of and 0.46 g (1 mmol) N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methylmethanamine in 8 ml of dioxane obtain 0.3 g (65%) expected the second product in the form of a film.

Example 33

N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-yl]-2-phenylacetamide

(a) 5-(3'-Aminobiphenyl-4-ylmethylene)thiazolidine-2,4-dione

For a similar example 10(C) method of 5 g (13 mmol) of tert-butyl[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-yl]carbamate obtained according to example 27(C), gain of 5.2 g (100%) of the expected product.

(b) N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-yl]-2-phenylacetamide

Similar to example 1(d) the method by reaction of 1.2 g (2.3 mmol) of 5-(3'-aminobiphenyl-4-ylmethylene)thiazolidine-2,4-dione from 0.43 ml (3 mmol) of phenylacetylene get 0,92 g (97%) of the expected product.

(C) N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-yl]-2-phenylacetamide

Similar to example 1(g) the method of 0,58 g (1.4 mmol) of N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-yl]-2-phenylacetamide in 10 ml of a mixture of dioxane and methanol (in the ratio 50:50) at a pressure of 3 ATM obtain 0.14 g (15%) of the expected product with a melting point 165°C.

Example 34

N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyloctanoic

(a) N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methyloctanoic

Similar to example 1(d) the method by reaction of 0.5 g (0.9 mmol) of 5-(3'-methylaminomethyl-4-ylidenemethyl)thiazolidin-2,4-dione obtained according to example 10(C), with 0.17 ml (1 mmol) octanoylthio obtain 0.25 g (62%) expected the th connection.

(b) N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyloctanoic

Similar to example 1(g) the method of 0,22 g (0.5 mmol) N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methylacrylamide in 10 ml of dioxane obtain 0.12 g (53%) of the expected product with a melting point 36°C.

Example 35

N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylheptanoic

(a) N-[4'-(2,4-Dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methylheptanoic

Similar to example 1(d) the method by reaction of 1 g (1.8 mmol) of 5-(3'-methylaminomethyl-4-ylidenemethyl)thiazolidin-2,4-dione obtained according to example 10(C), 0.3 ml (2 mmol) of leptanilloides obtain 0.45 g (57%) of the expected compound.

(b) N-[4'-(2,4-Dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylheptanoic

Similar to example 1(g) the method of 0.36 g (0.8 mmol) of N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-methylheptanoic in 15 ml of dioxane at a pressure of 3 ATM receive 0,23 g (66%) of the expected product in the form of a colorless film.

Example 36

Monoamide N-hydroxy-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonic acid

At a temperature of 60°C for 18 hours to heat the mixture of 0.13 g (0.3 mmol) of dimethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonate obtained according to example 15(b), 2 ml methanol, 2 the l of tetrahydrofuran, of 0.48 g (4.5 mmol) of sodium carbonate and 0.2 ml (1.5 mmol) of hydroxylaminopurine. The reaction medium is neutralized to pH 6-7 with hydrochloric acid, extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, evaporated. The resulting residue is purified by chromatography on a column of silica, elwira with a mixture of heptane and ethyl acetate (75:25 ratio). Obtain 0.09 g (72%) of the expected product with a melting point of 60°C.

Example 37

Agonistic activity towards the PPARγ compounds according to the invention may be assessed by tests on the binding and transactivation. Obtained for the compounds according to the invention the results are presented in the following table:

Connection% activation of PPARα% activation of PPARγBinding of PPARγ Kd in nmol
Standard 1: Wy 14643100*n.a.n.a.
Standard 2: SB 219994n.a.1000,5
Standard 3: BRL 49,65338323
Example 18,2102,255
Example 28,242,9263
Example 10022,1800
Example 112,474,5289
Example 12060,47
Example 130to 70.224
Example 2114,990190
Example 227,5for 95.376,6
Example 248,79572,3
Example 262,188,6N.T.
Example 281,179,8N.T.
Example 308,980,3N.T.
Example 32074,9N.T.
Example 3417,6102,52
Example 351156N.T.
where: n.a. means inactive;

N.T. means not tested;

*...: % activation at a concentration of 1 Microm.

These results show the affinity of the compounds to PPARγ and their activity towards TRANS-activation. These results show, in particular, the specificity of activation of the compounds according to izobreteniy subtype of PPARγ compared with the activation of compounds in relation to the subtype of PPARα.

Example 38

In this example explains the different concrete compositions based on compounds according to the invention.

As for the introduction of the oral

(a) Tablet weight of 0.2 g contains g:

Connection 10,001
Starch0,114
The dicalcium phosphate0,020
Silicon dioxide0,020
Lactose0,030
Talc0,010
Magnesium stearate0,005

(b) Suspension for drinking in ampoules of 5 ml contains:

Connection 50,001
Glycerin0,500
Sorbitol 70%0,500
The sodium saccharinate0,010
Methyl-p-hydroxybenzoate0,040
FlavorEnough
Purified waterTo a total volume of 5 ml

(C) Tablet weight of 0.8 g contains g:

Connection 20,500
Pre gelatinous the initial starch 0,100
Microcrystalline cellulose0,115
Lactose0,075
Magnesium stearate0,010

(d) Suspension for drinking in the ampoule of 10 ml contains:

Connection 40,200
Glycerin1,000
Sorbitol 70%1,000
The sodium saccharinate0,010
Methyl-p-hydroxybenzoate0,080
FlavorEnough
Purified waterTo a total volume of 10 ml

- For the introduction of locally

(a) Ointment contains:

Connection 60,020
Isopropylmyristate81,700
Liquid vaseline oil9,100
Silica ("Aerosil 200",

manufactured by DEGUSSA)
9,180

(b) Ointment contains:

Connection 20,300
Pharmacopoeial white petrolatum to the total number of100

(C) Cream, water-in-oil, non-ionic contains:

Connection 10,100 g
A mixture of emulsive lanolin alcohols, waxes and oils ("Eucerine anhydre"manufactured by BDF)39,900 g
Methyl-p-hydroxybenzoate0.075 g
Propyl-p-hydroxybenzoate0.075 g
Sterile demineralized waterTo total amount 100 g

(d) Lotion contains:

Connection 30,100
Polyethylene glycol (PEG 400)69,900
Ethanol, 95%30,000

(e) Hydrophobic ointment contains:

Connection 50,300
Isopropylmyristate36,400
Silicone oil ("Rhodorsil 47 V 300", manufactured by RHONE-POULENC)36,400
Beeswax13,600
Silicone oil ("Abil 300.000 cSt", manufactured by GOLDSCHMIDT)To total amount 100

(f) Cream oil-in-water, non-ionic contains:

Connection 21,000 g
Cetyl alcohol4,000 g
Glycerylmonostearate 2,500 g
Stearate PEG-502,500 g
Oil Karite9,200 g
Propylene glycol2,000 g
Methyl-p-hydroxybenzoate0.075 g
Propyl-p-hydroxybenzoate0.075 g
Sterile demineralized waterTo total amount 100 g

1. Compounds characterized in that they meet the General formula (I)

in which R1means a radical of the following formulae (a) and (b):

and Y, R5and R6have the following values;

R2and R3identical or different, denote a hydrogen atom, alkyl with 1-12 carbon atoms, aryl, radical OR7and R7has the following value;

X means connecting the fragment of the following form: -(CH2)m-(Z)n-(CO)p-(W)q-, with the specified binding fragment can be read from left to right or Vice versa, and Z, W, m, n, p, q have the following values;

R4denotes alkyl with 1-12 carbon atoms, aryl, aralkyl, heteroaryl or 9-fluorenylmethyl;

Y represents a radical CH2or sulfur atom;

R5means hydroxyl, alkoxy with 1-6 atoms angle of the ode, the radical NH-OH or a radical N(R8)(R9), and R8and R9have the following values;

R6denotes alkyl with 1-12 carbon atoms, the radical OR10or the radical (CH2)r-COR11and r, R10and R11have the following values;

R7means a hydrogen atom or aralkyl;

Z means oxygen atom or a radical NR12and R12has the following value;

W denotes an oxygen atom, a radical NR13or the radical CH2and R13has the following value;

m, n, p, q, same or different, can take the values 0 or 1,

provided that the sum (m+n+p+q) is higher or equal to 2 and when p is 0, then n or q is 0;

R8means a hydrogen atom;

R9means a hydrogen atom or aryl;

r is 0 or 1;

R10denotes alkyl with 1-12 carbon atoms;

R11means hydroxyl, radical OR14;

R12means a hydrogen atom or alkyl with 1-12 carbon atoms;

R13means a hydrogen atom or alkyl with 1-12 carbon atoms;

R14denotes alkyl with 1-12 carbon atoms;

and optical and geometrical isomers of the above compounds of formula (I)and their salts.

2. Connection on p. 1, characterized in that they are in the form of salts of alkali or alkaline earth metal, zinc salts or salts of an organic amine.

3. Compounds according to any one of p. 1 or 2, characterized in that the alkyl radical with 1-12 carbon atoms is chosen among methyl, ethyl, isopropyl, butyl, tert-butyl, hexyl, Attila, decyl or dodecyl.

4. Compounds according to any one of p. 1 or 2, characterized in that alkoxy with 1-6 carbon atoms selected from the group consisting of methoxy, ethoxy, isopropoxy-, tert-butoxy or hexyloxy.

5. Compounds according to any one of p. 1 or 2, characterized in that the aryl is chosen among phenyl which may be mono - or Disaese a halogen atom, the radical CF3, alkyl with 1-12 carbon atoms, alkoxyl with 1-6 carbon atoms, a nitrogroup, simple polyether radical, a hydroxyl, possibly protected by acetyl, benzoline or amino group, possibly protected by acetyl, benzoyl or possibly substituted by at least one alkyl with 1-12 carbon atoms.

6. Compounds according to any one of p. 1 or 2, characterized in that aralkyl choose among benzyl or Venetia, which may be mono - or Disaese a halogen atom, the radical CF3, alkyl with 1-12 carbon atoms, hydroxyl, alkoxyl with 1-6 carbon atoms, a nitrogroup, simple polyether radical, a hydroxyl, possibly protected by acetyl, benzoline or amino group, possibly protected AC is tilam, the benzoyl or possibly substituted by at least one alkyl with 1-12 carbon atoms.

7. Compounds according to any one of p. 1 or 2, characterized in that heteroaryl selected from the group consisting of pyridyl, furil, tanila or isoxazolyl, possibly substituted by at least one halogen atom, alkyl with 1-12 carbon atoms, alkoxyl with 1-6 carbon atoms, a nitrogroup, simple polyether radical, a hydroxyl, possibly protected by acetyl, benzoline or amino group, possibly protected by acetyl, benzoyl or possibly substituted by at least one alkyl with 1-12 carbon atoms.

8. Compounds according to claim 1, characterized in that select them, individually or as a mixture, from the group consisting of

N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylbenzamide;

2-methyl-3-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-yl)propionic acid;

(S)-2-ethoxy-3-(3'-{[methyl-(1-phenylethanol)amino]methyl}brenil-4-yl)propionic acid;

nanometrology ether 2-(3'-{[methyl-(1-phenylethanol)amino]methyl}brenil-4-ylmethyl)malonic acid;

dimethyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonate;

methyl-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}biphenyl-4-ylmethyl)malonamate;

5-{3'-[(methylpyridin-2-ylamino)methyl]biphenyl-4-ylmethyl}the pelvis is lidin-2,4-dione;

N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]benzamide;

N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-ethylbenzamide;

N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-pentylbenzene;

tert-butyl[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamate;

tert-butyl[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]ethylcarbamate;

tert-butyl[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]propylgallate;

N-fluoren-9-ylmethyl-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]methylcarbamate;

N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-2,2,N-trimethylpropane;

N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylacrylamide;

N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylmaleimide;

N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methyl-3-phenylpropionamide;

1-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-3-phenylacetone;

N-[4'-(2-carbamoylethyl)biphenyl-3-ylmethyl]-N-methylbenzamide;

N-methyl-N-[4'-(2-phenylcarbamoyloxy)biphenyl-3-ylmethyl]benzamide;

N-[4'-(2-hydroxycarbamoyl)biphenyl-3-ylmethyl]-N-methylbenzamide;

2-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-yl]-N-methyl-N-phenylacetamide;

1-[4'-(2,4-who dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-1-methyl-3-phenylacetone;

ethyl-3-{3'-[(benzoylamino)methyl]biphenyl-4-yl}-2-methylpropionate;

monoamide N-hydroxy-2-(3'-{[methyl-(1-phenylethanol)amino]methyl}brenil-4-ylmethyl)-malonic acid;

N-[4'-(2,4-dioxothiazolidine-5-ylidenemethyl)biphenyl-3-ylmethyl]-N-propylbenzamide;

tert-butyl[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-yl]carbamate;

monoamide 2-(3'-{[methyl-(1-phenylethanol)amino]methyl}brenil-4-ylmethyl)malonic acid;

N-benzyl-N-methyl-4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-carboxamide;

N-benzyl-4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-carboxamide;

N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylmethanamine;

N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-yl]-2-phenylacetamide;

N-octyl-4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-carboxamide;

N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylheptane;

N-[4'-(2,4-dioxothiazolidine-5-ylmethyl)biphenyl-3-ylmethyl]-3,4-diethoxy-N-methylbenzamide.

9. Connection under item 1 or 2, characterized in that they have at least one of the following characteristics:

R1means a radical of the formula (a) or a radical of formula (b), where R5means hydroxyl and R6means radical OR10;

X means connecting the fragment of the structure-CH2-N(R12)-CO-, itemy from left to right or Vice versa.

10. Compounds according to any one of paragraphs. 1-9 as a medicinal product that has the property activator of PPAR-γ.

11. Cosmetic composition for care of the body or hair, characterized in that it comprises in a physiologically acceptable medium, at least one of the compounds specified in any of paragraphs. 1-9.

12. The composition according to claim 11, characterized in that the concentration of compounds (compounds) according to any one of paragraphs. 1-9 is 0.001-3% by weight of the total composition.

13. The use of a composition specified in any of paragraphs. 11 or 12, cosmetics for care of the body, or for hair care.

14. The use of compounds according to any one of claims 1 to 9 to obtain a composition intended for regulating and/or restoring the metabolism of skin lipids.

15. The use of compounds according to any one of claims 1 to 9 to obtain a composition intended for the treatment of

dermatological diseases associated with disorders of keratinization affecting differentiation and proliferation, in particular, ordinary, youth, polymorphic, pink acne; nodular-cystic, nodular acne; senile acne, secondary acne such as solar, drug or occupational acne;

of ichthyosis, idiotphone States, disease Daria, Palmar-plantar keratoderma, leukoplakia and Le is koplatadze States, skin Stripping or Stripping of the mucosa (oral lichen);

dermatological diseases with inflammatory immunoallergic component, with or without violation of disorders of cell proliferation, in particular, cutaneous, mucosal or ungual psoriasis, psoriatic rheumatism, cutaneous atopy, such as eczema, respiratory atopy or gingival hypertrophy;

benign or malignant dermal or epidermal of proliteracy viral origin or not, in particular, ordinary, common warts, flat warts, resembling a wart of epidermodysplasia, oral or floriduh of papillomatosis, lymphoma T;

proliferate, which can be provoked by ultraviolet rays, in particular, basic and speckletone of epithelium;

precancerous lesions, in particular keratoacanthoma;

immune dermatoses, in particular lupus erythematosus;

bullous immune diseases;

collagen diseases, such as scleroderma;

dermatological or systemic diseases with an immunological component;

skin disorders occurring as a result of being under the influence of ultraviolet radiation, photo-induced or age-related skin aging or pigmentations and actinic ke is Amosov, or any pathologies associated with age or actinic ageing, in particular xerosis;

disorders of adipose function, in particular acne giperborei or simple seborrhoea;

of impaired wound healing or scarring on the skin when it is stretched;

disorders of pigmentation, such as hyperpigmentation, melasma, hypopigmentation or vitiligo;

disorders of lipid metabolism, such as obesity, hyperlipidemia, or non-insulin-dependent diabetes;

inflammatory diseases such as arthritis;

cancerous or precancerous conditions;

alopecia of various origins, in particular alopecia resulting from chemotherapy or irradiation;

disorders of the immune system such as asthma, diabetes type I, multiple sclerosis, or other selective dysfunctions related to the immune system;

diseases of the cardiovascular system such as arteriosclerosis or hypertension.

16. Pharmaceutical composition, distinguishing property of akovali receptor type PPAR-γ, characterized in that it comprises in a physiologically acceptable medium, at least one of the compounds specified in any of paragraphs. 1-9.

17. The composition according to item 16, characterized in that the concentration of compounds (compounds) according to any one of claims 1 to 9 is 0.001-10% about what her mass of the composition.

18. The composition according to item 16, characterized in that the concentration of compounds (compounds) according to any one of claims 1 to 9 is 0.01-1% by weight of the total composition.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to substituted bicyclic heterocyclic compounds of the formula (I): their tautomeric forms, stereoisomers, polymorphous forms, pharmaceutically acceptable salts and pharmaceutically acceptable solvates wherein groups R1, R2, R3 and R4, and groups R5 and R6 when they are bound with carbon atom they represent hydrogen, halogen atom, hydroxy-group, alkyl, alkoxy-group; R5 and R6 as a single group or both can represent also an oxo-group when they are bound with carbon atom; when R5 and R6 are bound with nitrogen atom then they represent hydrogen atom, hydroxy-group or such unsubstituted groups as alkyl, alkoxy-group, aralkyl. X means oxygen or sulfur atom; Ar means phenylene, naphthylene or benzofuryl. Proposed compounds can be used against obesity and hypercholesterolemia. Also, the invention describes methods for preparing compounds, pharmaceutical compositions, method for treatment and using compounds proposed.

EFFECT: valuable medicinal properties of compounds and compositions.

52 cl, 77 ex

FIELD: organic chemistry, medicine, hematology.

SUBSTANCE: invention elates to new compounds that inhibit activated blood coagulating factor X (Fxa factor) eliciting the strong anti-coagulating effect. Invention proposes compound of the formula (1): Q1-Q2-C(=C)-N-(R1)-Q3-N(R2)-T1-Q4(1) wherein R1, R2, Q1, Q2, Q4 and T1 have corresponding values, and Q2 represents the group of the formula: wherein R9, R10 and Q5 have corresponding values also, or its salt, solvate or N-oxide. Invention provides the development of a novel compound possessing strong Fxa-inhibiting effect and showing the rapid, significant and stable anti-thrombosis effectin oral administration.

EFFECT: valuable medicinal properties of compounds.

13 cl, 1 tbl, 195 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention elates to novel derivatives of uracil of the formula [I] possessing herbicide activity, a herbicide composition based on thereof and to a method for control of weeds. In derivatives of uracil of the formula [I] the group Q-R3 represents a substituted group taken among:

wherein a heterocyclic ring can be substituted with at least a substitute of a single species taken among the group involving halogen atom, (C1-C6)-alkyl-(C1-C6)-alkoxy; Y represents oxygen, sulfur atom, imino-group or (C1-C3)-alkylimino-group; R1 represents (C1-C3)-halogenalkyl; R2 represents (C1-C3)-alkyl; R3 represents OR7, SR8 or N(R9)R10; X1 represents halogen atom, cyano-group, thiocarbamoyl or nitro-group; X2 represents hydrogen or halogen atom wherein each among R7, R8 and R10 represents independently carboxy-(C1-C6)-alkyl and other substitutes given in the invention claim; R9 represents hydrogen atom or (C1-C6)-alkyl. Also, invention relates to intermediate compounds used in preparing uracil derivatives.

EFFECT: improved preparing method, valuable properties of compounds.

40 cl, 16 sch, 12 tbl, 65 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to substituted pyridines and pyridazines with angiogenesis inhibition activity of general formula I

(I)1, wherein ring containing A, B, D, E, and L represents phenyl or nitrogen-containing heterocycle; X and Y are various linkage groups; R1 and R2 are identical or different and represent specific substituents or together form linkage ring; ring J represents aryl, pyridyl or cycloalkyl; and G's represent various specific substituents. Also disclosed are pharmaceutical composition containing claimed compounds, as well as method for treating of mammalian with abnormal angiogenesis or treating of increased penetrability using the same.

EFFECT: new pyridine and pyridazine derivatives with angiogenesis inhibition activity.

26 cl, 6 tbl, 114 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to biologically active compounds, in particular, to substituted 5R1,6R2-thiadiazine-2-amines and pharmaceutical compositions comprising thereof that can be used in medicine as potential pharmacologically active substances eliciting the unique combination of properties: expressed anticoagulant activity in combination with capacity to inhibit aggregation of platelets. Effect of these substances differ from preparations used in medicinal practice and they can be used therefore in treatment of such diseases as myocardium infarction, disturbance in cerebral circulation, rejection of transplanted organs and tissues and so on. Indicated compounds correspond to the formula (I):

wherein values of radicals R1, R2 and R3 are given in the invention claim.

EFFECT: valuable medicinal properties of compounds.

4 cl, 2 tbl, 7 dwg, 33 ex

FIELD: organic chemistry, pesticides, agriculture.

SUBSTANCE: invention relates to compounds that elicit high pesticide activity and can be used in control of pests of domestic and agricultural animals. Indicated compounds show the formula (I):

wherein R1 means halogen atom, (C1-C6)-halogenalkyl; R2 means hydrogen atom (H), (C1-C6)-alkyl, (C1-C6)-alkylene-phenyl; X1 means nitrogen atom (N); X2 means group C(CN); X3 means oxygen atom (O); Q means CH; R3 and R4 mean independently of one another hydrogen atom (H) or in common with carbon atom with which they are bound form (C3-C7)-cycloalkyl ring; R5 means a substitute taken among group including (C1-C6)-halogenalkyl, halogen atom being if m above 1 then substitutes R5 can be similar or different; m = 1, 2 or 3; n = 0 or 1. Also, invention describes a method for their preparing and method for control of pests.

EFFECT: valuable pesticide properties of compounds.

7 cl, 3 tbl, 14 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of phenyloxazolidine that have a relationship with a 4-8-membered heterocyclic rings of formula I and their pharmaceutically acceptable salts, where X represents NR1, S(O)gor Oh, R1represents H, C1-6alkyl, optionally zamesheny one or more CN or halogen, -(CH2)h-phenyl, -COR1-1, -СООR1-2, -CO-(CH2)h-COR1-1, -SO2- C1-6alkyl or -(CO)i-Het, R2represents H, -CO-(C1-6)alkyl or fluorine, R3and R4are the same or different and represent H or halogen, R5is1-6alkyl and C3-6cycloalkyl, optionally substituted by one or more halogen, g=0, 1, or 2, h=1 or 2, i=0 or 1, m=0, 1, 2, 3, n= 0, 1, 2, 3, provided that m and n taken together, is equal to 1, 2, 3, 4 or 5

The invention relates to new optically active derivative of General formula I, where R1represents a hydrogen atom, R2represents an alkyl group containing from 1 to 6 carbon atoms, and n is 1

The invention relates to a series of new derivatives of thiazolidinone and oxazolidinone containing nitroacetanilide group, and to methods of producing these compounds may find use of these compounds as vasodilators, for example, for the treatment and prevention of cardiovascular diseases

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new N-acylated pseudodipeptides comprising acidic group in neutral or charged form by one end of pseudodipeptide and accessory functionalized branching by the opposite end and corresponding to the general formula (I): wherein each R1 and R2 means acyl group of saturated or unsaturated, linear or branched carboxylic acid comprising from 2 to 24 carbon atoms, unsubstituted or comprising a substitute or substitutes chosen from hydroxyl, alkoxy- and acyloxy-groups; coefficient n has values from 0 to 3; coefficients p and q have values from 1 to 3; coefficient m has values from 1 to 3 except for a case when X means carboxyl or one of its derivative, and in this case it means values form 0 to 3; Y means oxygen atom (O) or -NH; X and Z mean accessory functionalized branching or acidic group in neutral or charged form chosen from the following groups: carboxyl, carboxy-(C1-C5)-alkoxy-, carboxy-(C1-C5)-alkylthio-, phosphono-(C1-C5)-alkoxy-, dihydroxyphosphoryloxy-, hydroxysulfonyloxy-, (carboxy-(C1-C5)-alkyl)aminocarbonyl, (dicarboxy-(C1-C5)-alkyl)aminocarbonyl, (ammonio-(C1-C5)-aminocarbonyl, carboxy-(amino-(C1-C5)-alkyl)aminocarbonyl under condition that at least one substitute among X and Z means an accessory functionalized branching, and their enantiomers and diastereoisomers. Proposed compounds show immunomolulating properties as adjuvants and these compounds can be grafted to antigen to modulate the immune response or can be grafted to pharmacophore to improve the therapeutic effect or its directed delivery.

EFFECT: improved preparing methods, improved and valuable medicinal properties of substances and compositions.

48 cl, 3 tbl, 112 dwg, 5 ex

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