Prostaglandin analogs, method for their preparing and pharmaceutical composition possessing selective agonistic activity with respect to ep4-receptor

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to analogs of prostaglandin of the formula (I): , wherein A means -CH2-CH2- or -CH=CH-; B is absent or means phenyl; Z means -C(O)OR' or tetrazole-5-yl wherein R' means hydrogen atom or (C1-C6)-alkyl; m = 1, 2, 3, 4, 5 or 6; R1 means (C1-C6)-alkyl, unsubstituted phenyl or phenyl substituted with at least one substitute chosen from the group comprising trifluoromethyl, halogen atom, -Y-Ra, -Y-ORa and -Y-C(O)Ra wherein Y means chemical bond or (C1-C3)-alkylene group; Ra means (C1-C6)-alkyl, unsubstituted phenyl or phenyl substituted with at least one substitute chosen from the group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl and halogen atom under condition that B means phenyl and R3, R4, R5 and R6 do not mean hydrogen atom simultaneously; or R1 means unsubstituted phenyl or phenyl substituted with at least one substitute chosen from the group comprising trifluoromethyl, -Y-Ra, -Y-ORa and -Y-C(O)Ra wherein Y means chemical bond or (C1-C)-alkylene group; Ra means (C1-C6)-alkyl, unsubstituted phenyl or phenyl substituted with at least one substitute chosen from the group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl and halogen atom under condition that B is absent and R3, R4, R5 and R6 means hydrogen atom simultaneously; R2 means hydrogen atom; each among R3, R4, R5 and R6 means independently of one another hydrogen atom or (C1-C6)-alkyl, or its pharmaceutically acceptable salt or individual isomer. Compounds of the formula (1) possess a selective agonistic activity with respect to ER4-receptors and therefore they can be used in pharmaceutical composition.

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

22 cl, 2 tbl, 12 ex

 

The invention relates to certain analogues of 8-Aza-11-deoxyprostaglandin, corresponding pharmaceutical compositions, methods of use as selective agonists of prostaglandin EP4and methods for their preparation.

In the literature there are many publications devoted to prostaglandins or prostanoids (PGs). The term prostanoids is the international nonproprietary name of natural and synthetic prostaglandins and prostaglandinovykh compounds for which it is known that even small changes in chemical structure or stereochemistry have a significant impact on their biological activity.

Prostaglandins or prostanoids (PGs) are a group of biologically active compounds isolated from membrane phospholipids formed from essential fatty acids containing 20 carbon atoms and containing cyclopentane ring. These compounds are divided into several main classes, denoted by the letters, and differ in the substituents in the cyclopentane ring. The main classes are divided into subtypes, denoted by the indices 1, 2 or 3, which correspond to their fatty acid predecessors.

For example, a particular representative of prostaglandin E is PGE2formula

Currently, there are four different subspecies of receptors PGE2that marked EP1EP2, EP3and EP4.

The use of compounds with high activity of the receptor binding PGE2includes prevention and/or treatment of immunological diseases (autoimmune diseases, organ transplantation and the like), asthma, disorders of bone formation, neuronal death, thrombosis and stroke, Hepatology, abortion, disorders of the male and female sexual dysfunction, premature birth, inflammation, such as rheumatoid arthritis, or neuropathic disorders of the retina, such as glaucoma.

More prostaglandins and their associated receptors are described, for example, article .Abramovitz and others, The Utilization of Recombinant Prostanoid Receptors to Determine the Affinities and Selectivities of Prostaglandins and Related Analogs, Biochimica et Biophysica Acta, 1483, 285-293 (2000).

Participation receptor agonists of prostaglandin E in bone resorption described, for example, articles T.Suzawa and others The Role of Prostaglandin E Receptor Subtipes in Bone Resorption: An Analysis Using Specific Agonists for the Respective EP4, Endocrinology, 141, 1554-1559 (2000), K.Ono, and other, Important Role of EP4that is a Subtype of Prostaglandin (PG) E Receptor in Osteoclast-like Cell Formation from Mouse Bone Marrow Cells Induced by PGE2, J. of Endocrinology, 158, R1-R5 (1998), M.Suda and others, Prostaglandin E Receptor Subtipes in Mouse Osteoblastic Cell Line, Endocrinology, 137, 1698-1705 (1996).

These selective agonists of the receptor is prostaglandin E are also used in the treatment of pathological changes in the gastrointestinal tract, see, for example, H.Araki and others, The Roles of Prostaglandin E Receptor Subtypes in the Cytoprotective Action of Prostaglandin E2in the Rat Stomach, aliment oil displayed pure. Pharmacol. Ther., 14 (Suppl.l), 116-124 (2000), T.Kunikata and others, E-Type Prostaglandin Inhibits Indomethacin-Induced Small Intestinal Lesions Through EP3and EP4Receptors: A Study Using Rats and Knockout Mice, Gastroenterology, 118, absr., No. 3787.

Other examples of the application of receptor agonists prostaglandin E include activation of kidney function, see, for example, M.D.Breyer and others, Prostaglandin E Receptors and the Kidney, Am. J. Physiol., 279, F12 F23 (2000), and K.E.Purdy and others, EP1and EP4Receptors Mediate Prostaglandin E2Actions in the Microcirculation of the Rat Kidney, Am. J. Physiol., 279, F755-F764 (2000), treatment of thrombosis and stroke, and other conditions under which favorable effect of inhibition of platelet aggregation, see, for example, .Z.S.Paul and others, Distribution of Prostaglandin IP and EP Receptor Subtypes and Isoforms in Platelets and Human Umbilical Artery Smooth Muscle Cells, Br. J. Haematol., 102, 1204-1211 (1998), an anti-inflammatory effect through inhibition of education αTNF, see, for example, ..Meja and others, Characterization of prostanoid receptor(s) on human blood monocytes at which prostaglandin E2 inhibits lipopolysaccharide-induced tumor necrosis factor-alpha generation, Br. J. Pharmacol., 122, 149-157 (1997), and A.Eigler and other Anti-inflammatory activities of cAMP-elevating agents: enhancement of IL-10 synthesis and concurrent suppression of TNF production, J. Leukoc. Biol., 63, 101-107 (1998), or the treatment of glaucoma, see, for example, M.Takamatsu, etc.. Localization of Prostaglandin E Receptor Subtypes in the Ciliary Body of the Mouse Eye, Exp. Eye Res., 70, 623-628 (2000), and D.F.Woodward and other, Molecular Characterization and Ocular Hypotensive Properties of the Prostanoid EP2Receptor, J. Ocul. Pharmacol. Ther., 1, 447 (1995).

Treatment of impotence and/or erectile dysfunction with the use of prostaglandins, which are selective ligands of the receptor EP2and/or EP4stated in published international application WO 99/02164 filed by the company Pharmacia & decision Upjohn AB.

For more information on prostaglandins and their receptors contained in the monograph Goodman and Gillman, The Pharmacological Basis of Therapeutics, 9thedition, McGraw-Hill, New York, GL, CTR-616 (1996).

Analogues of 8-Aza-11-deoxyprostaglandin corresponding PGE2have the following structure

Replacement of the carbon atom in position 8 at the nitrogen atom leads to a change in the three-dimensional conformation derived prostaglandin, and because the connection has biological activity, such conformational changes have a significant impact on biological activity. 8-Aza-11-deoxyprostaglandin E, containing natural side chains described in the literature, see, for example, BE 841165 (Syntex USA Inc.).

Compounds of the present invention are 8-isoprostaglandin containing non-natural side chain at position C-12 pyrrolidone cycle (in accordance with the nomenclature of prostaglandins), and the specified chain at position C-15 contains heterocyclyl, aryl or heteroaryl. These compounds possess high selectivity of you as agonists of the receptor EP 4. The increase in selectivity reduces side effects, often observed with the introduction of selective agonists of prostaglandin. There is therefore a need in the compounds of the present invention.

The present invention relates to compounds of formula I

where

And means-CH2-CH2- or-CH=CH-,

In absent or denotes aryl or heteroaryl,

Z denotes-C(O)OR', -C(O)NR'r R", -C(O)NSO2R', -PR'(O)(OR'), -PO(OR')2or tetrazol-5-yl, where R' and R" independently of one another denote hydrogen or C1-C6alkyl,

m is 1, 2, 3, 4, 5 or 6,

R1means alkyl, alkenyl, quinil, cycloalkenyl, geterotsiklicheskikh, aryl, arylalkyl or heteroaryl assuming that means aryl or heteroaryl, and R3, R4, R5and R6at the same time do not represent a hydrogen, or R1means geterotsiklicheskikh, aryl or heteroaryl if that is absent, and R3, R4, R5and R6simultaneously denote hydrogen,

R2means hydrogen or C1-C6alkyl, C1-C6alkenyl or C1-C6quinil,

R3, R4, R5and R6each independently of one another denotes hydrogen or C1-C6alkyl, or R3and R4, R5and R6or R3and R5the place with atom, to which they are attached, form a cyclic3-C7alkyl;

or their pharmaceutically acceptable salts or MES, an individual isomer or a racemic or prizemistoj mixture of isomers.

Another object of the invention are pharmaceutical compositions containing a therapeutically effective amount of at least one compound of formula I or its pharmaceutically acceptable salt, or MES, prodrugs, individual isomer or a racemic or prizemistoj mixture of isomers in a mixture with at least one suitable carrier, diluent or excipient.

Another object of the invention is a method of treatment of diseases, especially diseases of the bone, mammal treatable by administration of agonist receptor prostaglandin EP4moreover , the method includes the introduction of a therapeutically effective amount of the compounds of formula I or its pharmaceutically acceptable salt.

Another object of the invention is a method of obtaining compounds of formula I.

Unless otherwise stated, terms used in the description of the application and the claims, shall have the meanings specified below.

"Alkoxy"used alone or in combination, means a radical - OR where R is alkyl, with the values specified in the proposal, such as the methods of the si, ethoxy, propoxy, butoxy etc.

"Alkyl", used alone or in combination, means a linear saturated monovalent hydrocarbon radical containing from one to six carbon atoms, or branched saturated monovalent hydrocarbon radical containing from three to six carbon atoms, for example methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl etc.

"Alkylen used separately or in combination, means a linear saturated divalent hydrocarbon radical containing from one to six carbon atoms, or a branched saturated divalent hydrocarbon radical containing from three to six carbon atoms, for example methylene, ethylene, 2,2-dimethylethylene, propylene, 2-methylpropene, butylene, pentile etc.

"Alkylthio" or "alkylsulfanyl used separately or in combination, means a radical - SR where R is alkyl having values above, for example methylthio, ethylthio, propylthio, butylthio and etc.

"Aryl"used alone or in combination, means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical, which optionally independently from each other substituted by one or more substituents, preferably one, two or three substituents selected from the group comprising alkyl, halogenated, halogen, nitro, cyano, amino, methylenedioxy, Ethylenedioxy, Y-aryl, Y-heteroaryl, Y-cycloalkyl, -Y-heterocyclyl, -Y,-OR', -Y-R NR'r", -Y-C(O)-R', -Y-S(O)0-2-R', -Y-N-SO2-R', -Y,-SO2-R NR'r", -Y-N-C(O)N-R R, where Y is absent or means C1-C3alkylenes group, and R' and R" each independently of one another denotes hydrogen, alkyl, halogenated, hydroxy, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl. More specifically the term aryl includes, without limitation, phenyl, chlorophenyl, methoxyphenyl, methoxymethanol, phenoxyphenyl, 1-naphthyl, 2-naphthyl and derivatives thereof.

"Cycloalkyl used separately or in combination, means a saturated monovalent cyclic hydrocarbon moiety containing in the cycle from three to seven carbon atoms, such as cyclopropyl, cyclobutyl, cyclohexyl, 4-methylcyclohexyl etc.

"Halogen"used separately or in combination, means fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine.

"Halogenated used separately or in combination, means an alkyl substituted by one or more identical or different halogen atoms, such as-CH3Cl-CF3, -CH2CF3, -CH2CCl3etc.

"Heteroaryl used separately or in combination, means a monovalent monocyclic or bicyclic radical, in a loop containing from 5 to 12 atomowy at least one aromatic cycle, including in cycle one, two or three heteroatoms selected from the series N, O or S and the remaining atoms in the cycle are carbon atoms, and heteroaryl radical attached to the aromatic cycle. Heteroaryl cycle optionally substituted independently from each other by one or more substituents, preferably one or two substituents selected from the series alkyl, halogenated, halogen, nitro, cyano, amino, methylenedioxy, Y-aryl, Y-heteroaryl, Y-cycloalkyl, -Y-heterocyclyl, -Y,-OR', -YNR'R", -Y-C(O)-R', -Y,-O-C(O)-R', -Y-S(O)0-2-R', -Y-N-SO2-R', -Y,-SO2-R NR'r", -Y-N-C(O)N-R R, where Y is absent or means C1-C3alkylenes group, a R' and R" each independently of one another denotes hydrogen, alkyl, halogenated, hydroxy, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl. More specifically, the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolin, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrofuranyl, isobenzofuranyl, benzothiazolyl, benzothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, hinely, tetrahydroquinoline, ethanolic, benzimidazolyl, benzisoxazole or sensational, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazoles and their derivatives.

"Heterocyclyl", used alone or in Combinat and, means a saturated or unsaturated non-aromatic cyclic radical containing from 3 to 8 atoms in the cycle, of which one or two atoms in the cycle are heteroatoms selected from the series N, O or S(O)0-2and the rest of the atoms in the cycle are carbon atoms and one or two carbon atom optionally replaced by a carbonyl group. Heterocyclyl optionally substituted independently of one another one, two or three substituents selected from the series alkyl, halogenated, halogen, nitro, cyano, Y is aryl, Y-heteroaryl, Y-cycloalkyl, Y-heterocyclyl, -Y,-OR', -YNR'R", -Y-C(O)-R', -Y-S(O)0-2-R', -Y-N-SO2-R', -Y,-SO2-R NR'r", -Y-N-C(O)N-R R, where Y is absent or means C1-C3alkylenes group, a R' and R" each independently of one another denotes hydrogen, alkyl, halogenated, hydroxy, alkoxy, aryl, heteroaryl, cycloalkyl, heterocyclyl. More specifically, the term heterocyclyl includes, without limitation, tetrahydropyranyl, piperidinyl, N-methylpiperidin-3-yl, piperazinil, N-methylpyrrolidine-3-yl, 3-pyrrolidinyl, morpholinyl, thiomorpholine, thiomorpholine-1-oxide, thiomorpholine-1,1-dioxide, pyrrolidyl, imidazolyl, N-methanesulfonamido-4-yl, and their derivatives.

"Leaving group" means a group whose name is usually associated with its use in synthetic organic chemistry, i.e oznachaet the atom or group, which is substituted by a nucleophile and includes halogen (such as chlorine, bromine or iodine), alkanesulfonyl, arenesulfonyl, alkylcarboxylic (for example, acetoxy), arylcarboxylic, mesilate, tosyloxy, tripterocalyx, aryloxy (for example, 2,4-dinitrophenoxy), methoxy, N,O-dimethylhydroxylamine etc.

"Optionally substituted phenyl", as used separately or in combination, means a phenyl cycle, which is optionally substituted independently from each other by one or more substituents, preferably one or two substituents selected from the group comprising alkyl, hydroxy, alkoxy, halogenated, halogenoalkane, heteroalkyl, halogen, nitro, cyano, amino, methylenedioxy, Ethylenedioxy and acyl.

"Isomerism" means compounds with the same chemical formula but differ in the nature or sequence of links between atoms or by the spatial arrangement of atoms. Isomers that differ in the spatial arrangement of atoms, called "stereoisomers". Stereoisomers that are not mirror images of each other, are called "diastereoisomers"and stereoisomers that are incompatible mirror images are called "enantiomers" or in some cases, optical isomers. Carbon atom associated with four different what zamestitelyami, called "chiral center".

"Chiral isomer" means a compound with one chiral center. This connection has two enantiomers with opposite chirality and can exist in the form of an individual enantiomer or as a mixture of enantiomers. A mixture containing equal number of individual enantiomeric forms of the opposite chirality, is called a "racemic mixture". Compound containing more than one chiral center may exist in the form 2n-1enantiomeric pairs, where n means the number of chiral centers. Compound containing more than one chiral center may exist in the form of an individual diastereoisomer or mixture of diastereoisomers, which is called "diastereomeric mixture". If there is one chiral center, stereoisomer can be characterized by the absolute configuration (R or S) specified chiral center. The absolute configuration means the spatial arrangement of the substituents attached to the chiral center. The substituents attached to the specified chiral center, classified by rule Kahn, Ingold and Prelog (Cahn and others, Angew. Chem. Inter. Edit., 5, 385, (1966) (errata s), Cahn and others, Angew. Chem., 78, 413 (1966), Cahn and Ingold., J. Chem. Soc. (London), 612 (1951), Cahn and others, Experientia, 12, 81, (1956), Cahn, J. Chem. Educ., 41, 116 (1964)).

"Geometric isomers" means the dia is tiresomely, formed by the slow rotation around double bonds. These configurations are indicated by the prefixes CIS - and TRANS-, or Z and E, which means that the groups are located on the same or on different sides of the plane of the double bond according to the rules of Cahn-Ingold-Prelog.

"Tropicheskie isomers" refers to isomers that are formed due to the slow rotation of volume groups around a Central connection. Compounds of the present invention can exist in stereoisomeric form, therefore, you can get them as individual stereoisomers or mixtures thereof.

"Pharmaceutically acceptable excipient" means excipient, which is used in obtaining pharmaceutical compositions and which is generally safe, non-toxic, harmless to biological or other respects, and includes a carrier that is acceptable in veterinary medicine and in the pharmaceutical industry. "Pharmaceutically acceptable excipient"used in the description and claims, includes one or more of such excipients.

"Pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the necessary pharmacological activity of the parent compound. Such salts include:

(1) acid additive salts of inorganic acids, such as aristolochiaceae acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonate, econsultation, 1,2-ethicalfashion, 2-hydroxyethanesulfonic, benzosulfimide, 4-chlorobenzenesulfonate, 2-naphthalenesulfonate, 4-toluensulfonate, camphorsulfacid, 4-methylbicyclo[2.2.2]Oct-2-ene-1-carboxylic acid, glucoheptonate acid, 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid and the like; or

(2) salts formed when replacing the acidic proton present in the original compound, metal ion, such as alkali metal ion, ion, alkaline earth metal or aluminum ion, or in the formation of proton coordination compounds with organic based is eat, such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like

It is assumed that all references to pharmaceutically acceptable salts include them solvated (solvate) or crystalline (polymorphic modifications) of the form specified acid additive salts, as described in the proposal.

"Crystalline form" (or polymorphic modifications) mean crystal structure, in which the compound is present in different crystal forms, which have the same elemental composition. Such crystalline forms usually have different x-ray diffraction patterns, different infrared spectra have different melting points, different density, strength and shape of the crystals vary in optical and electrical properties, stability and solubility. Education the predominant crystalline form is affected by various factors such as the solvent used for recrystallization, crystallization rate and temperature of storage.

"Solvate" means solvated forms, which contain a stoichiometric or non-stoichiometric amount of solvent. Such compounds in the crystalline state held fixed molar quantity of the solvent molecules, forming MES. If R is storytale water is used, the resulting MES called hydrate, if the solvent is the alcohol formed MES called alcoholate. Hydrates are formed by combining one or more water molecules with the molecule of the substance, and the water retains the molecular form of H2O, such a combination capable of forming one or more hydrates.

The term "prodrug" means any compound that when administered to a mammal releases the active source drug of formula I in vivo when such prodrug is administered to a mammal. Prodrugs of the compounds of formula I is obtained by modifying one or more functional group (s)contained in the compound of formula I and a modified group (group) can be converted in vivo with the formation of the original connection. Prodrugs include compounds of formula I, in which hydroxy, amino, sulfhydryl, carboxy or carbonyl group of the compounds of formula I associated with any group that can be chipped off in vivo with the formation of free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include, without limitation, esters (e.g. acetate, dialkylaminomethyl, formate, phosphate, sulfate and benzoate) and carbamates (for example, N,N-dimethylaminoethyl) hydroxyl functionality the selected groups, ester group (for example, ethyl esters, morpholinoethyl esters) carboxyl functional groups, N-acyl derivatives (e.g. N-acetyl) Mannich bases, chiffony grounds and enaminone functional amino groups, oximes, acetals, ketals and enol esters of ketone and aldehyde functional groups in compounds of formula I, and so on (see Bundegaard, H., Design of Prodrugs, Elsevier, New York-Oxford, 1-92 (1985)).

"Protective group" means a group of atoms that, when linking reactive group blocks it, preventing its participation in the primary reaction. Examples of protective groups can be found in the monographs by T.W. Green and P.G.M.Futs, Protective Groups in Organic Chemistry, (Wiley, 3 ed. (1999) and Harrison and others, Compendium of Synthetic Organic Methods, V.1-8, J.Wiley and Sons (1971-1996). Typical aminosidine groups include formyl, acetyl, TRIFLUOROACETYL, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilylethynyl (SES), trityl and substituted triteleia group, allyloxycarbonyl, 9-fluorenylmethoxycarbonyl (FMOC), nitroferricyanide (NVOC), etc. Typical hydroxyamine group include groups in which a hydroxyl allerban or alkylated group, such as benzyl, triteleia ethers, and alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.

"Therapy" Il the "treatment" zabolevaniya includes: (1) the prevention of disease, i.e. suppressing the development of clinical symptoms of the disease in the subject, which is exposed to or predisposed to the disease but which are not detected or do not manifest symptoms of the pathological condition; (2) suppression of the disease, such as suppressing or reducing the intensity of development of the disease or its clinical symptoms; (3) weakening diseases, such as stimulation regression of the disease or its clinical symptoms.

"Therapeutically effective amount" means an amount of compound that when administered to a mammal for treating a disease, is sufficient to provide said treatment. Therapeutically effective amount may vary depending on the type of connection, type of disease to be treated, the severity of the disease, age and weight, etc. of the mammal to be treated.

"Prostaglandin analog" means a man-made compound which structurally is close prostaglandin.

"Prostaglandin receptor" or "prostanoid receptor" means a natural binding protein prostaglandins, and which after the formation of the complex alters the functioning of cells. Prostaglandin receptors can be stimulating or relaxing properties. Such receptors include, without limitation perejil is authorized, EP1EP2, EP3EP4, DP, FP, IP, TP1and TR2. In addition, these receptors are discussed in the review of Coleman and others, Pharmacological Reviews, 6, No. 2, 205-229 (1994).

Used in the description of the abbreviations have the following meanings:

DME dimethyl ether of ethylene glycol

DMF dimethylformamide

DMSO dimethyl sulfoxide

EtOAc ethyl acetate

MS mass spectrum

THF tetrahydrofuran

CT room temperature.

Nomenclature

The name and numbering of the compounds of the present invention is illustrated below:

In General, the nomenclature used in the description of the application is based on AUTONOM software™version 4.0, computer systems Institute Bilstein for the formation of IUPAC systematic nomenclature.

For example, the compound of formula I, where Z denotes-C(O)HE, m is 5, R2, R3, R4, R5and R6mean hydrogen, a represents-CH=CH-, B is absent, and R1means phenyl, called 7-[(R)-2-((E)-3-hydroxy-3-phenylpropyl)-5-oxopyrrolidin-1-yl]heptane acid.

While the broadest definition of the compounds of the present invention is described in the brief description of the invention, certain compounds of formula I are preferred.

In the first embodiment of the invention are typical connections In which there is no, R1means aryl, A, R2, R3, R4, R5, R6and Z have the values listed above. In this embodiment, preferred compounds in which R1means aryl, optionally substituted Deputy, chosen from a number of trifluoromethyl, halogen, -Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans hydrogen, C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl. Preferably R1means aryl, optionally substituted Deputy, chosen from a number of-Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, and Randmeans unsubstituted phenyl or substituted phenyl containing at least one Deputy, selected from the range of C1-C6alkyl, C1-C6alkoxy, trifluoromethyl or halogen.

In the second embodiment, compounds of the formula I is absent, And R2, R3, R4, R5, R6and Z have the meanings indicated above, and R1means phenyl, substituted by a group-Y-Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, and Rameans phenyl, optionally substituted by a Deputy selected from the range of C1-C6alkyl, C1-C6alkoxy, trifluoromethyl or g is lågen. Preferably R1means phenyl, substituted with at least one group Y ORawhere Y denotes a chemical bond or a C1-C3alkylenes group, and Rameans phenyl, optionally substituted C1-C6alkyl, C1-C6alkoxy, trifluoromethyl or halogen. More preferably R1means phenyl, substituted-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans phenyl, optionally substituted by a Deputy selected from the range of C1-C6alkyl, C1-C6alkoxy, trifluoromethyl or halogen.

The third variant of the invention includes the compounds of formula I, where absent, And means-CH=CH-, R2, R3, R4, R5, R6and Z have the meanings indicated above, and R1means heteroaryl. Typical compounds are compounds, in which the heteroaryl group is substituted by the Deputy, chosen from a number of trifluoromethyl, halogen, -Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, and Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl.

The fourth variant of the invention includes the compounds of formula I, which is absent, And means-CH2-CH2-, R2, 3, R4, R5, R6and Z have the meanings indicated above, and R1means heteroaryl. Typical compounds are compounds, in which the heteroaryl group is substituted by the Deputy, chosen from a number of trifluoromethyl, halogen, -Y-R-Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl.

The fifth variant of the invention includes the compounds of formula I, in which there is no, R3and R4mean C1-C6alkyl, R2, R3, R6and Z have the meanings indicated above, And means-CH2-CH2-, and R1means phenyl, heteroaryl, alkyl or cycloalkyl. Preferably R1means phenyl, substituted by at least one Deputy, chosen from a number of trifluoromethyl, halogen, -Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl. More preferably R1means heteroaryl, substituted by at least one Deputy, chosen from a number of trifluoromethyl, halogen, -Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3and krenovou group, a Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl. Most preferably, R1means alkyl or cycloalkenyl.

The sixth variant of the invention includes compounds in which there is no, R2, R3, R4, R5, R6and Z have the meanings indicated above, a represents a-CH=CH-, R1means phenyl, optionally substituted Deputy, chosen from a number of trifluoromethyl, halogen, -Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl.

The seventh version of the invention includes compounds in which there is no, R2, R3, R4, R5, R6and Z have the meanings indicated above, a represents a-CH2-CH2-, R1means phenyl, optionally substituted Deputy, chosen from a number of trifluoromethyl, halogen, -Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl.

The eighth version of the invention includes compounds in which means aryl, m is 1 or 2, R2, R3, R4, R5, R6, A and Z have the meanings at Azania above, and R1means alkyl or aryl, optionally substituted Deputy, chosen from a number of trifluoromethyl, halogen, -Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl. Preferably R1means optionally substituted phenyl.

A ninth variant of the invention includes compounds in which means heteroaryl, m is 1 or 2, R1means alkyl, R2, R3, R4, R5, R6, A and Z have the values listed above. Preferred compounds in which a represents-CH=CH-.

In addition, preferred compounds of formula I in which R2means hydrogen.

Preferred are also the compounds of formula I in which R3-R6independently selected from a number of hydrogen and alkyl. The most preferred compounds of formula I in which R3-R6independently selected from a number of hydrogen and methyl.

Another preferred variant of the present invention are the compounds of formula I in which R3-R6mean hydrogen.

The compounds of formula I include optical isomers, diastereomers, enantiomers specified patterns or pharmaceutically acceptable salts, their biohydrology amides, esters or imide is. The preferred stereochemical structure similar to natural PGE2.

Compounds of the present invention can exist in the form of resolutiony forms, as well as in the form of a solvate, including hydrates. In General, the solvated forms, including hydrates, equivalently nonsolvated forms and are also included in the scope of the present invention.

In addition, the compounds of formula I form pharmaceutically acceptable basic additive salt. Such forms are also included in the scope of the present invention.

The present invention primarily relates to compounds of formula I,

where

And means-CH2-CH2- or-CH=CH-,

In absent or denotes aryl or heteroaryl,

Z denotes-C(O)OR', -C(O)NR'r R", -C(O)NSO2R', -PR'(O)(OR'), -PO(OR')2or tetrazol-5-yl, where R' and R" independently of one another denote hydrogen or C1-C6alkyl,

m denotes 1, 2, 3, 4, 5 or 6,

R1means alkyl, alkenyl, quinil, cycloalkenyl, geterotsiklicheskikh, aryl, arylalkyl or heteroaryl assuming that means aryl or heteroaryl, and R3, R4, R5and R6at the same time do not represent a hydrogen, or R1means geterotsiklicheskikh, aryl or heteroaryl if that is absent, and R3, R4, R5and R6at the same time who appoints hydrogen

R2means hydrogen or C1-C6alkyl, C1-C6alkenyl or C1-C6quinil,

R3, R4, R5and R6each independently of one another denotes hydrogen or C1-C6alkyl, or R3and R4, R5and R6or R3and R5together with the atom to which they are attached form a cyclic3-C7alkyl,

or their pharmaceutically acceptable salts or MES, an individual isomer or a racemic or prizemistoj mixture of isomers.

Preferred are the compounds of formula I, which is absent, and R1means aryl, optionally substituted Deputy selected from the group comprising trifluoromethyl, halogen, -Y-Ra, -Y-OR-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, and Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl.

In addition, preferred compounds of formula I in which R1means unsubstituted phenyl.

Another preferred object of the present invention are the compounds of formula I in which R1means phenyl, substituted Deputy selected from the group comprising trifluoromethyl, halogen, -Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C 3alkylenes group, and Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl.

Preferred are also the compounds of formula I in which Rameans phenyl, optionally substituted by a Deputy selected from the group comprising C1-C6alkyl, C1-C6alkoxy, trifluoromethyl and halogen.

Also preferred are the compounds of formula I in which R1means phenyl, substituted by at least one Deputy-Y-Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, and Rameans phenyl, optionally substituted by a Deputy selected from the group comprising C1-C6alkyl, C1-C6alkoxy, trifluoromethyl and halogen.

Another preferred object of the present invention are the compounds of formula I in which R1means phenyl, substituted by at least one Deputy-Y-Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans optionally substituted heteroaryl.

Also preferred are the compounds of formula I in which R1means phenyl, substituted by at least one Deputy-Y ORawhere Y denotes a chemical bond or a C1-C3alkylenes group and R ameans phenyl, substituted Deputy selected from the group comprising C1-C6alkyl, C1-C6alkoxy, trifluoromethyl and halogen.

Another object of the present invention are the compounds of formula I in which R1means phenyl, substituted by at least one Deputy-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, and Rameans phenyl, optionally substituted by at least one Deputy, selected from the group comprising C1-C6alkyl, C1-C6alkoxy, trifluoromethyl and halogen.

In addition, preferred compounds of formula I, which is absent, and R1means heteroaryl.

In addition, the preferred object of the present invention are the compounds of formula I in which R1means heteroaryl, substituted Deputy selected from the group comprising trifluoromethyl, halogen, -Y-Ra, -Y Oraand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, and Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl.

Preferred are also the compounds of formula I, which is absent, and R3and R4mean C1-C6alkyl.

Another preferred object of the present invented the I are the compounds of formula I, in which R1means phenyl, optionally substituted by a Deputy selected from the group comprising trifluoromethyl, halogen, -Y-Ra-Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl.

Another preferred object of the present invention are the compounds of formula I in which R1means heteroaryl, optionally substituted Deputy selected from the group comprising trifluoromethyl, halogen, -Y-Ra,-Y ORaand-Y-(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, and Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl.

In addition, preferred compounds of formula I in which R1means alkyl or cycloalkenyl.

Another preferred object of the present invention are the compounds of formula I in which a represents-CH2-CH2-.

In addition, preferred compounds of formula I, in which there is no, and a represents-CH2-CH2-.

Another preferred object of the present invention are the compounds of formula I, which is absent, and R1means phenyl, optionally substituted replace the eat, selected from the group comprising trifluoromethyl, halogen, -Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans C1-C6alkyl, aryl, heterocyclyl, heteroaryl or heterocyclyl.

Preferred are also the compounds of formula I, which means aryl, m is 1 or 2, and R1means alkyl, aryl or heteroaryl.

In addition, preferred compounds of formula I in which R1means optionally substituted phenyl.

Another preferred object of the present invention are the compounds of formula I in which R1means alkyl.

In addition, preferred compounds of formula I, which means heteroaryl, m is 1 or 2, and R1means alkyl.

Preferred compounds of formula I are selected from the group comprising the following compounds:

7-[2-((E)-3-hydroxy-3-naphthalene-2-ylpropyl)-5-oxopyrrolidin-1-yl]heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-phenoxyphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-[(R)-2-(E)-3-hydroxy-3-phenylpropyl)-5-oxopyrrolidin-1-yl]heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(morpholine-4-sulfonyl)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-methoxyphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(4-phenoxyphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-(3-benzoylphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-(3-ethoxyphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-(3-ethylphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-(3-benzoylphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-(3-bromophenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-[(R)-2-((E)-3-biphenyl-3-yl-3-hydroxypropyl)-5-oxopyrrolidin-1-yl]heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(2'-methylbiphenyl-3-yl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(S)-2-[3-hydroxy-3-(5-orthomolecular-2-yl)propyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(S)-2-[3-(1-benzyl-1H-pyrazole-4-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-5-[(E)-3-hydroxy-3-(5-triptorelin-2-yl)propenyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}heptane acid,

7-(R)-{2-[(E)-3-hydroxy-3-(3-hydroxyphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-pyrrol-1-ylmethylene)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-pyrazole-1-ylmethylene)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-methoxymethyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)3-(3-cyclopentylacetyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-(2'-ethoxymethyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-(2'-chlorobiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(4-methoxyphenoxy)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-{(R)-2-[(E)-3-(4'-chlorobiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid and

7-{(R)-2-[(E)-3-(3'-chlorobiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid.

In addition, preferred compounds are selected from the following groups:

7-{(R)-2-[(E)-3-(3-cyclopentylacetyl)-3-hydroxypropyl] -5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-(2'-ethoxymethyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-(2'-chlorobiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(4-methoxyphenoxy)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-{(R)-2-[(E)-3-(4'-chlorobiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-(3'-chlorobiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(5-triptorelin-2-yl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-triptoreline)propenyl]-5-oxopyrrolidin-1-yl}heptane who Isleta,

7-((S)-2-{3-[3-(4-pertenece)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-phenoxymethyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

methyl ether 7-{(R)-2-[(E)-3-hydroxy-3-(3-phenoxymethyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(1-methyl-1H-pyrrol-2-yl)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

methyl ester of 7-((R)-2-{(E)-3-hydroxy-3-[3(1-methyl-1H-pyrrol-2-yl)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-{(R)-2-[(E)-3-(3-butoxyphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-(3-benzyloxyphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-((R)-2-{(E)-3-[3-(2-chlorobenzoyloxy)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-{(R)-5-[(E)-3-hydroxy-3-(5-triptorelin-2-yl)propenyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}heptane acid,

7-[(R)-5-((E)-3-hydroxycut-1-enyl)-3,3-dimethyl-2-oxopyrrolidin-1-yl]heptane acid,

7-[2-((E)-3-hydroxycut-1-enyl)-3,3-dimethyl-2-oxopyrrolidin-1-yl]heptane acid,

7-[(R)-5-((S)-(E)-5-cyclobutyl-3-hydroxyben-1-enyl)-3,3-dimethyl-2-oxopyrrolidin-1-yl]heptane acid,

7-{5-[(E)-3-hydroxy-4-(3-methoxymethyl)buta-1-enyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}heptane acid,

7-((R)-5-((E)-3-hydroxy-3-[3-(4-IU is oxybenzyl)phenyl]propenyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-methacryloxypropyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-((R)-2-{(E)-3-[3-(3-pertenece)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-((R)-2-{(E)-3-[3-(3-phenoxy)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(3-methoxyphenoxy)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-((R)-2-((E)-3-hydroxy-3-[3-(4-triptoreline)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-orthotoluidine)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-[(R)-2-((E)-3-biphenyl-2-yl-3-hydroxypropyl)-5-oxopyrrolidin-1-yl]heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(3-triptoreline)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(2-methoxyphenoxy)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(2-morpholine-4-yl-ethoxy)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-{(R)-2-[(E)-3-(6,2'-dimethylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(S)-2-[(R)-3-hydroxy-3-(3-triptoreline)propyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-paratoluidine)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-((R)-2-{(E)-3-[3-(4-pertenece)phenyl]-3-HYDR is cyprodinil}-5-oxopyrrolidin-1-yl)heptane acid,

7-((R)-2-{(E)-3-[3-(4-chlorophenoxy)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-{(R)-2-[(E)-3-(4'-chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[3-(4'-chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(methyl-orthotolidine)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(methylpentylamino)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-penetrometer)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-[(R)-2-((E)-3-hydroxy-3-{3-[2-(2-oxopyrrolidin-1-yl)ethoxy]phenyl}propenyl)-5-oxopyrrolidin-1-yl]heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(4'-hydroxy-2'-methylbiphenyl-3-yl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-indol-1-ylphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-((Z)-3-propylphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-propylphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-2-[(E)-3-(3-dimethylcarbamoyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-((R)-2-{(E)-3-[3-(2-tert-butoxyethoxy)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-((R)-2-{(E)-3-[3-(3-horfe is hydroxy)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-{(S)-2-[(R)-3-hydroxy-3-(4'-hydroxy-2'-methylbiphenyl-3-yl)propyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(4-methoxybenzyl)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(tetrahydropyran-4-ylidenemethyl)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(tetrahydropyran-4-ylmethyl)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid,

7-[(R)-2-((E)-3-hydroxy-3-{3-[1-(4-methoxyphenyl)methanol]phenyl}propenyl)-5-oxopyrrolidin-1-yl]heptane acid,

7-{(R)-5-[(E)-3-(4'-chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}heptane acid,

4-{3-[(R)-2-((S)-(E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]propyl}benzoic acid,

3-{3-[(R)-2-((S)-(E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl] propyl }benzoic acid,

ethyl ester of 4-{2-[(R)-2-((S)-(E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]ethyl}benzoic acid,

2-{3-[(R)-2-((S)-(E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]propyl}benzoic acid,

4-{2-[(R)-2-((S)-(E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]ethyl}benzoic acid,

1-{2-[(R)-2-((E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]ethyl}-1H-pyrazole-4-carboxylic acid,

5-[(R)-2-((E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]ethyl)thiophene-2-carboxylic acid,

4-(2-{(S)-2-[(R)-3-(4'-chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-who cooperrider-1-yl}ethyl)benzoic acid.

More preferred compounds of formula I are selected from the group comprising the following compounds

7-{(R)-2-[(E)-3-(4'-chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-5-[(E)-3-hydroxy-3-(5-CryptoMemory-2-yl)propenyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}heptane acid,

7-{(R)-5-[(E)-3-hydroxy-4-(3-methoxymethyl)buta-1-enyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}heptane acid,

7-((R)-2-{(E)-3-[3-(4-chlorophenoxy)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid,

4-{2-[(R)-2-((E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]ethyl}benzoic acid,

4-(2-{(S)-2-[(R)-3-(4'-chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid and

5-[(R)-2-((E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]ethyl)thiophene-2-carboxylic acid.

Also preferred are the compounds of formula I for use as therapeutically active substances.

Another preferred object of the present invention are the compounds of formula I to obtain drugs for the prevention and treatment of diseases associated with dysfunction of the bone tissue.

Preferred is also the use of compounds of formula I to obtain drugs for the prevention and treatment of diseases asso is eireannach with dysfunction of the bone tissue.

In addition, the preferred option of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of the compounds of formula I in a mixture with at least one suitable carrier, diluent or excipient.

Another preferred object of the present invention is a method of treating disease in a mammal, which can be cured by the introduction of a selective agonist of prostaglandin EP4moreover , the method comprises the administration to a mammal a therapeutically effective amount of the compounds of formula I. preferred is this method of treatment of diseases associated with dysfunction of the bone tissue.

In addition, preferred is a method of obtaining the compounds of formula I, which includes the interaction of the compounds of General formula

where R3, R4, R5and R6have the meanings indicated above, a R1means methyl or ethyl, with a phosphonate of General formula m

where R1matter mentioned above, subsequent recovery and optional hydrolysis with the formation of the compounds of formula I

where R2means hydrogen, a m, R1, R3, R4, R5, R6and Z have the values above.

In addition, preferred is a method of obtaining the compounds of formula I, which includes the interaction of the compounds of General formula

where m, R3, R4, R5and R6have the meanings indicated above, a R1means methyl or ethyl, with a phosphonate of General formula m

where R1has the values listed above, the subsequent interaction with the ORGANOMETALLIC compound of the formula R2M, where M means a metal or a magnesium halide, and R2matter above and optional hydrolysis with the formation of the compounds of formula I

where A, m, R1, R2, R3, R4, R5, R6and Z have the values listed above.

In addition, the preferred option of the present invention is a method of obtaining the compounds of formula I, which includes

a) interaction of the compounds of formula

where Rpmeans a protective group, R3, R4, R5and R6have the meanings indicated above, with an amine of the formula

where m and Z have the values listed above, then remove hydroxylamino group with the formation of the compounds of formula

b) activation obtained above in connection hydroxyl group and the interaction of the compounds with the substrate and subsequent removal hydroxylamino group with the formation of the compounds of formula

C) oxidation of the compound obtained in stage b) with the formation of the aldehyde of the formula

g) the interaction of the above aldehyde with a phosphonate of General formula m

where R1has the values listed above, with the formation of the compounds of formula

d) the interaction of the compound obtained in stage d) with the ORGANOMETALLIC compound of the formula R2M, where M means a metal or a magnesium halide, and R2has the values listed above, and

e) optional hydrolysis of ester with the formation of compounds of formula I.

The General scheme of synthesis

Compounds of the present invention be made by methods shown in the schemes of reactions. For the person skilled in the art it is obvious that within the scope of the invention, there may be some modification of these schemes, for example, some stages, including the use of protective groups for some functional groups that are incompatible with the specific conditions of the reactions is.

Starting materials and reagents used in the preparation of these compounds are commercial preparations supplied by firms Aldrich Chemical Co. (Milwaukee, WI), Bachem (Torrance, CA) or Sigma (St.Louis, MO) or get methods known to experts in this field. These diagrams are only illustrative of some methods of synthesis of compounds of the present invention, and various modifications to these schemes reactions can be used by the person skilled in the art with reference to the materials of the present application.

Unless otherwise stated, the described reaction is carried out at atmospheric pressure at a temperature of from about -78°With up to approximately 150°S, more preferably from approximately 0°With up to approximately 125°and most preferably at about room temperature, for example, approximately at 20°C.

The diagram below shows a General method of preparing compounds of formula I and their analogues. In General, these compounds are obtained when the interaction of the phosphonate of the formula m with an aldehyde of the formula and with the formation of the compounds of formula b.

Scheme And

Aldehydes of formula a (where R' is methyl, A is absent, m is 5, R3, R4, R5and R6mean hydrogen, and the radicals have the meanings specified for formula (I) are known and connections. For example, (R)-5-(hydroxymethyl)-2-pyrrolidinone is a commercial product, and its reception and transformation of the connection as described in article S.Saijo etc., Chem. Pharm. Bull., 28, 1449-1458 (1980), (R)-3,3-dimethyl-5-(hydroxymethyl)-2-pyrrolidinone, in which R3and R4mean methyl, and R5and R6mean hydrogen, can be obtained by the method described Y.Nakagawa and others, Tetrahedron, 54, 10295-10307 (1998), and 4,4-dimethyl-5-(hydroxymethyl)-2-pyrrolidinone, in which R3and R4mean hydrogen, and R5and R6means methyl, can be obtained by the method described R.L.Mackman etc., J. Chem. Soc., Perkin Trans., 2111-2122 (1997).

In the interaction of the aldehyde and β-ketotifenum General formula m in the presence of a base such as sodium hydride, tert-piperonyl potassium, hexamethyldisilazide potassium or lithium chloride, and a tertiary amine in a solvent such as acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane or tert-butyl methyl ether, to obtain the compound of General formula b, where SN=SN - corresponds to the group a in formula I.

Simply restoring the ketone b-hydride, such as zinc borohydride, in a solvent such as dichloromethane, toluene, ethanol or tetrahydrofuran, or a combination of sodium borohydride/cerium chloride (III) in proton solvent such as methanol, leads to the formation of diastereomeric mixture of alcohols of the formula ie,

For the teachings of the compounds of formula I, where a represents-CH2-CH2-, a R1means aryl or heteroaryl, compound b, first restore the double bond in hydrogen atmosphere in the presence of a catalyst such as platinum oxide or palladium on coal. As other hydrides to obtain connection can be used, for example, stoichiometric combination of alumoweld lithium/ethanol/(R)-(-)-binaphthol, as described R.Noyori etc., J. Am. Chem. Soc., 106, 6717-6725 (1984), the combination of catalytic amounts of (S)-2-methyl-CBS-oxazaborolidine with the stoichiometric quantity of borane/dimethyl sulfide, as described E.J.Corey etc., J. Am. Chem. Soc., 109, 7925-7926 (1987), or stoichiometric amounts of (S)-3-PINANYL-9-borabicyclo[3.3.1]nonane as described ..Midland etc., J. Am. Chem. Soc., 102, 867-869 (1980).

In another embodiment, a saturated alcohol (i.e. related to the compounds of General formula e in the diagram (A) of General formula I (where R1means aryl or heteroaryl) can be obtained directly from compounds of formula b in the interaction with sodium borohydride in proton solvent such as ethanol or 2-methoxyethanol.

Compounds of General formula d receive when interacting compounds of formulas b and c with halide magyarkanizsa connections, including R2with the values specified for formula I, more preferably a Grignard reagent of General formula R2MgBr.

Complex EF the factors C and e hydrolyzing with formation of the corresponding acids d and f on techniques, well known to the person skilled in the art, for example, in the presence of a base such as lithium hydroxide, sodium or potassium, or in the presence of acid, such as sulfuric acid or hydrochloric acid in proton solvent or in a solvent from the group of ethers containing water, or using lipase type VII in 0.05 M phosphate buffer solution, pH 6.8, as described C.Luthy etc., J. Am. Chem. Soc., 100, 6211-6217 (1978).

Phosphonate of General formula m produced by the method shown below in scheme B.

Scheme B

Derivatives of benzoic acid, for example, compounds of formulas g and i. (where L is a leaving group, with the values specified above) are known compounds or can be obtained by the known methods, and then converted into compounds of formulas h and k respectively. Conditions for obtaining compounds of formula h are described D.A.Evans and others, Tetrahedron Lett., 39, 2937 (1998). Methods for obtaining compounds of formula k is described A.M.Echavarren and J.K.Stille., J. Am. Chem. Soc., 109, 5478-5486 (1987), N.Miyaura and A.Suzuki, Chem. Rev., 95, 2457-2483 (1995) and A.F.Littke etc., J. Am. Chem. Soc., 122, 4020-4028 (2000). Connections h and k make the connection m when interacting with dialkyldithiophosphate, which is first treated with a base, such as n-utility or diisopropylamide lithium, in an inert solvent from the group of ethers, such as tetrahydrofuran or tert-is utilmately ether.

A diagram shows the General method of preparing compounds of formula I, where In denotes aryl or heteroaryl.

Schema

Starting compound of the formula q are known compounds. For example, furano formula q in which R3, R4, R5and R6mean hydrogen, is a commercial product. The compounds of formula r are also known compounds. For example, penicillin, in which the group Z in the compound r is para-C(O)HE a m is 1, is a commercial product, using which a person skilled in the art can obtain the corresponding ester.

In the first stage of the scheme In the hydroxyl group in the compound q to protect the group specified in the bid, such as benzyl group. Protected lactone q condensed with the amine r, dissolving in Amina or in a polar solvent such as acetonitrile, N-methyl-2-pyrrolidinone, isopropanol or tetrahydrofuran, with the formation of compound s. The compounds of formula t is obtained using the activation of the primary hydroxyl group in the compound s (with the formation of the leaving group) in collaboration with benzosulphochloride or methanesulfonanilide. The lactam is obtained by treatment with base, such as tert-piperonyl potassium, sodium methoxide and the like, the Protective group of the primary hydroxyl is the group delete recovery for example, gaseous hydrogen in the presence of a catalyst, such as Raney Nickel, platinum oxide or palladium on coal, thus obtain compounds of General formula t. Of the compounds of formula't receive the aldehyde AA known methods. Then the aldehyde AA is converted into a compound according to the invention by a method shown in the diagram above And for the conversion of aldehyde and.

Industrial applicability

Compounds of the present invention are selective agonists of prostaglandin EP4and can be used for treatment of several pathological conditions associated with diseases, mediated by receptors of prostaglandin EP4first of all pathological conditions associated with dysfunction of the bone tissue, characterized by low bone mass and degradation of bone tissue with a consequent increase in bone fragility and susceptibility to fractures, especially those States that require a significant increase in bone mass, bone mass, or bone strength. Condition associated with low bone mass include such a condition in which there is a decrease in bone mass below the normal level, typical of this age norms. These States are also infantile idiopathic and primary osteoporosis. Treatment OST is oporoza includes the prevention or reduction of the intensity of long-term complications, such as curvature of the spine, loss of height, an implantable prosthesis, the healing of fractures and prevention of disorders of the prostate gland. The invention also includes the treatment of the reduction of bone mass associated with periodontitis and ingrowth prostheses. For the person skilled in the art it is obvious that the term bone mass refers in fact to the mass of bone per unit area, which is sometimes referred to as bone density. It is established that the analogues of 8-Aza-11-deoxyprostaglandin of the present invention can be used for treatment of dysfunction of the bone tissue.

Other applications of these compounds include prevention and/or treatment of allergies, alveolar abscess, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), arthritis, asthma, atopy, bronchitis, burns, cancer, cardiovascular disease, Crohn's disease, chronic obstructive lung disease, congestive heart failure, gingivitis, glomerulonephritis, hepatitis, liver damage, acute hepatitis, hypertension (hypertension), hypercytokinemia, immune disorders, inflammatory diseases of the gastrointestinal tract, Kawasaki disease, insufficiency of liver function, liver disease, deficiency of lung function, syndrome the and activation of macrophages, multiple organ failure, multiple sclerosis, myocardial ischemia, nephritis, neurodegeneration, neuronal death, rejection of transplanted organs, periodontitis, aggregated platelets, lung damage, pulmonary fibrosis, emphysema, disorder of the kidneys, renal failure, renal impairment, pulmonary insufficiency, septicemia, sepsis, shock, sleep disorders and disorders of platelet aggregation, of still's disease, systemic granuloma, thrombosis, ulcerative colitis and uraemia or the use of these compounds as the promoter of osteogenesis.

Biological tests

The compounds of formula I of the present invention bind to receptors EP4and affect receptors EP4who are subspecies receptor PGE2. The action of the compounds according to the present invention was determined by analysis of binding to cells expressing the subspecies prostanoid receptors, as described in detail in example 10. The activity of compounds is determined at competitive binding of these compounds with the appropriate target, as described in example 11. Compounds of the present invention can be analyzed for their effects on bone density according to the method described Gunness-Neue and Hock, Metab. Bone Dis., 5, 177-181 (1984), as described in detail in PR is as 12.

Methods of administration and pharmaceutical compositions

In General, the compounds of the present invention can be introduced in a therapeutically effective amount by any acceptable route of administration, accepted for agents of similar purpose. The actual number of compounds of the present invention, i.e. the active ingredient, will depend on many factors such as the severity of the disease to be treated, the age and relative health of the subject, the activity of the used connection method and form of administration and other factors.

Therapeutically effective amounts of compounds of formula I can vary from approximately 0,00005-10 mg per kg of body weight of the recipient per day, preferably approximately of 0.0001-1 mg/kg/day. Thus, when administered to a patient weighing 70 kg, the dose will be from about 0.01 mg to 1.0 mg per day.

In General, the compounds of the present invention is administered as pharmaceutical compositions by one of the following ways: oral, systemic (e.g., transdermal, intranasal or by using a suppository), or parenteral (e.g. intramuscular, intravenous or subcutaneous) administration. The preferred method of administration is oral, with appropriate daily regimen medicines, cat heaven shall be appointed in accordance with the severity of the disease. Compositions can take the form of tablets, pills, capsules, semi-solid compositions, powders, compositions for sustained release, solutions, suspensions, elixirs, aerosols, or any other suitable compositions.

The choice of structure depends on many factors such as method of administration of the medicinal product (for example, for oral administration, the preferred compositions in the form of tablets, pills or capsules) and bioavailability of the active compounds. Recently developed pharmaceutical compositions especially for drugs with low bioavailability. The method is based on the fact that the bioavailability can be increased by increasing the surface area, i.e. by reducing the size of the particles. For example, in US 4107288 described pharmaceutical composition containing particles of size from 10 to 1000 nm, in which the active compound is fixed on the matrix of cross-linked polymer. In the US 5145684 described obtaining a pharmaceutical composition, in which the drug compound is pulverized to nanoparticles (average rasmar particles is 400 nm) in the presence of the surface modifier, and then dispersed in a liquid medium with the formation of the pharmaceutical composition, have a much higher bioavailability.

In General, the compositions include a compound of formula I in combination for men is our least one pharmaceutically premimum excipients. Suitable excipients are non-toxic, contributing to the introduction and not having a negative effect on therapeutic properties of the compounds of formula I. Such excipient can be a solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient, usually well-known specialist in this field.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and other Liquid and semi-solid excipients are selected from a number of glycerine, propylene glycol, water, ethanol, and various oils, including mineral, animal, vegetable or synthetic oils, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. are Preferred liquid carriers, particularly for injecion solutions, include water, saline, aqueous dextrose, and glycols.

For dispersing the compounds of the present invention in aerosol form are used compressed gases. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

Other pharmaceutically acceptable excipients and their formulations are described in the book Remington''s Pharmaceutical Sciences, ed. by E.W.Martin, Mack Publishing Company,18th edition (1990).

The content of soedineniya in the composition may vary within the range known to the person skilled in the art. Typically, the composition contains from about 0.01 to about 99.99 wt.% the compounds of formula I, calculated on the total weight of the composition taking into account the mass of one or more suitable pharmaceutical excipients. Preferably the content of the compound is about 1-80 wt%. Typical farmatsevticheskii compositions comprising a compound of formula I, described in example 9

Examples

The following preparations and examples are given with the purpose of enabling the person skilled in the art will be familiar with the proposed invention and use it in practice. Examples are given to illustrate and not limit the scope of the invention.

Example 1

7-{(R)-2-[(E)-3-(3-Benzoylphenyl)-3-hydroxypropyl-5-oxopyrrolidin-1-yl)heptane acid (1)

Stage 1

Methyl ether 3-benzylbenzoate acid

3-Benzoylbenzene acid (5,12 g, and 22.6 mmol) was stirred in methanol (45 ml) with conc. H2SO4(2.0 ml) at 60°C for 18 hours the Reaction mixture was diluted with ethyl acetate and washed with aqueous solution of NaHCO3.

The organic layer was dried over MgSO4was filtered and concentrated, to receive the methyl e is Il-3-benzoylbenzene acid (5.4 g, to 22.6 mmol) in quantitative yield as yellow oil.

Methyl ether 3-benzoylbenzene acid (653 mg, of 2.72 mmol) was stirred triperoxonane acid (3 ml) with triethylsilane (1.3 ml, 8,15 mmol) at room temperature for 22 hours, the Reaction mixture was diluted with ethyl acetate and washed with aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. The resulting oil was purified by chromatography on a column (eluent:hexane/ethyl acetate 25:1), was obtained methyl ether 3-benzylbenzoate acid (589 mg, 2.6 mmol) in the form of oil.

Stage 2

Dimethyl ether [2-(3-(benzoylphenyl)-2-oxoethyl]phosphonic acid

To a solution of dimethylmethylphosphonate (0,423 ml, 3.9 mmol) in THF (10 ml) at -78°C was added 1.6 M solution of BuLi in hexane (2,44 ml, 3.9 mmol). After 1 h the solution was added methyl ether 3-benzylbenzoate acid (589 ml, 2.6 mmol) in THF (5 ml). After 15 min the reaction mixture was heated to room temperature and stirred for another 3 hours the Reaction was stopped by addition of an aqueous solution of NaHCO3and were extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on a column (eluent: ethyl acetate/hexane, 18:1), was obtained dimethyl ether [2-(3-benzoylphenyl)-2-oxo is Teal]phosphonic acid (677 mg, a 2.12 mmol) in the form of oil.

Stage 3

Ethyl ester of 7-{(R)-2-[(E)-3-(3-benzoylphenyl)-3-oxopropyl]-5-oxopyrrolidin-1-yl}heptane acid

To 60%of the resultant solution of sodium hydride in mineral oil (20 mg, 0.51 mmol) was added a solution of dimethyl [2-(3-(benzoylphenyl)-2-oxoethyl]phosphonic acid (164 mg, 0.51 mmol) in DME (5 ml). After 1.5 h the solution was added ethyl ester 7-(R)-2-formyl-5-oxopyrrolidin-1-yl)heptane acid (126 mg, 0.47 mmol) in DME (5 ml). The reaction mixture was stirred for 45 min at room temperature, diluted with ethyl acetate and washed with aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on a column (eluent: ethyl acetate/hexane, 2,5:1), was obtained ethyl ester of 7-{(R)-2-[(E)-3-(3-benzoylphenyl)-3-oxopropyl]-5-oxopyrrolidin-1-yl}heptane acid (112 mg, 0.24 mmol) in the form of oil.

Stage 4

7-{(R)-2-[(E)-3-(3-Benzoylphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (1)

To a solution of ethyl ester of 7-{(R)-2-[(E)-3-(3-benzoylphenyl)-3-oxopropyl]-5-oxopyrrolidin-1-yl}heptane acid (112 mg, 0.24 mmol) in ethanol (5 ml) was added NaBH4(37 mg, 0.97 mmol). The reaction mixture was stirred at room temperature for 2 h and then koncentrira is whether almost dry. The residue was dissolved in ethyl acetate and washed with saline. The organic layer was dried over MgSO4was filtered and concentrated, to receive ethyl ester of 7-{(R)-2-[(E)-3-(3-benzoylphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (122 mg, 0.24 mmol) as an oil in quantitative yield. The resulting substance was dissolved in ethanol (5 ml) was added an aqueous solution (2.5 ml) of the monohydrate of lithium hydroxide (44 mg, 1.05 mmol). After stirring at room temperature for 4 h the reaction mixture was concentrated almost to dryness. The obtained concentrated solution was diluted salt solution and washed with dichloromethane. The aqueous layer was acidified using 1 N. HCl and the product was extracted with dichloromethane. The organic layer was dried over MgSO4was filtered and concentrated, to receive 7-{(R)-2-[(E)-3-(3-benzoylphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (1) (77 mg, 0.18 mmol) in the form of oil. MS: 436 [(M+N)+].

The following compounds of formula I were obtained in the same way as described in example 1, replacing in stage 3 of dimethyl ether [2-(3-benzoylphenyl)-2-oxoethyl]phosphonic acid following the corresponding phosphonates derived from the corresponding known acids or methyl esters, as described in stages 1 and/or 2:

7-[(R)-2-((E)-3-hydroxy-3-naphthalene-2-ylpropyl)-5-oxopyrrolo the one-1-yl]heptane acid (2), MS: 396 [(M+N)+], was obtained from dimethyl (2-naphthalene-2-yl-2-oxoethyl)phosphonic acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-phenoxyphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (3), MS: 438 [(M+N)+], was obtained from dimethyl [2-oxo-2-(3-phenoxyphenyl)ethyl]phosphonic acid,

7-[(R)-2-((E)-3-hydroxy-3-phenylpropyl)-5-oxopyrrolidin-1-yl]-heptane acid (4), MS: 346 [(M+N)+], was obtained from dimethyl (2-oxo-2-phenylethyl)phosphonic acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-methoxyphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (5), MS: 376 [(M+N)+], was obtained from dimethyl [2-(3-methoxyphenyl)-2-oxoethyl]phosphonic acid,

7-{(R)-2-[(E)-3-hydroxy-3-(4-phenoxyphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (6), MS: 438 [(M+N)+], was obtained from dimethyl [2-oxo-2-(4-phenoxyphenyl)ethyl]phosphonic acid,

7-{(R)-2-[(E)-3-(3-ethoxyphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (7), MS: 390 [(M+N)+], was obtained from dimethyl [2-(3-ethoxyphenyl)-2-oxoethyl]phosphonic acid,

7-{(R)-2-[(E)-3-(3-ethylphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (8), MS: 374 [(M+N)+], was obtained from dimethyl [2-(3-ethylphenyl)-2-oxoethyl]phosphonic acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(morpholine-4-sulfonyl)phenyl]-propenyl}-5-oxopyrrolidin-1-yl)heptane is islote (9), MS: 495 [(M+N)+], was obtained from dimethyl [2-(3-morpholine-4-sulfonyl)phenyl-2-oxoethyl]phosphonic acid,

7-{(R)-2-[(E)-3-(3-bromophenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (10), MS: 425 [(M+N)+], was obtained from dimethyl [2-(3-bromophenyl)-2-oxoethyl]phosphonic acid,

7-(R)-{2-[(E)-3-hydroxy-3-(3-hydroxyphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (11), MS: 362 [(M+N)+], was obtained from dimethyl [2-(3-hydroxyphenyl)-2-oxoethyl]phosphonic acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-pyrrol-1-yl-were)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (12), MS: 425 [(M+N)+], was obtained from dimethyl [2-(3-pyrrol-1-ylmethylene)-2-oxoethyl] phosphonic acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-pyrazole-1-yl-were)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (13), MS: 426 [(M+N)+], was obtained from dimethyl [2-(3-pyrazole-1-ylmethylene)-2-oxoethyl]phosphonic acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-methoxymethyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (14), MS: 390 [(M+N)+], was obtained from dimethyl [2-(3-methoxymethyl)-2-oxoethyl]phosphonic acid,

7-{(R)-2-[(E)-3-(3-cyclopentylacetyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (15), MS: m/z 430 (M+1), was obtained from dimethyl [2-(3-cyclopentyloxy)-2-oxoethyl] Fofonov the th acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-triptoreline)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (16), MS: m/z 414 (M+1), was obtained from dimethyl [2-(3-triptoreline)-2-oxoethyl]phosphonic acid,

7-{(S)-2-[(R)-3-hydroxy-3-(3-triptoreline)propyl]-5-oxopyrrolidin-1-yl}heptane acid (17), (MS: m/z 416 (M+1), was obtained from dimethyl [2-(3-triptoreline)-2-oxoethyl]-phosphonic acid, however, instead of recovering the sodium borohydride spent hydrogenation product at stage 3 (when the pressure of hydrogen gas of 1 ATM, the catalyst is 10% palladium on carbon in EtOAc for 1.5 h and then the product vosstanavlivali under the conditions described E.J.Corey and others, SOC., 109, 7925-7926, (1987), using as the catalyst a 1 M solution of (S)-2-methyl-CBS in toluene (Aldrich company)),

7-{(R)-2-[(E)-3-hydroxy-3-(3-phenoxymethyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (18), MS: m/z 452 (M+1), was obtained from dimethyl [2-(3-phenoxymethyl)-2-oxoethyl]phosphonic acid;

methyl ether 7-{(R)-2-[(E)-3-hydroxy-3-(3-phenoxymethyl)-propenyl]-5-oxopyrrolidin-1-yl}heptane acid (19), MS: m/z 466 (M+1),

7-((R)-2-{(E)-3-hydroxy-3-[3(1-methyl-1H-pyrrol-2-yl)phenyl]-propenyl}-5-oxopyrrolidin-1-yl)heptane acid (20), MS: m/z 425 (M+1), was obtained from dimethyl 2-[3-(1-methyl-1H-pyrrol-2-yl)phenyl)-2-oxoethyl]foston the howling acid,

methyl ester of 7-((R)-2-{(E)-3-hydroxy-3-[3-(1-methyl-1H-pyrrol-2-yl)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid (21), MS: m/z 440 (M+1),

7-{(R)-2-[(E)-3-(3-butoxyphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (22), MS: m/z 418 (M+1), was obtained from dimethyl [2-(3-butoxyphenyl)-2-oxoethyl]phosphonic acid,

7-{(R)-2-[(E)-3-(3-benzyloxyphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (23), MS: m/z 452 (M+1), was obtained from dimethyl [2-(3-benzyloxyphenyl)-2-oxoethyl]-phosphonic acid,

7-{(R)-2-[(E)-3-(2-chlorobenzylidene)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (24), MS: m/z 487 (M+1), was obtained from dimethyl {2-[3-(2-chlorobenzoyloxy)phenyl]-2-oxoethyl}phosphonic acid,

7-[(R)-2-((E)-3-biphenyl-2-yl-3-hydroxypropyl)-5-oxopyrrolidin-1-yl]heptane acid (25), MS: m/z 422 (M+1), was obtained from dimethyl 2-[2-biphenyl)-2-oxoethyl]phosphonic acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(2-morpholine-4-ylethoxy)phenyl]-propenyl}-5-oxopyrrolidin-1-yl)heptane acid (26), MS: m/z 475 (M+1), was obtained from dimethyl [2-(3-(2-morpholine-4-yl-ethoxy)phenyl)-2-oxoethyl]phosphonic acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(methylpentylamino)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid (27), MS: m/z 451 (M+1), was obtained from dimethyl [3-(methylpentylamino is)phenyl-2-oxoethyl]phosphonic acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(methylacetanilide)phenyl]-propenyl}-5-oxopyrrolidin-1-yl)heptane acid (28), MS: m/z 465 (M+1), was obtained from dimethyl [3-(methylacetanilide)phenyl-2-oxoethyl]phosphonic acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-penetrometer)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (29), MS: m/z 466 (M+1), was obtained from dimethyl [2-(3-penetrometer)-2-oxoethyl]phosphonic acid,

7-[(R)-2-((E)-3-hydroxy-3-{3-[2-(2-oxopyrrolidin-1-yl)ethoxy]-phenyl}propenyl)-5-oxopyrrolidin-1-yl]heptane acid (30), MS: m/z 473 (M+1), was obtained from dimethyl [2-{3-[2-(2-oxopyrrolidin-1-yl)ethoxy] phenyl}-2-oxoethyl] phosphonic acid,

7-((R)-2-{(E)-3-[3-(2-tert-butoxyethoxy)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid (31), MS: m/z 462 (M+1), was obtained from dimethyl [2-[3-(2-tert-butoxyethoxy)-phenyl]-2-oxoethyl]phosphonic acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-indol-1-ylphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (32), MS: m/z 461 (M+1), was obtained from dimethyl [2-[3-indol-1-ylphenyl]-2-oxoethyl]phosphonic acid,

7-{(R)-2-[(E)-3-hydroxy-3-((Z)-3-propylphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (33), MS: m/z 386 (M+1), was obtained from dimethyl {2-[(Z)-3-propylphenyl]-2-oxoethyl} phosphonic acid,

7-{(R)-2-[(E)-3-hydroxy-3-(3-propylphenyl)prop the Nile]-5-oxopyrrolidin-1-yl}heptane acid (34), MS: m/z 388 (M+1), was obtained from dimethyl [2-(3-propylphenyl)-2-oxoethyl]phosphonic acid,

7-{(R)-2-[(E)-3-(3-dimethylcarbamoyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (35), MS: m/z 417 (M+1), was obtained from dimethyl [2-(3-dimethylcarbamoyl)-2-oxoethyl]phosphonic acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(tetrahydropyran-4-ylidenemethyl)-phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid (36), MS: m/z 442 (M+1), was obtained from dimethyl {2-[3-(tetrahydropyran-4-ylidenemethyl)phenyl]-2-oxoethyl} phosphonic acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(tetrahydropyran-4-yl-methyl)phenyl]-propenyl}-5-oxopyrrolidin-1-yl)heptane acid (37), MS: m/z 444 (M+1), was obtained from dimethyl {2-[3-(tetrahydropyran-4-yl-methyl)phenyl]-2-oxoethyl}phosphonic acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(4-methoxybenzyl)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid (38), MS: m/z 466 (M+1), was obtained from dimethyl {2-[3-(4-methoxybenzyl)phenyl]-2-oxoethyl}phosphonic acid, and

7-{(R)-2-[(E)-3-hydroxy-3-(5-triptorelin-2-yl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (39), MS: m/z 404 (M+1), was obtained from dimethyl [2-oxo-2-(5-triptorelin-2-yl)ethyl]phosphonic acid.

Example 2

7-{(R)-2-[(E)-3-(3-Benzoylphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (40)

Stage 1

Methyl ester 3-(dimethoxytrityl)benzoic acid

A solution of 3-benzoylbenzene acid (2 g, 8,84 mmol) and methanesulfonic acid (0,115 ml, 1.77 mmol) in methanol (15 ml) was heated at 65°C for 20 h and then cooled to room temperature. To the solution was added triethylorthoformate (1,45 ml, 13,26 mmol) and was stirred for 24 h, the Reaction mixture was diluted with ethyl acetate and washed with a solution of NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. After cleaning, Express chromatography (eluent: hexane/ethyl acetate, 20:1, +0.25% triethylamine) was obtained methyl ester 3-(dimethoxytrityl)benzoic acid (951 mg) as oil.

Stage 2

Dimethyl ether {2-[3-(dimethoxymethyl)phenyl]-2-oxoethyl}phosphonic acid

To a solution of dimethylmethylphosphonate (0.54 ml, to 4.98 mmol) in THF (15 ml) at -78°C was added 1.6 M solution of BuLi (3,11 ml, to 4.98 mmol). After stirring for 40 min the solution was added methyl ester 3-(dimethoxytrityl)benzoic acid (951 mg, of 3.32 mmol) in THF (5 ml). After 15 min the reaction mixture was heated to room temperature and was stirred for another 1 h and then the reaction was stopped by adding a solution of NaHCO3. The reaction mixture was diluted with ethyl acetate, the m and washed with a solution of NaHCO 3. The organic layer was dried over MgSO4, filtered and concentrated. After cleaning, Express chromatography (eluent:ethyl acetate/hexane, 15:1, +0.25% triethylamine) was obtained dimethyl ether {2-[3-(dimethoxymethyl)phenyl]-2-oxoethyl}phosphonic acid (784 mg, 2,07 mmol) in the form of oil.

Stage 3

Ethyl ester of 7-((R)-2-{(E)-3-[3-(dimethoxymethyl)phenyl]-3-oxopropyl}-5-oxopyrrolidin-1-yl)heptane acid

To 60% solution of sodium hydride (20 mg, 0.51 mmol) was added a solution of dimethyl ether {2-[3-(dimethoxymethyl)phenyl]-2-oxoethyl}phosphonic acid (193 mg, 0.51 mmol) in dimethoxyethane (5 ml). After 1.5 h, to the mixture was added a solution of ethyl ester of 7-((R)-2-formyl-5-oxopyrrolidin-1-yl)heptane acid (126 mg, 0.47 mmol) in dimethoxyethane (5 ml). The reaction mixture was stirred for 1 h, diluted with ethyl acetate and washed with a solution of NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated. After the rapid-chromatography (eluent: ethyl acetate/hexane 3:1 +0.25% triethylamine) was obtained ethyl ester of 7-((R)-2-{(E)-3-[3-(dimethoxymethyl)phenyl]-3-oxopropyl}-5-oxopyrrolidin-1-yl)heptane acid (124 mg, 0.24 mmol) in the form of oil.

Stage 4

7-((R)-2-{(E)-3-[3-(Dimethoxymethyl)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid

To a solution of ethyl ester of 7-((R)-2-{(E)-3-[3-(dimethoxytrityl)-phenyl]-3-oxopropyl}-5-oxopyrrolidin-1-yl)heptane acid (124 mg, 0.24 mmol) in ethanol (5 ml) was added NaBH4(36 mg, 0.96 mmol). The reaction mixture was stirred for 2.25 hours and then concentrated to dryness. The residue was dissolved in ethyl acetate and washed with a solution of NaHCO3. The organic layer was dried over MgSO4was filtered and concentrated, to receive ethyl ester of 7-((R)-2-{(E)-3-[3-(dimethoxymethyl)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid. To a solution of ethyl ester of 7-((R)-2-{(E)-3-[3-(dimethoxymethyl)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid in methanol (5 ml) was added an aqueous solution (2.5 ml) of LiOH monohydrate (46 mg, of 1.09 mmol). The reaction mixture was stirred for 6 h and then concentrated to remove methanol. The aqueous concentrate was diluted with CH2Cl2and added 1 N. HCl, and was extracted with CH2Cl2and was dried over MgSO4. The resulting mixture was filtered and concentrated, to receive 7-((R)-2-{(E)-3-[3-(dimethoxymethyl)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid (116 mg, 0.23 mmol) in the form of oil.

Stage 5

7-{(R)-2-[(E)-3-(3-Benzoylphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid

Rast is the EOS acid/Catala 7-((R)-2-{(E)-3-[3-(dimethoxytrityl)-phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid (116 mg, 0.23 mmol) in dioxane (5 ml) was stirred mixture of 1 N. HCl (1 ml, 1.0 mmol) for 18 hours, the Reaction mixture was diluted with ethyl acetate and washed with a solution of NaHCO3. The organic layer was dried over MgSO4was filtered and concentrated, to receive 7-{(R)-2-[(E)-3-(3-benzoylphenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (40) (83 mg, 0.18 mmol) as an oil; MS: 450 [(M+N)+].

The following compound of formula I was obtained when replacing in stage 3 dimethyl ether {2-[3-(dimethoxymethyl)phenyl]-2-oxoethyl}-phosphonic acid next phosphonate obtained from the corresponding known acid or ester, as described in stages 1 and/or 2:

7-[(R)-2-((E)-3-hydroxy-3-{3-[1-(4-methoxyphenyl)methanol]phenyl}-propenyl)-5-oxopyrrolidin-1-yl]heptane acid (41), MS: m/z 480 (M+1), was obtained from dimethyl (2-{3-[dimethoxy-(4-methoxyphenyl)methyl]phenyl}-2-oxoethyl)phosphonic acid.

Example 3

Methyl ether 7-{(R)-2-[(E)-3-hydroxy-3-(2'-methylbiphenyl-3-yl)-propenyl]-5-oxopyrrolidin-1-yl)heptane acid (42)

Stage 1

Methyl ether 7-{(R)-2-[(E)-3-(3-bromophenyl)-3-oxopropyl]-5-oxopyrrolidin-1-yl}heptane acid

To a solution of NaH (0.14 g, 1 EQ.) in 30 ml of dimethyl ether of ethylene glycol, stir at 0°C in nitrogen atmosphere, add recipients who do dimethyl ether [2-(3-bromophenyl)-2-oxoethyl]phosphonic acid (1,82 g, of 1.05 EQ.). The mixture was stirred at 0°C for 1 h, and then was slowly added methyl ether 7-((R)-2-formyl-5-oxopyrrolidin-1-yl)heptane acid (1.44 g, 5,64 mmol) in 2 ml of DME. The ice bath was removed and the mixture was stirred at room temperature for 3 hours Then to the mixture was added a saturated solution of ammonium chloride and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure and purified by chromatography (eluent: EtOAc/hexane, 1:1, then EtOAc/hexane, 5:1), was obtained 1.6 g of methyl ester of 7-{(R)-2-[(E)-3-(3-bromophenyl)-3-oxopropyl]-5-oxopyrrolidin-1-yl}heptane acid.

Stage 2

Methyl ether 7-{(R)-2-[(E)-3-(3-bromophenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid

To a solution of methyl ester of 7-{(R)-2-[(E)-3-(3-bromophenyl)-3-oxopropyl]-5-oxopyrrolidin-1-yl}heptane acid (0,78 g, to 1.79 mmol) in 15 ml of methanol, stirred at 0°C in an atmosphere of nitrogen, was added sodium borohydride (0,074 g) and the reaction mixture was stirred at room temperature for 6 hours Then added 1 N. HCl and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated and purified by chromatography (eluent: 50% EtOAc in hexane, then 100% EtOAc), received 670 mg metrov the th ether 7-{(R)-2-[(E)-3-(3-bromophenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid.

Stage 3

Methyl ether 7-{(R)-2-[(E)-3-hydroxy-3-(2'-methylbiphenyl-3-yl)-propenyl]-5-oxopyrrolidin-1-yl}heptane acid

To a solution of methyl ester of 7-{(R)-2-[(E)-3-(3-bromophenyl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (0.2 g, 0.46 mmol) in 10 ml of DME, stir at room temperature was added Pd(Ph3R)4(0.03 g, of 0.05 EQ.) After stirring for 5 min was added orthocarbonate acid (0.12 g, 2 equiv.) 2 M solution of Na2CO3(0.6 ml, 2.5 EQ.) and the mixture is boiled under reflux in a nitrogen atmosphere over night. The reaction mixture was cooled to room temperature, diluted 25% solution of NH4OAc (10 ml)was stirred for 5 min and extracted with ethyl acetate. The organic layer was dried over MgSO4(anhydrous), and concentrated under reduced pressure and purified, when it received 87 mg of methyl ester of 7-{(R)-2-[(E)-3-hydroxy-3-(2'-methylbiphenyl-3-yl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid.

Stage 4

7-{(R)-2-[(E')-3-Hydroxy-3-(2'-methylbiphenyl-3-yl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid

To a solution of methyl ester of 7-{(R)-2-[(E)-3-hydroxy-3-(2'-methylbiphenyl-3-yl)-propenyl]-5-oxopyrrolidin-1-yl}heptane acid (87 mg) in methanol (5 ml) was added an aqueous solution (2.5 ml) of LiOH monohydrate, the Reaction mixture was stirred for 6 h and then concentrated to remove methanol. The aqueous concentrate was diluted with CH2Cl2and was added 1N. HCl, and was extracted with CH2Cl2and was dried over MgSO4. The resulting mixture was filtered and concentrated, when it received 62 mg of 7-{(R)-2-[(E)-3-hydroxy-3-(2'-methylbiphenyl-3-yl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid (42) (50) in the form of oil. MS: 435 [(M+N)+].

The following compounds were obtained when replacing orthocarbonic acid in stage 3 on the corresponding substituted phenylboronic acid:

7-[(R)-2-((E)-3-biphenyl-3-yl-3-hydroxypropyl)-5-oxopyrrolidin-1-yl]heptane acid (43), MS: m/z 422 [(M+1)+],

7-{(R)-2-[(E)-3-(2'-ethoxymethyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (44), MS: m/z 466 [(M+1)+],

7-{(R)-2-[(E)-3-(2'-chlorobiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (45), MS: m/z 457 [(M+1)+],

7-{(R)-2-[(E)-3-(4'-chlorobiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (46), MS: m/z 457 [(M+1)+],

7-{(R)-2-[(E)-3-(3'-chlorobiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (47), MS: m/z 457 [(M+1)+],

7-{(R)-2-[(E)-3-(4'-chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (48), MS: m/z 471 [(M+1)+],

7-{(R)-2-[(E)-3-(4'-hydroxy-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid is the (49), MS: m/z 452 [(M+1)+];

7-{(R)-2-[(E)-3-(4'-chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (50), MS: m/z 473 [(M+1)+], was obtained by hydrogenation of the product obtained in stage 1, when the pressure of hydrogen gas of 1 ATM in the presence of a catalyst 10% palladium on coal in EtOAc for 1.5 h,

7-{(S)-2-[(R)-3-hydroxy-3-(4'-hydroxy-2'-methylbiphenyl-3-yl)-propyl]-5-oxopyrrolidin-1-yl}heptane acid (51), MS: m/z 454 [(M+1)+]got after stage 3, with the exception of the processing described in stage 2, the hydrogenation at a pressure of hydrogen gas of 1 ATM in the presence of a catalyst 10% palladium on coal in EtOAc for 1.5 h, and then restoring the conditions described E.J.Corey and others, SOC., 109, 7925-7926, (1987), using as the catalyst a 1 M solution of (S)-2-methyl-CBS in toluene (Aldrich company),

7-{(R)-2-[(E)-3-(6,2'-dimethylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (52), MS: m/z 362 [(M+N)+]got a similar manner when used in stage 1 of dimethyl ether [2-(3-bromo-4-were)-2-oxoethyl]phosphonic acid.

Example 4

7-{(S)-2-[3-(1-Benzyl-1H-pyrazole-4-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid (53)

Stage 1

Dimethyl ether[2-(1-benzyl-1H-pyrazole-4-yl)-2-oxoethyl]-phosphonic acid

A suspension of ethyl ester of 4-pyrazolylborate acid (2.2 g, 15.7 mmol) and cesium carbonate (5.2 g, 15.7 mmol) in dimethylformamide (100 ml) at room temperature was treated with benzylbromide (1.9 ml, 15.7 mmol). The mixture was heated at 90°C for 45 min, cooled to ambient temperature and distributed between water (400 ml) and hexane/ethyl acetate, 1:1 (4×150 ml). The combined organic extracts washed with brine (2×100 ml) and dried over anhydrous magnesium sulfate. Volatile components were removed, the residue was applied onto a column of silica gel. The desired product was suirable hexane/ethyl acetate (3:1), the product was obtained in a solid white color (3.4 g). In a separate vessel a solution dimethylmethylphosphonate (company Aldrich, 1.6 ml, 15 mmol) in tetrahydrofuran (80 ml) was cooled to -78°and treated With n-butyllithium (6,0 ml, 15 mmol). After 45 min, to the mixture was added a solution of the above ester (2.3 g, 10 mmol) in tetrahydrofuran (20 ml) and the mixture was heated to 0°C for 30 minutes Sawthem the mixture was poured into aqueous ammonium chloride and was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water (2×50 ml), brine and dried over anhydrous sodium sulfate. Volatile components were removed on a rotary evaporator, the residue was applied onto the Alonso with silica gel. The desired dimethyl ether [2-(1-benzyl-1H-pyrazole-4-yl)-2-oxoethyl]phosphonic acid was suirable with ethyl acetate/methanol (20:1), the product was obtained as oil (1.68 g).

Stage 2

Ethyl ester of 7-{(R)-2-[(E)-4-(1-benzyl-1H-pyrazole-4-yl)-3-exabot-1-enyl]-5-oxopyrrolidin-1-yl}heptane acid

Ethyl ester of 7-{(R)-2-[(E)-4-(1-benzyl-1H-pyrazole-4-yl)-3-exabot-1-enyl]-5-oxopyrrolidin-1-yl}heptane acid was obtained as described in example 1, step 3, using dimethyl ether [2-(1-benzyl-1H-pyrazole-4-yl)-2-oxoethyl]phosphonic acid (820 mg, of 2.66 mmol) in dimethoxyethane mixed with the sodium hydride (95%, 70 mg of 2.66 mmol) and ethyl ester of 7-((R)-2-formyl-5-oxopyrrolidin-1-yl)-heptane acid (800 mg, 2.8 mmol). Required Aenon (419 mg, of 0.93 mmol) was obtained in the form of oil.

Stage 3:

7-{(R)-2-[(E)-4-(1-Benzyl-1H-pyrazole-4-yl)-3-exabot-1-enyl]-5-oxopyrrolidin-1-yl}heptane acid

Pirateradio northward (210 mg, 0.46 mmol) was dissolved in methanol (5 ml), cooled to 0°and treated with sodium borohydride (50 mg, 1.3 mmol). The mixture was stirred at room temperature for 15 min was added acetone (2 ml) and the volatile components were removed. Then was added methanol and the volatiles were again removed. The residue is suspended in 0.05 M aqueous solution of phosphate at pH 6.5 (PR is approximately 50 ml), was treated with the enzyme lipase, type VII, Sigma, 2 g) and vigorously stirred at room temperature for 2 hours Then the suspension was diluted with diethyl ether (approximately 25 ml) and filtered through a layer of celite. The layers were separated and the aqueous layer was again washed with ether. The aqueous layer was acidified glacial acetic acid and was extracted with ethyl acetate (4×25 ml). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and the volatile components were removed, it was obtained the desired 7-{(R)-2-[(E)-4-(1-benzyl-1H-pyrazole-4-yl)-3-exabot-1-enyl]-5-oxopyrrolidin-1-yl}heptane acid (53) (70) (109 mg, 0.25 mmol). MS: 428 [(M+N)+].

Example 5

7-{(S)-2-[3-Hydroxy-3-(5-orthomolecular-2-yl)propyl]-5-oxopyrrolidin-1-yl}heptane acid (54)

Stage 1

Dimethyl ether [2-(5-bromofuran-2-yl)-2-oxoethyl]-phosphonic acid

Methyl ester of 5-bromo-2-frankenboob acid was obtained in the presence of trimethylsilyldiazomethane. Ester (10.2 g, 47 mmol) was dissolved in tetrahydrofuran (40 ml) and at -78°With the solution dimethylmethylphosphonate lithium (90 mmol). The desired dimethyl ether [2-(5-bromofuran-2-yl)-2-oxoethyl]-phosphonic acid (of 5.83 g of 19.5 mmol) was received, as described above.

Stage 2

Ethyl ester of 7-{(R)-2-[(E)-3-(5-bromofuran-2-yl)-3-oxopropanal-5-oxopyrrolidin-1-ILGA anovas acid

Ethyl ester of 7-{(R)-2-[(E)-3-(5-bromofuran-2-yl)-3-oxopropyl]-5-oxopyrrolidin-1-yl}heptane acid was obtained as described in example 4, step 1, using 5-bromo-2-furylphosphonous (1.12 g, 3.8 mmol) in solution in dimethoxyethane (95 ml) and sodium hydride (95%, 91 mg, 3.6 mmol), followed by treatment with methyl ether 7-((R)-2-formyl-5-oxopyrrolidin-1-yl)heptane acid (1.2 g, 4 mmol), was obtained ethyl ester of 7-{(R)-2-[(E)-3-(5-bromofuran-2-yl)-3-oxopropyl]-5-oxopyrrolidin-1-yl}heptane acid, MS: 442 (M+1+81Br), 440 (M+1+Br).

Stage 3

7-{(S)-2-[3-Hydroxy-3-(5-orthomolecular-2-yl)propyl]-5-oxopyrrolidin-1-yl}heptane acid

Ethyl ester of 7-{(R)-2-[(E)-3-(5-bromofuran-2-yl)-3-oxopropyl]-5-oxopyrrolidin-1-yl}heptane acid in an argon atmosphere was dissolved in anhydrous 1,4-dioxane (3 ml) and treated with potassium carbonate (130 mg, of 0.94 mmol), 2-methylphenylacetic acid (64 mg, 0.47 mmol) and dichloride bis(triphenylphosphine)palladium (33 mg, 0,047 mmol). The yellow suspension was heated at 55°C for 15 h and then remove volatile components. The residue was dissolved in methanol (10 ml)was stirred with sodium borohydride (35 mg, 0.9 mmol) at room temperature for 20 min and treated with acetone (1 ml). After removal of the fly the components, the residue was treated with methanol and the volatiles were again removed. The residue was applied to a plate of silicon oxide with a thickness of 1 mm and conducted twice TLC (eluent: 3% isopropanol/dichloromethane). Ethyl ester of 7-{(S)-2-[3-hydroxy-3-(5-orthomolecular-2-yl)propyl]-5-oxopyrrolidin-1-yl}heptane acid (54 mg) was obtained in the form of oil.

Ester (54 mg) was dissolved in methanol (3 ml)was treated with 5 M sodium hydroxide solution (0.5 ml) and stirred at room temperature for 1 h Then the mixture was treated with 1 M hydrochloric acid and was extracted with ethyl acetate, was obtained 7-{(S)-2-[3-hydroxy-3-(5-orthomolecular-2-yl)propyl]-5-oxopyrrolidin-1-yl}heptane acid (54) (71) (45 mg, 0.10 mmol). MS: 428 [(M+N)+].

Example 6

7-{(R)-5-[(E)-3-Hydroxy-3-(5-triptorelin-2-yl)propenyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl)heptane acid (55)

Stage 1

(R)-5-(1-Toxicokinetic')-3.3-dimethylpyrimidin-2-he

To a solution of (R)-5-hydroxymethyl-3,3-dimethylpiperidin-2-she (4.0 g, 28 mmol), obtained as described in Tetrahedron, 54, 10295-10307, (1998), and etilenovogo ether (4 ml, 42 mmol) in chloroform (26 ml) was added a catalytic amount triperoxonane acid (0,056 ml) and the reaction mixture was stirred at room temperature for 4 h Then the solution was washed with saturated sodium bicarbonate solution, brine and was dried in the magnesium sulfate. The crude oil obtained after removal of solvent was purified by chromatography on silica gel (eluent:hexane/ethyl acetate, 1:1), was obtained 2.6 g (R)-5-(1-toxicokinetic)-3,3-dimethylpiperidin-2-it.

Stage 2

Ethyl ester of 7-((R)-5-hydroxymethyl-3,3-dimethyl-2-oxopyrrolidin-1-yl)heptane acid

A solution of (R)-5-(1-toxicokinetic)-3,3-dimethylpiperidin-2-it (2.58 g, and 11.2 mmol) in dimethylformamide (4 ml) at 0°C in an atmosphere of nitrogen was slowly added to a suspension of 60% sodium hydride (450 mg, and 11.2 mmol) and potassium iodide (2,27 g, 13.7 mmol) in dimethylformamide (13 ml). The mixture was stirred at room temperature for 1 h, the solution was added ethyl ester 7-bromoheptanoate acid (2.66 ml, 13.7 mmol) in dimethylformamide (5 ml) and the mixture was heated at 50°C for 72 h, the Solvent was removed in vacuum, the residue is transferred to the ethyl acetate solution was washed with saline and dried over magnesium sulfate.

Then the solution was concentrated, the residue was dissolved in methanol (40 ml) and to the solution was added a catalytic amount of monohydrate paratoluenesulfonyl acid (170 mg). The reaction mixture was stirred for 7 h to complete the removal of the protective groups. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate, the solution washed with a saturated solution of bicarbonate into three who, saline solution, dried over magnesium sulfate and concentrated in vacuum. The obtained residue was purified by chromatography on silica gel (eluent: hexane/ethyl acetate, 2:1 to 1:2), were obtained 2.3 g of ethyl ester of 7-((R)-5-hydroxymethyl-3,3-dimethyl-2-oxopyrrolidin-1-yl)heptane acid in the form of a clear oil.

Stage 3

Ethyl ester of 7-((R)-5-formyl-3,3-dimethyl-2-oxopyrrolidin-1-yl)heptane acid

A solution of dimethyl sulfoxide (0,93 ml, 12 mmol) in dichloromethane (40 ml) was cooled to -78°C in nitrogen atmosphere and to the specified solution for 2 min solution was added oxalicacid (0,820 ml, 9.4 mmol) in dichloromethane (3 ml). The reaction mixture was stirred at -78°C for 30 min, and then was slowly added a solution of ethyl ester of 7-((R)-5-hydroxymethyl-3,3-dimethyl-2-oxopyrrolidin-1-yl)heptane acid (2.25 g, 7.5 mmol) in dichloromethane (20 ml). After complete addition, the reaction mixture was stirred at -78°C for 15 min, then was slowly added triethylamine (2.1 ml, 15.0 mmol), kept at room temperature and was stirred for a further 15 minutes the Reaction was stopped by adding 20 ml of water and 20 ml of diethyl ether and the reaction mixture was extracted with dichloromethane. The organic phase is dried over potassium carbonate and concentrated to dryness. The crude mixture was purified what cromatografia on silica gel (eluent: hexane/ethyl acetate, 2:1), was obtained 1.5 g of ethyl ester of 7-((R)-5-formyl-3,3-dimethyl-2-oxopyrrolidin-1-yl)heptane acid.

Stage 4

Ethyl ester of 7-{(R)-3,3-dimethyl-2-oxo-5-[(E)-3-oxo-3-(5-triptorelin-2-yl)propenyl]pyrrolidin-1-yl}heptane acid

To a solution of ethyl ester of 7-(R)-5-formyl-3,3-dimethyl-2-oxopyrrolidin-1-yl)heptane acid (360 mg, to 1.21 mmol) and dimethyl ether [2-oxo-2-(5-triptorelin-2-yl)ethyl]phosphonic acid (344 mg, to 1.21 mmol), obtained from 5-triptorelin-2-carboxylic acid, as described in the proposal) in acetonitrile (14 ml) under stirring was added lithium chloride (62 mg, 1,21 mmol and diisopropylethylamine (0,214 ml of 1.21 mmol) and the reaction mixture was stirred at room temperature for 2 days. Then the reaction was stopped by adding a saturated solution of ammonium chloride and the mixture was extracted with ethyl acetate. The organic phase is washed with saline and dried over magnesium sulfate, the crude solution was purified on a column of silica gel (eluent: hexane/ethyl acetate, 2:1). The solvent is evaporated, thus received 280 mg of ethyl ester of 7-{(R)-3,3-dimethyl-2-oxo-5-[(E)-3-oxo-3-(5-triptorelin-2-yl)propenyl]pyrrolidin-1-yl}heptane acid.

Stage 5

Ethyl ester of 7-{(R)-5-[(E)-3-hydroxy-3-(5-triptorelin-2-yl)propenyl]-3,3-dimethyl-2-oxopyrrolidin the-1-yl}heptane acid

To a solution of ethyl ester of 7-{(R)-3,3-dimethyl-2-oxo-5-[(E)-3-oxo-3-(5-triptorelin-2-yl)propenyl]pyrrolidin-1-yl}heptane acid (280 mg, 0.61 mmol) in methanol (4 ml) at -20°slowly added sodium borohydride (37 mg, 0.98 mmol) and the reaction mixture is kept at -10°C for 45 min After complete addition, the reaction the mixture was stirred at -10°C for 40 minutes After completion of the reaction to a mixture of acetone was added and concentrated to dryness. The residue was dissolved in ethyl acetate, the solution washed with saline and dried. After concentration the crude mixture was purified on a column of silica gel (eluent:hexane/ethyl acetate, 1:1), to receive 90 mg of ethyl ester of 7-{(R)-5-[(E)-3-hydroxy-3-(5-triptorelin-2-yl)propenyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}heptane acid.

Stage 6

7-{(R)-5-[(E)-3-Hydroxy-3-(5-triptorelin-2-yl)propenyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}-heptane acid

Ethyl ester of 7-{(R)-5-[(E)-3-hydroxy-3-(5-triptorelin-2-yl)propenyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}heptane acid (89 mg, 0.2 mmol) was dissolved in methanol (3 ml) and the solution was cooled in an ice bath. Then slowly added 20% sodium hydroxide solution (0,280 ml, 1.4 mmol) and after complete addition the mixture was stirred at room the temperature during the night. The reaction mixture was concentrated in vacuum, the residue is suspended in 5 ml of 0.1 n sodium hydroxide and twice washed with diethyl ether. Then the solution was acidified using 1 N. hydrochloric acid and was extracted three times with ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate and concentrated, when it received 55 mg of 7-{(R)-5-[(E)-3-hydroxy-3-(5-triptorelin-2-yl)propenyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}heptane acid (55) (80). MS: 432 [(M+N)+].

The following compounds of formula I were obtained when replacing the respective intermediate connection:

7-[(R)-5-((E)-3-hydroxycut-1-enyl)-3,3-dimethyl-2-oxopyrrolidin-1-yl]heptane acid (56), MS: m/z 368 (M+1), was obtained when using in stage 4 dimethyl ether (2-oxoethyl)phosphonic acid,

7-[2-((E)-3-hydroxycut-1-enyl)-3,3-dimethyl-5-oxopyrrolidin-1-yl]heptane acid (57), MS: m/z 368 (M+1), was obtained when using in stage 1 4,4-dimethyl-5-hydroxymethyl-2-pyrrolidinone,

7-[(R)-5-((S)-(E)-5-cyclobutyl-3-hydroxyben-1-enyl)-3,3-dimethyl-2-oxopyrrolidin-1-yl]heptane acid (58), MS: m/z 380 (M+1); he received when using in stage 4 of dimethyl ether [2-(cyclobutylmethyl)-2-oxoethyl]phosphonic acid,

7-{(R)-5-[(E)-3-hydroxy-4-(3-methoxymethyl)buta-1-enyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}heptane acid (59), MS: m/z 432 (M+1), who was alocale when using in stage 4 dimethyl ether {2-[(3-methoxymethyl)-methyl]-2-oxoethyl}phosphonic acid,

7-((R)-5-{(E)-3-hydroxy-3-[3-(4-methoxybenzyl)phenyl]propenyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)-heptane acid (60), MS: m/z 494 (M+1), was obtained when using in stage 4 dimethyl ether {2-[3-(4-methoxybenzyl)phenyl]-2-oxoethyl}phosphonic acid and

7-{(R)-5-[(E)-3-(4'-chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}heptane acid (61), MS: m/z 499 (M+1), was obtained when using in stage 4 of dimethyl ether [2-(4'-chloro-2'-methylbiphenyl-3-yl)-2-oxoethyl]phosphonic acid.

Example 7

7-((R)-2-{(E)-3-[3-(3-Pertenece)phenyl-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid (62)

This example describes the synthesis of phosphonate above formula by the method shown in scheme B.

Stage 1

A suspension of methyl ester of 3-hydroxybenzoic acid (5.4 g, 35.5 mmol), 3-ftorhinolonovy acid (5.5 g, 35.5 mmol), copper acetate (7,1 g, 35.5 mmol), molecular sieves 3 Å (9 g), pyridine (12 ml, 145 mmol) in dichloromethane (220 ml) was stirred at room temperature and atmospheric pressure for 11 days. Then the mixture was filtered through celite, the volatile components were removed, the residue was purified by chromatography on a column of silica gel (eluent: hexane/ethyl acetate 5:1), obtained was purified to the desired ether (3,68 g), which use the next stage.

Stage 2

A solution of dimethyl ester of methylphosphonic acid (4.0 ml, 37.5 mmol) in tetrahydrofuran (100 ml) was cooled to -78°C in an atmosphere of argon, was treated with n-butyllithium (15.0 ml, 2.5 M solution in hexane, 37.5 mmol) and peremalivala within 45 minutes of the Ester obtained in stage 1, (4,62 g, to 18.7 mmol) was dissolved in tetrahydrofuran (15 ml) and at -78°was added to the solution obtained as described above, and the mixture was stirred at 0°C for 1 h Then the yellow solution was distributed between an aqueous solution of ammonium chloride (100 ml) and ethyl ether (200 ml). The organic fraction was washed with water (3×30 ml), brine and dried over anhydrous sodium sulfate. After filtration and removal of volatiles in vacuo required β-ketotifen (5.8 g) as a viscous oil.

1H NMR (CDCl3, 300 MHz,): δ for 7.78 (dt, J of 0.6, and 0.9, 7.8 Hz, 1H), 7,63 (t, J 2.1 Hz, 1H), of 7.48 (t, J 8.1 Hz, 1H), 7,32-7,26 (m, 2H), 6.90 to-is 6.78 (m, 2H), 6,70 (dt, J 2,4, 9,9, 1H), 3,80 (d, J 11.2 Hz, 6N), 3,61 (d, J 22,6, 2H).

7-((R)-2-{(E)-3-[3-(3-Pertenece)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid (62) (90), MS: m/z 456 (M+1), was obtained from dimethyl {2-[(3-pertenece)phenyl]-2-oxoethyl}phosphonic acid as described in example 1.

The following compounds of formula I were obtained when replacing 3-ftorhinolonovy acid in stage 1 to appropriate eastwoodiae derived phenylboronic acid:

7-((R)-2-{(E)-3-(3-phenoxy)phenyl-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid (63), MS: m/z 438 (M+1), was obtained from phenylboronic acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(4-methoxyphenoxy)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid (64), MS: m/z 468 (M+1), was obtained from 4-methoxyphenylacetic acid,

7-((S)-2-{(E)-3-hydroxy-3-[3-(4-pertenece)phenyl]propyl}-5-oxopyrrolidin-1-yl)heptane acid (65), MS: m/z 458 (M+1), was obtained from 4-ftorhinolonovy acid (followed by hydrogenation at a pressure of 1 ATM hydrogen atmosphere in the presence of 10% palladium on coal),

7-((R)-2-[(E)-3-hydroxy-3-(3-methacryloxypropyl)propenyl]-5-oxopyrrolidin-1-yl)heptane acid (66), MS: m/z 452 (M), were obtained from metacarbonate acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(3-methoxyphenoxy)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid (67), MS: m/z 468 (M+1), was obtained from 3-methoxyphenylacetic acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(4-triptoreline)phenyl]-propenyl}-5-oxopyrrolidin-1-yl)heptane acid (68), MS: m/z 506 (M+1), was obtained from 4-triftormetilfullerenov acid,

7-((R)-2-[(E)-3-hydroxy-3-(3-orthotoluidine)propenyl]-5-oxopyrrolidin-1-yl)heptane acid (69), MS: m/z 452 (M+1), was obtained from orthocarbonic acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(3-triptoreline)phenyl]propenyl}-5-oxopyrrolidin-yl)heptane acid (70), MS: m/z 506 (M+1), was obtained from 3-triftormetilfullerenov acid,

7-((R)-2-{(E)-3-hydroxy-3-[3-(2-methoxyphenoxy)phenyl]propenyl}-5-oxopyrrolidin-1-yl)heptane acid (71), MS: m/z 468 (M+1), was obtained from 2-methoxyphenylacetic acid,

7-((R)-2-[(E)-3-hydroxy-3-(3-paratoluidine)propenyl]-5-oxopyrrolidin-1-yl)heptane acid (72), MS: m/z 452 (M+1), was obtained from protaliban acid,

7-((R)-2-{(E)-3-[3-(4-pertenece)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid (73), MS: m/z 456 (M+), was obtained from 4-ftorhinolonovy acid,

7-((R)-2-{(E)-3-[3-(4-chlorophenoxy)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid (74), MS: m/z 473 (M+1), was obtained from 4-Chlorfenvinphos acid and

7-((R)-2-{(E)-3-[3-(3-chlorophenoxy)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid (75), MS: m/z 473 (M+1), was obtained from 3-Chlorfenvinphos acid.

Example 8

4-{2-[(R)-2-((E)-3-Hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]ethyl}-benzoic acid (76)

Stage 1

To 1.27 g NaH (31,67 mmol, 60% dispersion in mineral oil) and of 5.26 g (31,67 mmol) KI in 0°C in an atmosphere of nitrogen was added 40 ml of DMF. Then was added dropwise a solution of 3.50 g (30,16 mmol) of (S)-(+)-dihydro-5-hydroxy-methyl-2(3H)-furanone (company Aldrich) in 15 ml DMF. A suspension of nagrevaniya room temperature and was stirred for 2.5 h, then was added dropwise to 5.4 ml (45,24 mmol) benzylbromide, the mixture was heated at 50°and was stirred for 16 hours Then the reaction mixture was distributed between 250 ml of a saturated solution of NH4Cl and 250 ml of ethyl acetate/hexane (60%).

The organic phase is washed with water (3×200 ml), 200 ml of brine, dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was purified by chromatography (eluent: 35% ethyl acetate/hexane), was obtained 3,37 g (16,34 mmol, yield 54%) of (S)-O-benzylthio-5-hydroxymethyl-2(3H)-furanone in the form of a yellow oil.

Stage 2

1.98 g (9,59 mmol) of (S)-O-benzylthio-5-hydroxymethyl-2(3H)-furanone 3.14 g (16,25 mmol) ethyl ester paraaminobenzoic acid was dissolved in 50 ml THF and stirred at 50°C for 20 hours the Reaction mixture was concentrated, the crude residue was purified by chromatography (eluent: 50% ethyl acetate/hexane), was obtained 2.24 g (5,61 mmol, yield 58%) of N'-[2-(4-carboethoxy)ethyl]-5-benzyloxy-4-hydroxybenzamide in a solid white color.

Stage 3

2.24 g (5,61 mmol) of N'-[2-(4-carboethoxy)ethyl]-5-benzyloxy-4-hydroxyethylamide was dissolved in 40 ml of THF and at 1.17 ml (8,43 mmol) of triethylamine and the resulting solution was stirred for 10 minutes Then added dropwise to allali of 0.57 ml (7,30 mmol) methanesulfonanilide and the reaction mixture was stirred for 2.5 h, the precipitate was separated by filtration and washed with 3 ml of THF. To the filtrate was added to 1.33 g (11,85 mmol) of tert-BuOK and the reaction mixture was stirred at room temperature for 2 hours After completion of the reaction the mixture was distributed between 200 ml of a saturated aqueous solution of NH4Cl and 250 ml of ethyl acetate. The organic layer was washed with 100 ml water, 200 ml of brine, dried over MgSO4and concentrated under reduced pressure. The crude oil was purified by chromatography (eluent: 1% MeOH/CH2Cl2), it was received 1.78 g (4,69 mmol, yield 83%) of (R)-N'-[2-(4-carboethoxy)ethyl]-5-benzoyloxymethyl-2-pyrrolidinone in the form of a clear oil.

Stage 4

1.78 g (4,69 mmol) of (R)-N'-[2-(4-carboethoxy)ethyl]-5-benzoyloxymethyl-2-pyrrolidinone was dissolved in 20 ml of ethanol. The reaction mixture was purged with gaseous argon, was added to 0.63 g of 10% Pd/C and 0,095 g (0.55 mmol) paratoluenesulfonyl acid, then the mixture was evacuated and purged with gaseous hydrogen was stirred at room temperature for 4 h and filtered through celite. The filtrate was concentrated, it was obtained 1.35 g (4,63 mmol, yield 98%) of (R)-N'-[2-(4-carboethoxy)ethyl]-5-hydroxymethyl-2-pyrrolidinone in the form of a colorless transparent oil.

Stage 5

The alcohol obtained in the previous phase were converted into the desired ester and the acid nohost Dinim method shown above in the diagram And, thus used a combination of a catalytic amount of (R)-2-methyl-CBS-oxazaborolidine with the stoichiometric quantity of borane/dimethyl sulfide, as described in article E.J.Corey etc., J. Am. Chem. Soc., 109, 7925-7926 (1987), received ester alcohol, MS: 388 [(M+N)+].

Benzoic acid (76), MS: m/z 360 (M+1), was obtained as white powder by the hydrolysis of the above ester.

The following compounds of formula I were obtained when replacing in stage 2 of the ethyl ester of para-aminobenzoic acid:

4-{3-[(R)-2-((E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]propyl}-benzoic acid (77), MS: m/z 374 (M+1)+received from the methyl ester of para-(3-aminopropyl)benzoic acid,

3-{3-[(R)-2-((E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]propyl}-benzoic acid (78), MS: m/z 374 (M+1)+received from the methyl ester of meta-(3-aminopropyl)benzoic acid,

2-{3-[(R)-2-((E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]propyl}-benzoic acid (79), MS: m/z 374 (M+1)+received from the methyl ester of ortho-(3-aminopropyl)benzoic acid,

1-{2-[(R)-2-((E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]ethyl}-1H-pyrazole-4-carboxylic acid (80), MS: m/z 349 (M+1)+was obtained from 1-(2-aminomethyl)-1H-pyrazole-4-carboxylic acid.

Another technique was to use as the source with the unity of dimethyl ether [2-(4'-chloro-2'-methylbutan-3-yl)-2-oxoethyl]-phosphonic acid, followed by reduction in hydrogen atmosphere at a pressure of 1 ATM in the presence of a catalyst 10% palladium on coal in EtOAc for 1.5 h and processed in reducing conditions, as described in article E.J.Corey and other J. Am. Chem. Soc., 109, 7925-7926 (1987), in the presence of 1 M solution of catalyst (S)-2-methyl-SW in toluene (Aldrich company), was obtained 4-(2-{(S)-2-[(R)-3-(4'-chloro-2'-methylbutan-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}ethyl)benzoic acid (81), MS: m/z 493 (M+1)+; or

5-[(R)-2-((E)-3-hydroxycut-1-enyl)-5-oxopyrrolidin-1-yl]ethyl)thiophene-2-carboxylic acid (82), MS: m/z 366 (M+1)+received from the ethyl ester of 5-(2-amino-ethyl)thiophene-2-carboxylic acid.

Example 9

The following examples are pharmaceutical compositions comprising a compound of formula I.

The tablet formulation

The following ingredients were mixed to a homogeneous state and extruded in scored tablets.

The capsules

The following ingredients were mixed to a homogeneous state and filled gelatin capsules with a hard shell.

The amount of each ingredientmg capsule
The connection according to the invention200
Lactose, dried in the spray dryer148
Magnesium stearate2

The composition of the suspensions

The following ingredients were mixed to the formation of the suspension for Perera inogo introduction.

IngredientNumber
The connection according to the invention1.0 g
Fumaric acid0.5 g
Sodium chloride2.0 g
Methylparaben0.15 g
Propylparaben0.05 g
Granulated sugar25,5 g
Sorbitol (70%solution)is 12.85 g
Veegum K (Vanderbilt Co.)1.0 g
Flavora 0.035 ml
Dyes0.5 mg
Distilled waterq.s. to 100 ml

The composition for injection

The following ingredients were mixed to form a composition for injection.

IngredientNumber
The connection according to the invention0.4 mg
Sodium acetate buffer solution, 0.4 M2.0 ml
HCl (1 BC) or NaOH (1 BC)q.s. to the required pH
Water (distilled, sterile)q.s. to 20 ml

Example 10

Determination of the functional activity of the receptor EP4(or EP2with ISOE what Itanium analysis method luciferase

Cells expressing the receptor EP4(or EP2), was perseval in the medium F-12, Gibco)containing 10% fetal calf serum, Gibco), and 25 mm HEPES in 96-well plates (Packard company) and incubated over night. The next morning, the culture medium was removed, cells were washed in buffer solution Hanks and was again placed in a medium F-12, Gibco)containing 0.1% BSA. After pre-incubation of the culture for 1.5 to 3 h, the culture was added to the analyzed compounds and incubated for a further 3 hours, the luciferase Activity in the cells was determined using the LucLite substrate (Packard company) according to the method of the manufacturer.

Example 11

Analysis of competitive binding [3H]-PGE2with receptor rEP1or rEP3

Cells maintained in culture, and then collected in the state of confluently. To obtain the membrane fraction of the cells were subjected to lysis and homogenized in 10 volumes of buffer solution of 20 mm HEPES, pH 7.4, containing 1 mm EDTA, 10 mm MgCl2, 20 μm indomethacin, in the homogenizer Polytron at 4°C for 15 sec, and then double-centrifuged at 12000 g for 15 min Inhibition by compounds in the analysis of the binding of [3N]-PGE2held in the above buffer solution containing 3 nm [+N]-PGE2, 2% DMSO, the analyzed compounds in different to what ncentrated and 25 μg membrane protein fraction. Incubation was carried out at 30°C for 1 h, and then was divided bound and free radioactivedecay ligand by rapid filtration. Residual [3H]-PGE2associated with the filter was measured on a scintillation counter. The value of Kifor the analyzed compounds were calculated using the software Prism (with the given binding site).

ConnectionEP4,
Ki
7-{5-[(E)-3-Hydroxy-4-(3-methoxymethyl)buta-1-enyl]-3,3-dimethyl-2-oxopyrrolidin-1-yl}heptane acid0,07
7-((R)-5-{(E)-3-Hydroxy-3-[3-(4-methoxybenzyl)phenyl]propenyl}-3,3-dimethyl-2-oxopyrrolidin-1-yl)heptane acid0,080
7-((R)-2-{(E)-3-[3-(4-Chlorophenoxy)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid0,010
7-{(R)-2-[(E)-3-(4'-Chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid0,003
7-{(R)-2-[3-(4'-Chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid0,008

Example 12

Analysis of bone mass

Compounds of the present invention were tested for their effect on bone is Assu rats with remote ovary (OVX).

In adult female rats of Sprague-Dawley or Wistar Hanover conducted sham operation or remove the ovaries according to the method of the Charles River. According to the method rats were placed in pairs in a room with a controlled environment and were acclimatized for at least one week. Animals in the process of acclimatization were fed in pairs.

Within 20 days after surgery, animals were treated with the investigational compound subcutaneous way once a day for 5 weeks. Issleduemoi compound was dissolved in 10% EtOH/saline (20 mm phosphate buffer solution.

Before treatment and at the completion of treatment was measured by the density of the mineral component of bone (BMD) scan for bone densitometer Hologic QRD-4500 using software high resolution. Then analyzed the images of individual areas of interest, such as all femur, proximal femur, the femur diaphysis, distal femur, distal femoral diaphysis, proximal tibia, proximal tibial diaphysis, vertebrae L2-L4 vertebrae 15.

To assess the impact of the removal of ovaries on bone mass were compared to the results of the scan fictitiously operated rats, OVX rats and rats treated with the filler, and the comparison was carried out on Crete is the Oia student. The OVX group were compared using one-way analysis of variance (ANOA), and then by the Fisher test (Junior meaningful category) to compare each group treated animal connection with the control group, provided that the total effect was statisticheski reliable. Prior to the above mentioned analysis of the data, you can organize and conduct a non-parametric analysis (using the criterion of Wilcoxon rank-sum or Well-Wallis).

Removal of the ovaries leads to a significant loss of total bone mass, mainly of Mature bone tissue. Total BMD in patients operated animals was decreased by 5-20% compared to fictitiously operated control animals.

Table 1
#StructureName (Autonom™)EP4 IC50
1A7-[2-(3-hydroxy-Oct-1-enyl)-5-oxopyrrolidin-1-yl]heptane acid0.02
1B7-[2-(3-hydroxyacyl)-5-oxopyrrolidin-1-yl]heptane acid0.07
2A7-[2-(3-hydroxy-4-phenyl-but-1-enyl)-5-oxopyrrolidin-1-yl]-heptane the traveler acid 0.006
2B7-[2-(3-hydroxy-4-phenylbutyl)-5-oxopyrrolidin-1-yl]heptane acid0.047
3A7-{2-[3-hydroxy-3-(3-phenoxyphenyl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid0.032
3B7-{2-[3-hydroxy-3-(3-phenoxyphenyl)propyl]-5-oxopyrrolidin-1-yl}heptane acid0.033
4A7-{2-[3-hydroxy-3-(3-triptoreline)propenyl]-5-oxopyrrolidin-1-yl}heptane acid0.14
4B7-{2-[3-hydroxy-3-(3-triptoreline)propyl]-5-oxopyrrolidin-1-yl}heptane acid0.073
5A7-{2-[3-(4'-chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid0.003
5V7-{2-[3-(4'-chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-oxopyrrolidin-1-yl}heptane acid0.008
6A 7-{2-[3-hydroxy-3-(4'-hydroxy-2'-methylbiphenyl-3-yl)propenyl]-5-oxopyrrolidin-1-yl}heptane acid0.005
6B7-{2-[3-hydroxy-3-(4'-hydroxy-2'-methylbiphenyl-3-yl)propyl]-5-oxopyrrolidin-1-yl}heptane acid0.008

1. The compound of the formula I

where a represents-CH2-CH2- or-CH=CH-;

In absent or denotes phenyl;

Z denotes-C(O)OR' or tetrazol-5-yl, where R' denotes hydrogen or C1-C6alkyl;

m is 1, 2, 3, 4, 5 or 6;

R1means C1-C6alkyl, unsubstituted phenyl or phenyl substituted by at least one Deputy, selected from the group comprising trifluoromethyl, halogen, -Y-Ra, -Y ORa, -Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, and

Rameans C1-C6alkyl, unsubstituted phenyl or phenyl substituted by at least one Deputy, selected from the group comprising C1-C6alkyl, C1-C6alkoxy, trifluoromethyl and halogen, provided that means phenyl, a R3, R4, R5and R6at the same time do not represent a hydrogen, or R1means unsubstituted phenyl or Fe is Il, substituted by at least one Deputy, selected from the group comprising trifluoromethyl, halogen, -Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans C1-C6alkyl, unsubstituted phenyl or phenyl substituted by at least one Deputy, selected from the group comprising C1-C6alkyl, C1-C6alkoxy, trifluoromethyl and halogen, provided that In no, a R3, R4, R5and R6simultaneously denote hydrogen;

R2means hydrogen;

R3, R4, R5and R6each independently of one another denote hydrogen or C1-C6alkyl, or its pharmaceutically acceptable salt, or an individual isomer.

2. The compound according to claim 1, where In is absent, R1means phenyl, optionally substituted by a Deputy selected from the group comprising trifluoromethyl, halogen, -Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans, C1-C6alkyl, phenyl.

3. The compound according to claim 1, where R1means unsubstituted phenyl.

4. The compound according to claim 2, where R1means phenyl, substituted Deputy selected from the group comprising trifluoromethyl, halogen, -Y-Ra, -Y ORa/sup> and-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans C1-C6alkyl, phenyl.

5. The compound according to any one of claims 1 to 4, where Rameans phenyl, optionally substituted by a Deputy selected from the group comprising C1-C6alkyl, C1-C6alkoxy, trifluoromethyl or halogen.

6. The compound according to claim 2, where R1means phenyl, substituted with at least one group-Y-Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans phenyl, optionally substituted by a Deputy selected from the group comprising C1-C6alkyl, C1-C6alkoxy, trifluoromethyl and halogen.

7. The compound according to claim 2, where R1means phenyl, substituted with at least one group-Y-Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans phenyl.

8. The compound according to claim 2, where R1means phenyl, substituted with at least one group Y ORawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans phenyl, substituted Deputy selected from the group comprising C1-C6alkyl, C1-C6alkoxy, trifluoromethyl and halogen.

9. The compound according to claim 2, where R1means phenyl, substituted by minority who she least one group-Y-C(O)R awhere Y denotes a chemical bond or a C1-C3alkylenes group, and Rameans phenyl, optionally substituted by at least one Deputy, selected from the group comprising C1-C6alkyl, C1-C6alkoxy, trifluoromethyl and halogen.

10. The compound according to claim 1, where In is absent, and R1means phenyl.

11. The compound according to claim 1, where R1is phenyl, substituted by the Deputy selected from the group comprising trifluoromethyl, halogen, -Y-Ra, -Y ORaand-Y-C(O)Rawhere Y denotes a chemical bond or a C1-C3alkylenes group, a Rameans C1-C6alkyl, phenyl.

12. The compound according to claim 1, where In is absent, and R3and R4mean C1-C6alkyl.

13. The compound according to claim 1, where R1means C1-C6alkyl.

14. The compound according to claim 1, where a represents-CH2-CH2-.

15. The compound according to claim 1, where In is missing, and a represents-CH2-CH2-.

16. The compound according to claim 1, where In denotes phenyl, m is 1 or 2, a R1means C1-C6alkyl, phenyl.

17. The compound according to claim 1, where R1means optionally substituted phenyl.

18. The compound according to claim 1, where R1means C1-C6alkyl.

19. The compound according to claim 1, selected from the group including

7-{(R)-2-[(E)-3-(4'-chloro-2'-methylbiphenyl-3-yl)-3-hydroxypropyl]-5-who cooperrider-1-yl}heptane acid,

7-((R)-2-{(E)-3-[3-(4-chlorophenoxy)phenyl]-3-hydroxypropyl}-5-oxopyrrolidin-1-yl)heptane acid.

20. Compounds according to any one of claims 1 to 19, used for getting medicines for the prevention and treatment of diseases associated with dysfunction of the bone tissue.

21. The method of obtaining the compounds of formula I

where R2means hydrogen, R1means methyl or ethyl, and m, R3, R4, R5, R6and Z have the meanings indicated in claim 1, including the interaction of the compounds of General formulaand

where m, R3, R4, R5and R6have the meanings indicated in claim 1, a R1means methyl or ethyl, with a phosphonate of General formulam

where R1means methyl or ethyl, subsequent recovery and optional hydrolysis with the formation of the target product.

22. Pharmaceutical composition having selective agonistic activity against receptor EP4containing a therapeutically effective amount of a compound according to any one of claims 1 to 20 in a mixture with at least one suitable carrier, diluent or excipient.



 

Same patents:

The invention relates to new biologically active chemical compounds from a range of 1-(4-nitrophenyl)-4-N-X-aminopyrrolidine General formula

< / BR>
(II);

-NH-C4H9(III);

-NH2(IV);

-NH-C2H5(V)

with astragalina and anti-stress activity, and method of production thereof

The invention relates to new biologically active chemical compounds from a range of 1-(4-nitrophenyl)-4-N-X-aminopyrrolidine General formula

< / BR>
(II);

-NH-C4H9(III);

-NH2(IV);

-NH-C2H5(V)

with astragalina and anti-stress activity, and method of production thereof

The invention relates to derivatives of hydroxamic acids of formula I where X is-CH2-, -NR5-, -C(O); Y represents-CH2-, -NR5provided that if X is-NR5-, Y represents-CH2-; R1means H, C1-C20alkyl, -(CH2)jaryl, -(CH2)jcycloalkyl and others; R2means H, C1-C20-alkyl, -(CH2)j-R8, -(CH2)j-NR6R7, -(CH2)j-NR5-; -C(O)R5and others; R3means H, C1-C6alkyl, -(CH2)j-aryl, -(CH2)j- C3-6-cycloalkyl etc., R5means H, C1-C6alkyl, possibly substituted by 1 to 3 Halogens, etc.; R6and R7identical or different, represent H, C1-C6alkyl and the other, R8means-S-R8and others, R9-halogen, C1-C6alkyl and the other, R10- H; aryl is phenyl, possibly substituted, Het is pyridinyl, thienyl and others, i - 1 - 6, j - 0 - 4

The invention relates to inhibitors of processes mediated by the action of DP-IV, which are characterized by the General formula:

A-B (Groups I and II) or

< / BR>
where is a

< / BR>
n = 1 or 2; m = 0, 1, or 2; NH or NR, where R = lower alkyl(C-C);

A is attached to Y;

-Y = -N, -CH, or C (when-CO group, A substituted group CH= CF,=),

R=H, CN, CHO, B(OH)2CC-R7or CH=N-R8;

R7=H, F, lower alkyl(C1-C6), CN, NO2OR9, CO2R9or COR9;

R8=Ph, HE, OR9, OCOR9or OBn;

R9= lower alkyl (C1-C6); and either oneor bothmay be missing

The invention relates to medicine, namely to the use of (S)-(-)--ethyl-2-oxo-1-pyrrolidineethanol formula

< / BR>
as an active principle of a medicinal product intended for the treatment of anxiety (anxiety)

The invention relates to new derivatives of 2-methyl-3-etoxycarbonyl-5-(2'-cyano-3'-aminopropyl-2'-enylidene)pyrrolin - 2-it-4 or 2-(2'-cyano-3'-aminopropyl-2'-enylidene)indolinone-3 of the General formula 1

< / BR>
where, if R = COOC2H5, R1= CH3, R2+ R3= (CH2)5(a) R2+ R3= CH2CH2OCH2CH2(b) R2= H, R3= CH2C6H5(C) R2= H, R3= CH2C6H4OCH3-4 (g) R2= H, R3= CH2C6H3(OCH3)-3,4 (d) R + R1= CH = CH-CH = CH R2= R3= H (e) R2= H, R3= (CH2)6(W) R2= H, R3= CH2CH2N(C2H5)2(C) R2= H, R3= CH2CH(OH)CH2OH and R2+ R3= CH2CH2OCH2CH2(K) R2+ R3= CH2CH2N(CH3)CH2CH2(l) R2+R3=CH2CH2= H, R3= CH2C6H4OCH3-4 (o) R2= H, R3= CH2C6H3(OCH3)-3,4 (p) R2= H, R3= CH(CH3)C6H5(p) R2= H, R3= CH2CH2C6H5(c) R2= H, R3= CH2CH2C6H3(OCH3)-3,4 (t) R2= H, R3= CH(CH3)CH2C6H5(u) R2= H, R3= C6H5(f) R2= H, R3= C6H4OCH3-4 (x) with antihypertensive activity

The invention relates to new chemical compounds having valuable pharmacological properties and relates to new pharmacologically active N-substituted derivatives of (3R, 4R)-3-ethyl-4- [(1-methyl-1H-imidazol-5-yl)methyl] -2-Pierre - oligonu that have antiglaucoma action and can find application in medicine

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to analogs of prostaglandin of the formula (I): , wherein A means -CH2-CH2- or -CH=CH-; B is absent or means phenyl; Z means -C(O)OR' or tetrazole-5-yl wherein R' means hydrogen atom or (C1-C6)-alkyl; m = 1, 2, 3, 4, 5 or 6; R1 means (C1-C6)-alkyl, unsubstituted phenyl or phenyl substituted with at least one substitute chosen from the group comprising trifluoromethyl, halogen atom, -Y-Ra, -Y-ORa and -Y-C(O)Ra wherein Y means chemical bond or (C1-C3)-alkylene group; Ra means (C1-C6)-alkyl, unsubstituted phenyl or phenyl substituted with at least one substitute chosen from the group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl and halogen atom under condition that B means phenyl and R3, R4, R5 and R6 do not mean hydrogen atom simultaneously; or R1 means unsubstituted phenyl or phenyl substituted with at least one substitute chosen from the group comprising trifluoromethyl, -Y-Ra, -Y-ORa and -Y-C(O)Ra wherein Y means chemical bond or (C1-C)-alkylene group; Ra means (C1-C6)-alkyl, unsubstituted phenyl or phenyl substituted with at least one substitute chosen from the group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, trifluoromethyl and halogen atom under condition that B is absent and R3, R4, R5 and R6 means hydrogen atom simultaneously; R2 means hydrogen atom; each among R3, R4, R5 and R6 means independently of one another hydrogen atom or (C1-C6)-alkyl, or its pharmaceutically acceptable salt or individual isomer. Compounds of the formula (1) possess a selective agonistic activity with respect to ER4-receptors and therefore they can be used in pharmaceutical composition.

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

22 cl, 2 tbl, 12 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the general formula: (A) and their pharmaceutically acceptable salts wherein X means -CONR5R6, -COOR7 or -COR8; R1 represents hydrogen (H), halogen atom, (C1-C6)-alkyl; R2 and R4 are similar or different and each means independently H, halogen atom, (C1-C6)-alkyl; R3 means H, halogen atom, (C1-C6)-alkyl substituted with one or more halogen atoms, (C2-C5)-alkenyl; R, R6 and R7 are similar or different and each means independently H, (C1-C6)-alkyl; R8 means -OH, (C1-C6)-alkyl. Compounds of the formula (A) can be used for synthesis of (S)-(-)-α-ethyl-2-oxo-1-pyrrolidine acetamide. Also, invention describes methods for synthesis of compound of the formula (A).

EFFECT: improved methods of synthesis.

11 cl, 3 tbl, 13 sch, 6 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-pyrrolidone of the formula (I): wherein Q means -CH2-, -O-; B means -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -CH=CH-, -CH2-CH=CH-, -CH=CH-CH2-, -CH2-CH=CH-CH2 under condition that if B means -CH=CH-, -CH=CH-CH2- then Q means -CH2-; X means -O-, -S-, -SO- or -SO2- or a simple bond under condition that if X meana simple bond then Q means oxygen atom; J means -(CRbRc)n- wherein n means a whole number from 1 to 4; both Rb and Rc mean hydrogen atom, or both Rb and Rc mean (C1-C4)-alkyl and one of them means hydrogen atom (H), or Rb and Rc in common with carbon atom to which they are bound form (C2-C5)-polymethylene group or -CH2-CH=CH-; A means -CH2-CH2-, -CH=CH- or -C≡C-; Z means -C(O)OR' wherein R' means H, (C1-C6)-alkyl; n means 1, 2, 3 or 4; R1 means -(CH2)pR7 wherein R7 means (C1-C)-alkyl, (C3-C8)-cycloalkyl, furanyl substituted with trifluoromethyl, phenyl or phenyl-Y-phenyl wherein Y means oxygen atom (O), a simple chemical bond and phenyl is optionally substituted with 1, 2 or three substitutes chosen independently from group comprising (C1-C6)-alkyl, (C1-C6)-alkoxy-group, halogen atom, halogen-(C1-C6)-alkyl; p means 0, 1, 2, 3, 4, 5; R2 means H, (C1-C6)-alkyl; R3, R4, R5 and R6 mean H, or their pharmaceutically acceptable salts or solvates, individual isomers or racemic or nonracemic mixture of isomers. Compounds of the formula (I) elicit competitive affinity in binding EP2, EP3 and EP4 that allows their using as components of pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

11 cl, 11 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: Described are derivatives of general formula I (all symbols are as described in specification), pharmaceutically acceptable salts thereof or cyclodextrin clathrates. Such compounds hardly bind of EP2 subtype of PGE receptor and are useful in prophylaxis of immune diseases, allergy, death of neuronal cells, liver or kidney insufficiency, etc.

EFFECT: new agent for prophylaxis of various diseases.

18 cl, 388 ex, 68 tbl, 3 dwg

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel pyrrolidine-2-ones of the formula (I): , wherein R1 means group chosen from the following formulae:

wherein each of them comprises optionally additional nitrogen (N) atom as a heteroatom; Z means optional substitute halogen atom, -CH2NH2, -NRaRb or -CN; Z' means optional substitute halogen atom, -CH2NH2 or -CN; alk means alkylene or alkenylene; T means sulfur atom (S), oxygen atom (O); R2 means hydrogen atom (H), -(C1-C3)-alkyl-CONRaRb, -(C1-C3)-alkyl-CO2-(C1-C4)-alkyl, -(C1-C3)-alkylmorpholino-group, -CO2-(C1-C4)-alkyl or -(C1-C3)-alkyl-CO2H; X means phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms chosen from O, N or S wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb; Y means: (i) a substitute chosen from H, halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb, or (ii) phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms, chosen from O, N or S and wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(CH2)nNRaRb, -(CH2)nN+RaRbCH2CONH2, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc, -S(O)2NRaRb, =O, oxide at N atom in cycle, -CHO, -NO2 and -N-(Ra)(SO2Rc) wherein Ra and Rb mean independently H, -(C1-C6)-alkyl; Rc means -(C1-C6)-alkyl; Rd means H, -(C1-C6)-alkyl; n means 0-2, and to their pharmaceutically acceptable salts or solvates. Compounds inhibit Xa factor that allows their using as components of pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 144 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidone of the formula (I): wherein Q means =N, =C(R24)-; X-Y means -CH2-CH2-, -CH=CH-, -CH2-O-; R1, R1.1 and R1.2 are chosen independently from group comprising hydrogen atom (H), halogen atom, halogen-(C1-C6)-alkyl, -CN, (C1-C6)-alkoxy group; R21, R22 and R23 are chosen independently of one another from group comprising H, halogen atom; R24 means H; R3 means -NHR6; R4 means H; R6 means -C(O)H, -C(O)-(C1-C3)-alkyl, -C(O)-halogen-(C1-C3)-alkyl, -C(O)O-(C1-C3)-alkyl, -C(O)-NH2, -SO2-(C1-C3)-alkyl, and also its individual isomers, racemic and nonracemic mixtures. Proposed compounds inhibit activity of monoamine oxidase B that allows its using in prophylaxis and treatment of disease mediated by monoamine oxidase B inhibitor, in particular, Alzheimer's disease and senile feeble-mindedness.

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

15 cl, 4 sch, 31 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention relates to novel pyrrolidone derivatives of formula I where Q stands for =N- or =C(R24)-; X-Y stands for -CH2-CH2-, -CH=CH-, -CH2-O-; R1, R1.1 and R1.2 independent on each other stand for halogen, C1-C6alkyl, halogen(C1-C6)alkyl, cyano, C1-C6alkoxy, halogen(C1-C6)alkoxy; R21, R22 and R23 independent on each other stand for H and halogen; R24 stands for H, CH3, halogen; R3 stands for -C(O)N(H)CH3, -CH2CN; R4 stands for H; as well as its individual isomers, racemic or non-racemic mixtures of isomers. Compounds inhibit monoaminooxidase, which allows to use them in pharmaceutical compositions for treatment and prevention of Alzheimer's disease and senile dementia.

EFFECT: invention ensures enhancing efficiency of composition and method of treatment.

19 cl, 5 dwg, 49 ex

FIELD: chemistry, medicine.

SUBSTANCE: invention relates to derivatives of 4-pyrrolidine phenyl benzole ether of formula where X-Y stands for -CH2-O-; R1, R1.1 and R1.2 independently on each other are selected from group, including H, haloid, haloid (C1-C6)alkyl, R21, R22 and R23 independently on each other stand for H; R24 stands for H; R3 stands for H; R4 stands for -CONHR5, -CN or -NHR6; R5 stands for H, (C1-C6)alkyl; R6 stands for -CO-H, -CO-(C1-C6)alkyl, -CO-NH2, -SO2-(C1-C6)alkyl; as well as its individual isomers and racemic and non-racemic mixtures. Compounds 1 inhibit monoaminooxidase B, which allows to apply them in pharmaceutical composition and for production of medications, intended for treatment and prevention of Alzheimer's disease and senile dementia.

EFFECT: invention ensures enhancing efficiency of composition and method of treatment.

15 cl, 7 dwg, 21 ex

FIELD: chemistry.

SUBSTANCE: in novel derivatives of 4-(4-alkoxy-3-hydroxyphenyl)-2-pyrrolidone of formula I , X represents O, R1 represents C1-C8alkyl, C3-C8cycloalkyl, C8-C16arylalkyl, C8-C16arylalkenyl, in which alkenyl fragment contains up to 5 carbon atoms, C4-C16cycloalkylalkyl, R2 represents C1-C4alkyl, unsubstituted or substituted with one or more halogens, R3 represents C3-C8cycloalkyl, C7-C16arylalkyl, substituted with one or more substituents from halogen line, C1-C8alkyl, C1-C8alkoxy, cyano or CF3, C3-C8alkoxyalkyl, -C(O)R4 or -CH2CONHR5; R4 represents C6-C14aryl, substituted with one or more substituents from halogen line, C1-C8alkoxy or nitro; R5 represents C6-C14aryl, unsubstituted or substituted with one or more substituents from halogen line, C1-C8alkyl, C1-C8alkoxy, nitro or amino, heterocyclic group, saturated, partially saturated or fully unsaturated, which contains in cycle from 5 to 6 atoms, from which one atom is N, or additionally second atom is represented with heteroatom, selected from N, O and S, heterocyclic group is unsubstituted or substituted with one or more substituents from halogen line, C1-C8alkyl, C1-C8alkoxy, or their combinations; or heterocyclylC1-C5alkyl, saturated, partially saturated or unsaturated, which contains in cycle from 5 to 6 atoms, from which one atom is N, O or S, and which is unsubstituted or substituted in heterocyclic fragment with C1-C8alkyl or C1-C8alkoxy group, and their physiologically acceptable salts, in each case compound can be in form of enantiomer mixture, such as racemate, or mixture of diastereomers, or can be in form of one enantiomer or one diastereomer; on condition that if R1 represents cyclopentyl and R2 represents methyl, R3 does not represent benzyl, 4-bromobenzyl, 3,4-dimethoxybenzyl or 4-cyanobenzyl. Compounds I inhibit activity of PDE-4 enzyme, which allows using them in pharmaceutical compositions.

EFFECT: increase of composition and treatment method efficiency.

38 cl, 11 ex

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