Derivatives of 2-renominate inhibiting pde iv, methods for their preparation, pharmaceutical composition based on them, the way of obtaining

 

(57) Abstract:

The invention relates to new derivatives of 2-renominate General formula (I), where R1and R2represent hydrogen, C1-C6-alkyl, deformity, trifluoromethyl, C3-C6-cycloalkyl, saturated 5-membered heterocycle containing one oxygen atom, indanyl, 6,7-dihydro-5H-cyclopentadienyl or1-C6-alkyl, substituted phenyl, indayla or3-C6-cycloalkyl, R3is hydrogen, R4represents hydrogen, halogen, C1-C6-alkyl, trifluoromethyl, or R4represents a radical of the formula-O-R7where R7is hydrogen, R5represents hydrogen or R4and R5taken together may form a bivalent radical of formula-CH2-CH2-O-CH2-CH2-, R6represents hydrogen or C1-C6-alkyl, -a-b - represents a bivalent radical of the formula- (CR10= CR11or R10-R11where each R10and R11independently represents hydrogen or C1-C6-alkyl, L represents hydrogen, C1-C6-alkyl, C1-C6-allyloxycarbonyl,1-C6-alkyl,th composition based on them, possessing inhibitory activity against phosphodiesterase IV, and method for producing the composition. The invention can be used in medicine for the treatment of allergic, atopic and inflammatory diseases. 6 c. and 6 C.p. f-crystals, 4 Il., 3 table.

The present invention relates to derivatives of 2-cyanoimino-imidazole having inhibitory activity against phosphodiesterase IV (ROS) and cytokines, and their receipt; it also relates to compositions containing them and their use as pharmaceuticals.

In WO 95/05386, published on 23 February 1995, Smithkline hm rrtin described derivatives phenethylamine, such as N-[2-(3-cyclopentyloxy-3-methoxyphenyl)ethyl] iminodicarboxylic and N'-cyano-1-[2-(3-cyclopentyloxy-4-methoxyphenyl)ethyl] carboxamide, useful for the treatment of painful conditions associated with phosphodiesterase IV. In this application given a General description of derivative phenethylamine containing cyanoguanidine part.

Compounds of the present invention differ in structure from known inhibitors D IV, since they necessarily contain 2-renominating part. They can be used in therapy for the treatment of a painful condition, the knitted harmful excess of cytokines, in particular, allergic, atopic and inflammatory diseases. Compounds of the present invention also have a minor adverse effect on the gastrointestinal tract, which is often associated with inhibitors D IV.

The present invention relates to derivatives of 2-renominate formula (I)

< / BR>
their N-oxide forms, pharmaceutically acceptable salts of the accession of acids or bases and stereochemical isomeric forms,

where each R1and R2independently, is hydrogen; C1-6-alkyl; deformity; trifluoromethyl; C3-6-cycloalkyl; a saturated 5-, 6 - or 7-membered heterocycle containing one or two heteroatoms selected from oxygen atoms, sulfur or nitrogen; indanyl; 6,7-dihydro-5H-cyclopentadienyl; bicyclo [2.2.1] -2-heptenyl; bicyclo [2.2.1] -heptanes; C1-6-alkylsulfonyl; arylsulfonyl; or (C1-10-alkyl, substituted by one or two substituents, each of which is chosen, independently, aryl, pyridinyl, teinila, furanyl, indanyl, 6,7-dihydro-5H-cyclopentenopyridine,3-7-cycloalkyl and saturated 5-, 6 - or 7-membered heterocycle containing one or two heteroatoms selected from R4represents hydrogen; halogen; C1-6-alkyl; trifluoromethyl; C3-6-cycloalkyl; carboxy; C1-4-allyloxycarbonyl; C3-6-cycloalkylcarbonyl; aryl; t1; or (C1-6-alkyl, substituted cyano, amino, hydroxy, C1-4-alkylcarboxylic, aryl or t1; or

R4represents a radical of the formula

-O-R7(a-1); or

-NH-R8(a-2);

where R7represents hydrogen; C1-6-alkyl; C1-6-alkyl, substituted hydroxy, carboxyla,1-4-allyloxycarbonyl, amino, mono - or di(C1-4-alkyl)amino, t1or aryl;

R8represents hydrogen; C1-6-alkyl; C1-4-alkylsulphonyl; C1-6-alkyl, substituted hydroxy, carboxyla, C1-4-allyloxycarbonyl, amino, mono - or di(C1-4-alkyl)amino, t1or aryl;

R5represents hydrogen, halogen, hydroxy, C1-6-alkyl or C1-6-alkyloxy; or

R4and R5together may form a bivalent radical of the formula

-(CH2)n- (b-1);

-CH2-CH2-O-CH2-CH2- (b-2);

-CH2-CH2-N(R9)-CH2-CH2- (b-3); or

-CH2-CH=CH-CH2- (b-4);

where n sulfonyl;

R6represents hydrogen or C1-4-alkyl; or

R4and R6together, may form a bivalent radical of the formula -(CH2)m-;

where m is 1, 2, 3 or 4;

-A-b - represents a bivalent radical of the formula

- (CR10=CR11- (s-1); or

-R10-R11(C-2);

where each R10and R11is, independently, hydrogen or C1-4-alkyl; and

L represents hydrogen; C1-6-alkyl; C1-6-alkylsulphonyl; C1-6-allyloxycarbonyl; C1-6-alkyl, substituted by one or two substituents selected from the group comprising hydroxy, C1-4-alkyloxy,1-4-allyloxycarbonyl, mono - and di(C1-4-alkyl)amino, aryl and t2;3-6alkenyl; C3-6alkenyl, substituted aryl; piperidinyl; piperazinyl, substituted C1-4the alkyl or aryl-C1-4-alkyl; C1-6-alkylsulfonyl or arylsulfonyl;

aryl represents phenyl or phenyl substituted one, two or three substituents selected from halogen, hydroxy,1-4-alkyl, C1-4-alkyloxy,3-6-cycloalkyl, trifloromethyl, amino, nitro, carboxyl,1-4-allyloxycarbonyl and C1-4-alkylsulphonyl-amino;

the 1-4-alkyl; thienyl; thienyl, substituted C1-4-alkylcarboxylic; hydroxypyridine, hydroxypyridine, substituted C1-4-alkyl or C1-4-alkoxy-C1-4-alkyl; imidazolyl; imidazolyl, substituted C1-4-alkyl; thiazolyl; thiazolyl, substituted C1-4-alkyl; oxazolyl; oxazolyl, substituted C1-4-alkyl; ethenolysis; ethenolysis, substituted C1-4-alkyl; fineliner; fineliner, substituted C1-4-alkyl; morpholinyl; piperidinyl; piperazinyl, substituted C1-4-alkyl, C1-4-allyloxycarbonyl or aryl-C1-4-alkyl; piperazinil; piperazinil, substituted C1-4-alkyl, C1-4-allyloxycarbonyl or aryl-C1-4-alkyl; and

t2is morpholinyl; piperidinyl; piperazinyl, substituted C1-4the alkyl or aryl-C1-4-alkyl; piperazinil; piperazinil, substituted C1-4the alkyl or aryl-C1-4-alkyl; pyridinyl; pyridinyl substituted WITH1-4-alkyl; furanyl, furanyl, substituted C1-4-alkyl; thienyl or thienyl, substituted C1-4-alkyl or C1-4-alkylcarboxylic.

Some of the compounds of formula (I) can also exist in tautomeric forms. It is assumed, bretania. In particular, the compounds of formula (I) in which L is hydrogen can exist in their corresponding tautomeric form.

IN R1and R2saturated 5-, 6 - or 7-membered heterocycles containing one or two heteroatoms selected from oxygen atoms, sulfur or nitrogen, can be a suitable way to choose among these heterocycles, such as, for example, tetrahydrofuranyl, DIOXOLANYL, pyrrolidinyl, morpholinyl, piperidinyl, piperazinil and tetrahydropyranyl. These heterocyclic radicals attached to the oxygen atom or C1-10-moiety through any carbon atom or, where appropriate, by means of the nitrogen atom.

Also in R1and R2the term "6,7-dihydro-5H-cyclopentadienyl", also known as 6,7-dihydro-5H-pyridinyl, is intended to denote 6,7-dihydro-5H-cyclopent[b] pyridine or 6, 7-dihydro-5H-cyclopent[C]pyridinyl who can join the rest of the molecule via any of the aliphatic or aromatic carbon atoms.

Used herein, the term "halogen" is common to refer to fluorine, chlorine, bromine and iodine; the term "C1-4-alkyl" refers to linear or branched saturated hydrocarbons having 1-4 atoms ug is butyl; the term "C1-6-alkyl" includes1-4-alkyl and the higher homologues with 5 or 6 carbon atoms, such as, for example, 2-methylbutyl, pentyl, hexyl and the like; the term "C1-6-alkyl" includes2-6-alkyl and lower homologues with 1 carbon atom, such as, for example, methyl;1-10-alkyl include1-6-alkyl and the higher homologues with 7-10 carbon atoms, such as, for example, heptyl, octyl, nonyl, decyl, 1-etylhexyl, 2-methylheptan and the like; the term "C3-6alkenyl" defines linear and branched hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms, such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like; and the carbon atom indicated WITH3-6-alkenyl connecting to a nitrogen atom preferably is saturated; the term "C3-6-cycloalkyl" is common to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the term "C3-7-cycloalkyl includes WITH3-6-cycloalkyl and cycloheptyl; the term "C1-4-alcander" includes linear and branched saturated divalent hydrocarbon radicals with 1-4 carbon atoms, such as, for example, methylene, 1,2-ethandiyl, 1, is here in the foregoing definitions and hereinafter, the term "halo-C1-4-alcander determines mono - or polyhalogen1-4-alcander, in particular, WITH1-4-alcander substituted by one or more fluorine atoms.

Pharmaceutically acceptable salts of the accession of the acids referred to above present form salts accession acids, which are usually obtained by treatment of compounds of formula (I) in the form of a Foundation of appropriate acids such as inorganic acids, such as halogen acid, e.g. hydrochloric or Hydrobromic, sulfuric, nitric, phosphoric or the like acids; or organic acids such as, for example, acetic, oxiana, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, reklamowa, salicylic, p-aminosalicylic, AMOVA and the like. Conversely, these forms salts accession acids can be converted in the form of free bases by treatment of the corresponding base.

The compounds of formula (I) containing an acidic proton, can also be converted into their non-toxic salts of joining metal or Mami are for example, ammonium salts, salts of alkali and alkaline earth metals such as lithium, sodium, potassium, magnesium, calcium salt, etc., salts of organic bases, for example, salt, benzathine, N-methyl-D-glucamine, geranamine and salts of amino acids such as, for example, arginine, lysine and the like.

The term "salt of the accession also includes a hydrate and solvate forms, which can form compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholate, etc.,

The N-oxide forms of the compounds of formula (I) include those compounds of formula (I) in which one or more atoms of nitrogen oxidized to the so-called N-oxide.

The term "stoichiometric isomeric forms" as used here, defines all the possible isomeric forms, which may be of the compounds of formula (I). If there are no other references and indications of the chemical names of compounds denotes the mixture of all possible stereochemical isomeric forms, and these mixtures containing all diastereomers and enantiomers of basic molecular structure. More specifically, stereogenic centers may have the R - or S-configuration, and =N-SP and replaced WITH3-6-alkeline groups can have the E - or Z-configure salt accession acids or bases and all stereoisomeric forms.

Some of the compounds of formula (I) and some of the intermediate compounds of the present invention may contain an asymmetric carbon atom. Pure stereochemical isomeric forms of these compounds and these intermediate compounds can be obtained using well known techniques.

For example, diastereoisomers can be separated using physical methods such as selective crystallization or by chromatographic methods, for example, counter current distribution, liquid chromatography and the like. Enantiomers can be obtained from racemic mixtures, turning first mentioned racemic mixture with suitable separating agents, such as, for example, chiral acids, mixtures of diastereomeric salts or compounds; with subsequent physical separation of these mixtures of diastereomeric salts or compounds with, for example, selective crystallization or chromatographic techniques, e.g. liquid chromatography and the like methods; and finally converting these separated diastereomeric salts or compounds into the corresponding enantiomers. Pure stereochemical isomeric form can also be obtained from the AI, the corresponding reactions are stereospecific. Pure and mixed stereochemical isomeric forms of the compounds of formula (I) is included in the scope of the present invention.

An alternative method of separating the enantiomeric forms of the compounds of formula (I) and intermediates include liquid chromatography, in particular liquid chromatography using a chiral stationary phase.

A special group of compounds are those compounds of formula (I), in which each of R1and R2is, independently, hydrogen; C1-6-alkyl; deformity, trifluoromethyl; C3-6-alkyl; a saturated 5-, 6 - or 7-membered heterocycle containing one or two heteroatoms selected from oxygen atoms, sulfur or nitrogen; indanyl; bicyclo[2.2.1] -2-heptenyl; bicyclo[2.2.1]heptenyl; C1-6-alkylsulfonyl; arylsulfonyl; or (C1-10-alkyl, substituted by one or two substituents, each of which, independently, selected from aryl, pyridinyl, teinila, furanyl,3-7-cycloalkyl and saturated 5-, 6 - or 7-membered heterocycle containing one or two heteroatoms selected from oxygen atoms, sulfur or nitrogen.

Interest compounds are those SUB>-cycloalkyl; deformity; a saturated 5-, 6 - or 7-membered heterocycle containing one or two heteroatoms selected from oxygen atoms, sulfur or nitrogen, which, preferably, tetrahydrofuranyl; indanyl or1-10is alkyl, substituted aryl, indenolol, 6,7-dihydro-5H-cyclopentadienyl or3-6-cycloalkyl.

Also interesting are those compounds of formula (I) in which R5represents hydrogen, and R4represents hydrogen, hydroxy or C1-6-alkyl, in particular, when R4represents methyl.

Another interesting group are those compounds of formula (I) in which L is hydrogen, C1-6-allyloxycarbonyl or1-6-alkyl, substituted by one or two phenyl rings.

Particularly noteworthy are those compounds of formula (I) in which R1is cyclopentyl, tetrahydrofuranyl, cyclopropylmethyl, 5-fenilpentil, 2-inanimate, 6,7-dihydro-5H-cyclopent[b]pyridinyl or indanyl; and R2represents methyl or deformity.

Preferred compounds are compounds in which R3, R5, R6, R10, R11and L represent hydrogen.

The most preferred Liden] cyanamide and[1-[2-[4-(methoxy)-3-[(1,3-dihydro-2H-inden-2-yl)oxy] -phenyl]propyl]-1, 3-dihydro-2H-imidazol-2-ilidene]cyanamide; their N-oxides, their stereochemical isomeric forms and pharmaceutically acceptable salts of the merger.

Wherever referred to hereinafter R1-R11That Y-a-b - and L, they have the values listed in the definition of formula (I), unless otherwise indicated.

The compounds of formula (I) in which-a-b - represents a radical of formula (C-1), and L is hydrogen, and these compounds are represented by formula (I-a-1), can conveniently be obtained by cyclization of an intermediate compound of formula (II) or its functional derivative in the presence of a suitable acid, such as hydrochloric acid

< / BR>
The above cyclization can be performed in an inert reaction solvent such as, for example, tetrahydrofuran or 1,4-dioxane or mixtures thereof. Mixing and heating can increase the reaction rate.

In this and the following methods of obtaining the reaction products can be isolated from the reaction medium and, if necessary, to further purify by known methods in this field, such as, for example, extraction, crystallization, rubbing and chromatography.

In particular, the compounds of formula (I-a-1), in which these intermediate compounds of formula (II-1), where R represents hydrogen or, preferably, is a protective trimethylsilyloxy group or its functional derivative in the manner similar to that described to obtain the compounds of formula (I-a-1) from the intermediate compounds of formula (II)

< / BR>
The compounds of formula (I) in which-a-b - represents a radical of formula (C-2), and L is hydrogen, and these compounds are represented by formula (I-a-2), can be obtained by cyclization of an intermediate compound of formula (III) or its functional derivative in the presence of a suitable reagent, such as, for example, dimethylcarbamodithioato or diphenyl-N-cyanocarbonimidate

< / BR>
On the other hand, the compounds of formula (I) can be obtained by the interaction of ORGANOMETALLIC intermediate compounds of formula (IV), where M is an appropriate metal ion or metal complex ion, such as, for example, Li+, (Mdwg)+IN(OH)2+or Sn(CH3)3+in an inert reaction solvent with a suitable derivative of 2-renominate formula (V), where W1represents a reactive leaving group such as, for example, halogen. In the case when R4and R5join vmovie, the intermediate compound of formula (IV) is a Grignard reagent

< / BR>
The above reaction can be performed in an inert reaction solvent such as, for example, dimethoxyethane, tetrahydrofuran or diethyl ether. Mixing and heating can accelerate the reaction. In the case when the specified reaction using intermediate compounds of formula (V) in which L replace with suitable protective group, compounds of formula (I) in which L is hydrogen, and these compounds are represented by the compounds of the formula (1-a), can be obtained using well-known in this field reactions removal of protective groups.

The compounds of formula (I) can also be transformed one into another in accordance with well-known in the field of methods of transformation of functional groups.

For example, the compounds of formula (I) in which L is different from hydrogen, and these compounds are represented by formula (I-b), can be obtained by the coupling of compounds of formula (I-a) L'-W2(VI) where L' has the same meaning as L in formula (I), but is not hydrogen, and W2represents a reactive leaving group such as, for example, halogen atom

< / BR>
To make the connection.

The compounds of formula (I) can also be converted into the corresponding N-oxide forms in accordance with known methods for the conversion of trivalent nitrogen into its N-oxide form. These reactions of N-oxidation, in General, can be realized by the interaction of the educt of the formula (I) with 3-phenyl-2-(phenylsulfonyl)oxaziridine or with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali metals or alkaline earth metals, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may be peroxyacids, such as, for example, phenoxybenzamine acid or halogen-substituted peroxybenzoate acid, for example, 3-chlorbenzene peroxynitrate, paracalanidae acid, for example, purakayastha acid, alkylhydroperoxide, for example, tert-butylhydroperoxide. Suitable solvents are, for example, water, lower fatty alcohols, such as ethanol, etc., hydrocarbons such as toluene, ketones, for example, 2-butanone, halogenated hydrocarbons such as dichloromethane and mixtures of such solvents.

The above intermediate compounds can be the ü first, the interaction of the amine of formula (VII) with dimethylcarbamodithioato or diphenylcarbonate or its functional derivatives. This interaction can be conveniently accomplished in an inert reaction solvent such as, for example, dichloromethane, benzene or toluene, optionally while cooling in an ice bath and in the presence of a base, such as, for example, N, N-diethylethanamine or sodium bicarbonate. Thus obtained intermediate compound then you can enter into interaction with an intermediate compound of formula (VIII) or its functional derivatives with the formation of intermediate compounds of formula (II). This interaction can easily carry out in an inert reaction solvent such as, for example, 1,4-dioxane, in the presence of a base, such as, for example, N,N-diethylethanamine, and, optionally, in the presence of a catalyst, such as, for example, N, N-dimethylpyridine. Mixing and fever can increase the reaction speed

< / BR>
Alternatively, the above interaction can be performed in reverse order, i.e. first enter into the reaction intermediate compound of formula (VIII) with dimethylcarbamodithioato or diphenylcarbonate or its functional derivative, and then thus obtained intermediate compound to enter in usaused hydrogen, moreover, these intermediate compounds represented by formula (III-1), can be obtained first by the interaction of the amine of formula (VII) with cyanoderivatives formula (IX), where W3represents a suitable leaving group, such as, for example, halogen, in the presence of a base, such as sodium carbonate, in an inert reaction solvent such as, for example, N, N-dimethylformamide. Then cyanide group in the thus obtained intermediate compound can be recovered by use of a suitable reductant such as, for example, alumoweld lithium or hydrogen, in the presence of a catalyst, such as, for example, Raney Nickel, thus obtaining an intermediate compound of formula (III-1)

< / BR>
Some of the intermediate compounds of formula (VII) are described in WO 92/00968, WO 93/15044 and WO 93/15045.

In particular, the intermediate compounds of formula (VII) can be obtained by the interaction of the intermediate compounds of formula (X), where W4represents a suitable leaving group, such as, for example, halogen, with an intermediate compound of formula (XI), where M is an appropriate metal ion or metal complex ion, such as, for example, Li+or (Mdwg)+and R predstavlyayuschego the compounds of formula (VII) with a protective group can then be split protective group is well known in the technique methods, for example, acid hydrolysis

< / BR>
Intermediate compounds of formula (VII) in which R6represents hydrogen, moreover, these intermediate compounds represented by formula (VII-1), can be obtained by recovering the unsaturated carbon-nitrogen in the intermediate compounds of formula (XII) with a suitable reducing agent, such as, for example, balancerationality complex, alumoweld lithium or hydrogen, in the presence of a catalyst, such as, for example, Raney Nickel. Cyanide group in the intermediate compounds of formula (XII) can also replace its functional derivatives, such as, for example, Axima group

< / BR>
Some of the intermediate compounds of formula (XII) are described in WO 92/00968, WO 93/15044 and WO 93/15045.

In particular, the intermediate compounds of formula (XII) in which R5represents a protected hydroxyl group, and R4represents hydrogen, moreover, these intermediate compounds represented by formula (XII-1), can conveniently be obtained by the interaction of the aldehyde of formula (XIII) with a reagent of formula (XIV) or its functional derivatives, in which R represents a protective group such as, for example, trimethylsilyl, etc., in inert for the reaction of rest the national derived. These intermediate compounds of formula (XII-1) then you can enter into interaction, as described above, and to obtain the form of the compounds of formula (I) in which R5represents hydroxy

< / BR>
The aldehydes of the formula (XIII) can be conveniently obtained by the method similar to that described itsunobu Hohwald in Synthesis, 1-28, 1981.

Some compounds of formula (I) and some intermediate compounds of the present invention have at least one asymmetric carbon atom. Pure stereochemical isomeric forms of these compounds and these intermediate compounds can be obtained using methods known in this field. For example, diastereoisomers can be separated using physical methods such as selective crystallization or chromatographic techniques, e.g. counter current distribution, liquid chromatography and the like methods. Enantiomers can be obtained from racemic mixtures by turning the first of these racemic mixtures with suitable separating agents, such as, for example, chiral acids in a mixture of diastereomeric salts or compounds; with subsequent physical separation of these mixtures of diastereomeric salts or compounds with POM the AI and such methods; and, finally, the transformation of these separated diastereomeric salts or compounds into the corresponding enantiomers.

Pure stereochemical isomeric forms of the compounds of formula (I) can also be obtained from pure stereochemical isomeric forms of the appropriate intermediates and starting compounds, provided that the reaction conversion are stereospecific. It is assumed that the stereochemical pure and mixed isomeric forms of the compounds of formula (I) are included in the scope of the present invention.

The compounds of formula (I), their N-oxide forms, pharmaceutically acceptable salt accession of acids and bases and their stereochemical isomeric form are strong inhibitors of phosphodiesterase isoenzymes (D) family IV (camp-specific family).

camp (cyclic adenosine-3',5'-monophosphate) is a key secondary messenger, the concentration of which affect the activity of specific cells through the activation of enzymes such as kinases. It is known that D IV hydrolyzes camp to its inactive metabolite 5'-monophosphate. Therefore, inhibition D IV increases levels of camp in specific cells, such as the R, the basophils, neutrophils and eosinophils, monocytes and mast cells. Suppose that the number of allergic, atopic and inflammatory diseases caused by concentrations D IY greater than normal, resulting in low levels of camp and hypersensitivity who have experienced this influence cells to excitatory stimuli. (Examples indicated hypersensitivity are, for example, excessive histamine release from basophils and mast cells or excessive formation of peroxide anion radicals by eosinophils.) Therefore, the compounds of the present invention having properties significantly inhibit phosphodiesterase IV, are considered to be useful to facilitate and/or treatment of allergic, atopic and inflammatory diseases. The functional effect of inhibitors D IV is, for example, relaxation of respiratory smooth muscle cells, increased bronchial lumen, the inhibition of platelet aggregation and inhibition of release of mediators by leukocytes. Examples of allergic diseases are asthma, cheilitis, conjunctivitis, contact dermatitis and eczema, painful sensitivity of the intestine, dry eczema, urticaria, vasculitis, vulva; PE diseases, for example, psoriasis and other hyperproliferative diseases.

Thus, the present invention also relates to compounds of formula (I) defined above, for use in medicine, in particular for use as a drug for the treatment of atopic diseases, or as anti-asthma remedies. Thus, the compounds of the present invention can be applied for the production of medicines for the treatment of atopic or asthmatic diseases, especially atopic dermatitis.

Inhibitory effect on D IV compounds of formula (I) can be demonstrated in the test "Inhibition of recombinant human mononuclear lymphocytic (NL) phosphodiesterase type IV produced in insect cells with a baculovirus vector". Some tests in vivo and in vitro can be used to demonstrate the usefulness of the compounds of formula (I) for the treatment described allergic, atopic and inflammatory diseases. Such tests are, for example, "Bronchostenosis of Guinea-pig trachea in vitro, Bronchostenosis of Guinea-pig trachea in vitro and in vivo test "Inflammation of the outer ear in mice induced by arachidonic acid, Vespa is soedineniya of the present invention have a very weak inhibitory effect on phosphodiesterase isoenzymes Familia III (family, ingibiruet G). Inhibition, in particular, D III leads to increased levels of camp in the heart muscle that causes the effect on the heart's contractility and relaxation of the heart. It is clear that the treatment described allergic, atopic and inflammatory diseases of the action on the cardiovascular system is undesirable. Therefore, since the compounds of the present invention inhibit D IV at significantly lower concentrations than those at which they inhibit D III, they can be used therapeutically, avoiding cardiovascular side effects.

Known inhibitors D IV often have harmful side effects on the gastrointestinal tract. Most of the compounds of the present invention have a low impact on the gastrointestinal tract that can be shown in the test "Emptying of the stomach from eating high calorie foods in rats".

Used here to denote "D III" and "D IV" refers to the classification of J. A. v and D. N. Rifsnydr, IS Rviws, ril 1990, PP. 150-155.

Compounds of the present invention have inhibitory effect on cytokines. The cytokine is any secretory polypeptide that affects the function is the reamers cytokines are Monokini and lymphokines, and they can be produced by many different cells. For example, manokin is generally regarded as produced and indirect managerno cell such as a macrophage and/or monocyte, but Monokini produced many other cells such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, astrocytes brain, stromal bone marrow cells, epidermal keratinocytes and lymphocytes. Lymphokines are usually considered as produced by lymphocytes. Examples of cytokines are interleukin-1 (IL-1), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-a) and tumor necrosis factor beta (TNF).

Cytokine, which is particularly preferably to inhibit, is a (TNF-a. Excessive or unregulated production of TNF is the reason for the transfer or exacerbating a number of diseases, including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, gram negative sepsis, toxic shock, respiratory distressing syndrome adults, cerebral malaria, chronic pneumonia, silicosis, sarcoidosis l is reenie allografts, fever and myalgia due to infectious diseases, such as influenza, cachexia resulting from infection or malignant tumors, cachexia due to acquired immunodeficiency syndrome (AIDS), IDS-R (AIDS related complex), the formation of keloid zone, formation of scar tissue, Crohn's disease, ulcerative colitis or heartburn.

Inhibitory cytokines action of the compounds of formula (I), such as the inhibition of production of TNF, can be shown in the test in vivo Production of cytokines in cultures of human whole blood".

In addition, it is expected that the compounds of the present invention will not show or show weak side effects of endocrine nature. It can be shown, for example, in test Testosterone in vivo", test, "Inhibition of aromatase activity in vitro and test the Inhibition of aromatase activity in vivo.

Taking into account the useful properties of inhibition D IV and cytokines discussed connections you can enter into the composition of various pharmaceutical compositions for the purposes of introduction, containing a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of soy is a great number for a compound in salt form attach a base or acid, as the active ingredient, combined with careful mixing with a pharmaceutically acceptable carrier which may be in various forms depending on the form of preparation desired for administration. These pharmaceutical compositions preferably are in the form of standard doses, suitable, preferably, for oral, rectal, local, percutaneous injection, injection inhalation or parenteral injection. For example, upon receipt of the compositions in oral dosage form to use conventional pharmaceutical environment, such as, for example, water, glycols, oils, alcohols and the like for liquid oral preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrators and the like substances in the case of powders, pills, capsules and tablets. Because of the ease of introduction of tablets and capsules represent the most preferred standard form of drugs for oral administration, which are, obviously, a solid pharmaceutical carriers. In the case of parenteral compositions, the carrier typically will contain sterile water, at the process, for example, solutions for injection, in which the medium contains saline solution, glucose solution or a mixture of saline and glucose solution. You can also get a suspension for injection, in which you can use the appropriate liquid carriers, suspendresume funds and similar substances. In the compositions suitable for percutaneous administration, the carrier contains, optionally, an agent that increases the penetration and/or a suitable wetting agent, United optionally with suitable additives of any nature in small quantities that do not have any harmful effects on the skin. These supplements can facilitate the introduction into the skin and/or may be useful for the preparation of the desired compositions. These compositions can be administered in a number of ways, for example, in the form of a transdermal patch, in the form of strokes or in the form of ointment. Suitable compositions for topical application can be called all songs, usually used for local administration of drugs, for example, creams, jellies, dressings, shampoos, tinctures, pastes, ointments, lipsticks, powders, etc., it is Possible to apply the composition with aerosol, for example, with the same propellant as nitrogen, denom condition, such as a thickened composition which can be applied by using a brush. In particular, semi-solid compositions such as lipsticks, creams, gels, ointments and the like, it will be convenient to use.

To improve the solubility and/or increase the stability of the compounds of formula (I) in pharmaceutical compositions can be advantageously be used-or-cyclodextrins or their derivatives, in particular, hydroxyacetaldehyde cyclodextrins, such as 2-hydroxypropyl--cyclodextrin. Also the solubility and/or stability of the compounds of formula (I) in pharmaceutical compositions can improve the co-solvents, such as alcohols. When receiving water compositions are more appropriate, obviously, salt accession of the discussed compounds because of their high solubility in water.

Especially preferably, to make the above pharmaceutical composition in unit dosage form for ease of administration and standardized dosage. Standard dosage form refers to physically discrete elements, suitable as a standard doses, where each element contains a predetermined quantity of active ingredient calculated to poluchyennykh dosage forms are tablets (including, tablets are scored or coated), capsules, pills, sachets of powder, pills, solutions or suspensions for injection and similar forms, and packages containing lots of them.

The present invention also relates to a method of treating warm-blooded animals suffering from painful conditions associated with abnormal enzymatic or catalytic activity D IV, and/or painful conditions are associated with a physiologically detrimental excess of cytokines, in particular, allergic, atopic and inflammatory diseases, more precisely, from asthma and atopic diseases, and most definitely, from atopic dermatitis. This method includes the introduction of therapeutically effective amounts of compounds of formula (I) or its N-oxide form, pharmaceutically acceptable salt accession acid or base, or a stereochemical isomeric form in a mixture with a pharmaceutically acceptable carrier.

In General, it is assumed that the effective daily amount may be from 0.01 mg/kg to 10 mg per kg of body weight. It is obvious that the effective daily amount can be reduced or increased depending on the patient's response and/or depending on the VA, the above, therefore, represents only a guide to action and in no way intended to limit the scope of the invention.

The following examples are intended to illustrate and not to limit the scope of the present invention.

Experimental part

Some compounds of formula (I) absolute stereochemical configuration was not determined. In these cases, the stereochemical isomeric form, which has allocated the first, denoted "A" and the second "In", without mentioning the exact stereochemical configuration.

Hereinafter "THF" means tetrahydrofuran, "CT" means room temperature, "DMF" means N,N-dimethylformamide and DIPA" refers to diisopropyl ether.

A. the production of intermediate compounds

Example A. 1

a) potassium Carbonate (0,0569 mol) in current of the N2added dropwise to a mixture of 4-deformedarse-3-hydroxybenzaldehyde (0,053 mol) and (tetrahydro-3-furanol)-4-methylbenzol-sulfonate (15,35 g) in DMF (100 ml). The reaction mixture is stirred for 4 hours at 100oC. the Mixture is cooled and added dropwise a solution of (tetrahydro-3-furanol)-4-methylbenzenesulfonate (3.98 g) in DMF is spruce is evaporated, and the residue is washed with a saturated aqueous solution of Na2CO3and then extracted DIPA. The separated organic layer is dried, filtered and the solvent is evaporated, getting 17,77 )-4-(deformedarse)-3-[(tetrahydro-3-furanyl)oxy]benzaldehyde (intermediate compound 1).

C) a Solution of sodium borohydride (0,0177 mol) is added by portions to a solution of intermediate compound 1 (0,0532 mol) in methanol (100 ml) and the reaction mixture is stirred for 1 hour at RT. The solvent is evaporated, the residue is washed with water and extracted with CH2CL2. The separated organic layer is dried, filtered and the solvent evaporated. The residue is purified by chromatography in open column on silica gel (eluent: CH2CL22-propanone, 96/4 and 90/10; CH2CL2with CH3HE 96/4). Pure fractions are collected and the solvent is evaporated, receiving 11.3 g(81%) ()-4-(deformedarse)-3-[(tetrahydro-3-furanyl)oxy] benzoimidazole (intermediate compound 2).

C) a Solution of intermediate compound 2 (0,039 mol) in toluene (45 ml) is added dropwise to the mixture Sl2(0,059 mol) and DMF (0,0019 mol) in toluene (75 ml) and stirred at 40oC. the resulting reaction mixture was stirred at 40oWith up until not tworoom Panso3and extracted with CH2CL2. The separated organic layer is dried, filtered and the solvent is evaporated, getting 10,59 g(96%) ()-4-(deformedarse)-3-[(tetrahydro-3-furanyl)oxy] benzoimidazole (intermediate compound 3).

d) a Mixture of KCN (0,076 mol) in N2O (4 ml), heated to 80oC, is added dropwise to a mixture of intermediate compound 3 (of 0.038 mol) in DMF (82,4 mol), stirred at 60oC. the resulting reaction mixture is stirred for 30 minutes at 60oC. the Reaction mixture is cooled, washed with water, and extracted DIPA. The extract is dried, filtered and evaporated the filtrate, get 8,23 g(80%) ()-4-(deformedarse)-3-[(tetrahydro-3-furanyl)oxy]benzoylacetonitrile (intermediate compound 4).

In a similar way get:

3-(cyclopropylmethoxy)-4-methoxyphenylacetonitrile (intermediate compound 5);

3-[1,3-dihydro-2H-inden-2-yl)oxy]-4-methoxyphenylacetonitrile (intermediate compound 6);

()-4-methoxy-3-[(tetrahydro-3-furanyl)oxy]benzoylacetonitrile (intermediate compound 7);

4-methoxy-3-[(5-fenilpentil)oxy] benzoylacetonitrile (intermediate compound 8);

4-(deformedarse)-3-[(5-fenilpentil)oxy] benzoylacetonitrile (intermediate compound 23).

2to the intermediate compound 4 (0,0309 mol) in THF (70 ml) and cooled to -78oC. the Mixture is stirred for 30 minutes at -78oC. is Added dropwise metanode (0,034 mol) and the reaction mixture is stirred for 2 hours at RT. The mixture is quenched with saturated aqueous NH4CL and extracted with ethyl acetate. The separated organic layer is dried, filtered and the solvent evaporated. The residue is purified by chromatography in a short open column on silica gel (eluent: CH2CL2), then HPLC on silica gel (eluent: hexane with ethyl acetate, 3/2). Collect the pure fractions and the solvent is evaporated, receiving with 4.64 g(53%) ()-4-(deformedarse)-alpha-methyl-3-[(tetrahydro-3-furanyl)oxy]benzoylacetonitrile (intermediate compound 9).

C) a Mixture of intermediate compound 9 (0,0129 mol) in CH3HE/NH3(100 ml) hydronaut CT with Raney Nickel (3 g) as a catalyst. After hydrogen absorption, the catalyst is filtered off, the filtrate evaporated and get 3,66 g (98%) )-4-(deformedarse)--methyl-3-[(tetrahydro-3-furanyl)oxy] benzenediamine (intermediate compound 10).

(C) a Mixture of intermediate compound 10 (0,0158 mol) and diphenyl-N-cyanocarbonimidate (0,0158 mol) in ethanol (60 ml) is stirred gel (eluent: hexane with ethyl acetate 3/2 and CH2CL2with CH3HE is 96/4, 90/10 and 85/5). Pure fractions are collected and the solvent is evaporated, receiving of 5.11 g (74%) ()-phenyl-N-cyano-N-[2-[4-(deformedarse)-3-[(tetrahydro-3-furanyl)oxy]-phenyl]propyl]carbamimidoyl (intermediate compound 11).

d) a Mixture of 2,2-dimethoxyethane (0,0129 mol), N, N-diethylethanamine (is 0.023 mol) and N,N-dimethyl-4-pyridylamine (0,0059 mol) in 1,4-dioxane (30 ml) was added to a solution of intermediate 11 (to 0.0117 mol) in 1,4-dioxane (10 ml) with stirring at RT. The reaction mixture is stirred and refluxed overnight. The solvent is evaporated and the residue is washed with water and 1 N Paon, then extracted with CH2CL2. The separated organic layer is purified by chromatography in open column on silica gel (eluent: CH2CL2with CH3HE 96/4). Pure fractions are collected and the solvent is evaporated, obtaining equal to 4.97 g (95%) ()-N"-cyano-N-[2[4-(deformedarse)-3-[(tetrahydro-3-furanyl)oxy] phenyl] -propyl]-N'-(2,2-dimethoxymethyl)guanidine (intermediate compound 12).

In a similar fashion get:

()-N"-cyano-N-[2-[3-(cyclopentyloxy)-4-methoxyphenyl] -propyl] -N'-(2,2-dimethoxymethyl)guanidine (intermediate compound 13);

()-N"-cyano-N-[2-[3-(cyclopentyloxy)-4-(deformedarse) f is(deformedarse) phenyl] ethyl]-N'-(2,2-dimethoxymethyl)guanidine (intermediate compound 15);

()-N"-cyano-N-[2-[3-(cyclopropylmethoxy)-4-(deformedarse) phenyl] propyl]-N'-(2,2-dimethoxymethyl)guanidine (intermediate compound 16);

()-N"-cyano-N-[2-[3-(1,3-dihydro-2H-inden-2-yl)oxy] -4-methoxyphenyl] propyl]-N'-(2,2-dimethoxymethyl)guanidine (intermediate compound 17);

()-N"-cyano-N-[2-[3-(cyclopropylmethoxy)-4-methoxyphenyl] propyl]-N'-(2, 2-dimethoxymethyl) guanidine (intermediate compound 18);

()-N"-cyano-N-(2,2-dimethoxymethyl)-N'-[2-[4-methoxy-3-[(5-fenilpentil)oxy]phenyl]propyl]guanidine (intermediate compound 19);

()-N"-cyano-N-(2,2-dimethoxymethyl)-N'-[2-[4-methoxy-3-[(tetrahydro-3-furanyl)oxy]phenyl]propyl]guanidine (intermediate compound 20);

N"-cyano-N'-(2,2-dimethoxymethyl)-N-[2-[4-(deformedarse)-3-[5-fenilpentil)oxy]phenyl]propyl]guanidine (intermediate compound 24);

N"-cyano-N'-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxyphenyl]ethyl] -N-(2,2-dimethoxymethyl)guanidine (intermediate compound 25);

()-N"-cyano-N-[2-[3-[2-(2,3-dihydro-1H-inden-2-yl)-ethoxy] -4-methoxyphenyl]propyl]-N'-(2,2-dimethoxymethyl) guanidine (intermediate compound 27);

()-N"-cyano-N-[2-[3-(2,3-dihydro-1H-inden-2-yl)oxy] -4-methoxyphenyl]-2-[(tetrahydro-2H-Piran-2-yl)oxy] ethyl] -N'-(2,2-dimethoxymethyl)guanidine (intermediate compound 28).

Example A. 3

a) See the rija (0,0219 mol) in DMF (200 ml) is stirred for 5 hours at 60oC. the Reaction mixture is filtered and the filtrate evaporated. The residue is washed with water, then extracted with 2-methoxy-2-methylpropanol. The separated organic layer is dried, filtered and the solvent evaporated. The residue is purified by chromatography in open column on silica gel (eluent: CH2CL2; CH2CL22-propanone, 96/4 and 90/10; then CH2CL2with CH3HE, 80/20). Pure fractions are collected and the solvent is evaporated, get 3,24 g(77%) ()-[[2-[3-(cyclopentyloxy)-4-methoxyphenyl]propyl] amino]-acetonitrile (intermediate compound 21).

C) a Mixture of intermediate 21 (to 0.0117 mol) in NH3/CH3HE (60 ml) hydronaut CT with Raney Nickel (2 g) as a catalyst. After absorption of H2the catalyst is filtered off and the filtrate evaporated. The residue is treated with 10% aqueous Hcl solution and the mixture extracted with ethyl acetate. The layers are separated. The aqueous phase is alkalinized and then extracted with ethyl acetate. The separated organic layer is dried, filtered and the solvent is evaporated, get a 2.71 g (75%) ()-N-[2-[3-(cyclopentyloxy)-4-methoxyphenyl]-propyl]-1,2-academia (intermediate compound 22).

Example A. 4

a) a Mixture of 6,7-dihydro-5H-cyclopent[b]pyridine-7-ol-(0,03544 moC in an atmosphere of N2. Added dropwise bis(1-methylethyl)deathandtaxes (0,0322 mol) and the resulting reaction mixture is stirred for 12 hours at RT. The solvent is evaporated and to the residue add CH2CL2. The mixture is washed with water, dried, filtered and the solvent evaporated. The residue is purified on silica gel on a glass filter (eluent: CH2CL2with CH3HE is from 100/0 to 98.5/1.5) does not. Collect the desired fraction and the solvent is evaporated. The residue is dissolved in 2-propanol and converted into the salt of hydrochloric acid (1:1) with Hcl in 2-propanol. The solvent is evaporated. The residue is stirred in DIPE, filtered and dried, obtaining of 8.2 g (83%) of the hydrochloride of 3-[(5,6-dihydro-7H-pyridin-7-yl)oxy]-4-methoxybenzaldehyde (intermediate compound 34).

b) a Solution of trimethylsilylacetamide (0,1472 mol) in CH2CL2(60 ml) is added dropwise to a mixture of 3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxybenzaldehyde (0,1227 mol) and zinc iodide (0,0061 mol) in CH2CL2(240 ml). The resulting reaction mixture is stirred for one hour at RT. The crude reaction mixture is washed with water and brine, then extracted with CH2CL2. The separated organic layer is dried, filtered -[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxy--[(trimethylsilyl)oxy]benzoylacetonitrile (intermediate compound 29).

C) an Intermediate compound 29 (0,1116 mol) is dissolved in methanol and add Hcl (3 N, 25 ml). The mixture is stirred for 5 minutes. Evaporate the greater part of the solvent and add CH2CL2. The organic layer is separated, washed with saturated aqueous Panso3, dried, filtered and the solvent evaporated. The residue is dissolved in CH2CI2(350 ml). Add 3,4-dihydro-2H-Piran (0,2231 mol) and 4-methylbenzenesulfonic acid (catalytic amount), the resulting reaction mixture is stirred over night at RT. The mixture was washed with saturated aqueous Panso3, dried, filtered and the solvent evaporated. The residue is purified by chromatography in a short open column on silica gel (eluent: hexane with ethyl acetate, 9/1 then 8/2). Collect the desired fraction, the solvent is evaporated and get 28,01 g(66%) ()-3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxy--[(tetrahydro-2H-Piran-2-yl)oxy]benzoylacetonitrile (intermediate compound 30).

Example 5 A.

a) a Solution of bis(1,1-dimethylethyl)dicarbonate (were 1,268 mol) in CH2CL2(1800 ml) is added dropwise to a solution of ()-3-[(2,3-dihydro-1H-inden-2-yl)oxy] -4-methoxy-methylbenzeneethanamine (1, 208 mol) in CH2CL2(1800 ml)throwaway and dried, get 420 g ()-1,1-dimethylethyl[2-[3-[(2,3-dihydro-2H-inden-2-yl)oxy] -4-methoxyphenyl] propyl] -carbamate (intermediate compound 31).

C) an Intermediate compound 31 (1,056 mol) purify and produce a chiral column chromatography on hiralpack AD (eluent: hexane with2H5HE and CH3HE 90/10/10). Gather a group of right fractions and the solvent is evaporated, getting 268 g of 1,1-dimethylethyl-In-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxyphenyl)propyl]carbamate (intermediate compound 32).

(C) a Mixture of intermediate 32 (0.67 mol) in Hcl (670 ml, 6 N) and methanol (2700 ml) is stirred and refluxed for 90 minutes. The solvent is evaporated. The residue is dissolved in CH2CL2. The organic solution is washed with N2O (1000 ml) and a saturated solution Panso3. The organic layer is separated, dried, filtered and the solvent is evaporated, getting 158 g (99%) (In)-3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxy-methylbenzeneethanamine (intermediate compound 33).

Then the intermediate connection 33 is injected into the interaction by the method described in example A. 2,b - A. 2, d, with the formation of the (In)-N"-cyano-N-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy] -4-methoxyphenyl] propyl] -N'-(2,2-dimethoxymethyl)guanidine which mediate connections 22 (0,0068 mol) and dimethylcarbamodithioato (0,0068 mol) in ethanol (20 ml) stirred and refluxed for 2 days. The solvent is evaporated and the residue is purified first by chromatography in a short open column on silica gel (eluent: CH2CL2CH2CL2with CH3HE 96/4 and 90/10), and then double-HPLC (eluent 1 - CH2CL2with CH3HE 90/10 and 2, eluent CH2CL2with CH3HE 96/4). Pure fractions are collected and the solvent is evaporated, receiving 0.3 g(13%) ()-[1-[2-[3-(cyclopentyloxy)-4-methoxyphenyl] propyl] -2-imidazolidinone] cyanamide (compound 1).

Example Century. 2

To a solution of intermediate compound 12 (0,0108 mol) in 1,4-dioxane (20 ml) under stirring and cooling in an ice bath is added dropwise a 0.5 N model HC1 (0,0162 mol). The reaction mixture is stirred for 2 days at RT. (Another option is 1,4-dioxane can be replaced THF and the reaction mixture instead of stirring for 2 days at RT can be boiled under reflux for 1 hour.) The reaction mixture is treated with water, alkalinized dilute solution Paon, then extracted with ethyl acetate. The separated organic layer is dried, filtered and the solvent evaporated. The residue is purified by chromatography in open column on silica gel (eluent: CH2CL22-propanone, 96/4; CH2CL2with CH3ABOUT THE CH3HE 97/3). Pure fractions are collected and the solvent is evaporated, getting 0.64 g(15%) ()-[1-[2-[4-(deformedarse)-3-[(tetrahydro-3-furanyl)oxy] -phenyl] propyl]-1,3-dihydro-2H-imidazol-2-ilidene]cyanamide (compound 2; so pl. 67,8oC).

Example Century. 3

a) Compound 7 (0,00644 mol) is separated into the enantiomers by chromatographia in chiral column hiralpack AD (20 μm, 250 g, 5 cm, flow rate: 60 ml/min; eluent: hexane/ethanol/methanol, 80/15/5). Gather two groups of the desired fractions. The solvent is evaporated from the first (A) group of fractions. The residue is stirred in DIPE, filtered off, washed, DIPE and dried. Then the resulting residue is purified column chromatography on silica gel rmsil (200 g, 5 μm; eluent: CH2CL2with CH3HE 100/0, after 30 minutes - 90/10).

Pure fractions are collected and the solvent evaporated. The residue is stirred in DIPE, filtered off, washed, DIPE, then dried, obtaining 0.39 g (50%) of (+)-()-[1-[2-[3-[2,3-dihydro-1H-inden-2-yl)oxy] -4-methoxyphenyl] propyl]-1H-imidazol-2-yl]cyanamide;

[]20D=+95,46o(C=0.1% in CH3HE) (compound 16).

The solvent is evaporated from the second (B) group factions. The residue is stirred in DIPE, filtered off, washed, DIPE and then dried. The residue is purified column . the East fractions are collected and the solvent evaporated. The residue is stirred in DIPE, filtered off, washed, DIPE, then dried, obtaining 0.5 g (90%) of (-)-()-[1-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy] -4-methoxyphenyl] propyl] -1H-imidazol-2-yl]-cyanamide; []20D=-109,04o(C=0.1% in CH3HE) (compound 17).

C) a Mixture of compound 17 (0,0026 mol) in DMF (40 ml) stirred at 0oC. Add sodium hydride (0,0028 mol; 60%) and the mixture is stirred for 30 minutes at 0oWith and for 30 minutes at RT. Add dropwise a solution of bromeilles (0,0028 mol) in DMF (10 ml) and the resulting reaction mixture is stirred for 3 hours at RT. The solvent is evaporated, add toluene and spend the azeotropic distillation on a rotary evaporator. The residue is dissolved in CH2CL2. Add the water. The organic layer is separated, dried, filtered and the solvent evaporated. The residue is purified by chromatography in a short column of silica gel (eluent CH2CL2with CH3HE, 98/2). Collect the desired fraction, the solvent is evaporated, gaining 0.7 g (63%) (In)-[1-[2-[3-[2,3-dihydro-1H-inden-2-yl)oxy] -4-methoxyphenyl] propyl]-3-phenylmethyl-1H-imidazol-2-yl] cyanamide (compound 23).

Example Century. 4

To a solution of intermediate is (0,0268 mol; 0.5 N). The reaction mixture is stirred and refluxed for 1.5 hours and then cooled in an ice bath. The mixture is treated with water and ethyl acetate, alkalinized solid Na2CO3. The organic layer is separated, dried, filtered and the solvent evaporated. The residue is purified by chromatography on a short open column on silica gel (eluent: CH2CL2with CH3HE, 97/3, then 95/5). Gather a group of pure desired fractions. The solvent is evaporated and the residue crystallized from CH3JV, filtered and dried, obtaining(35%) ()-[1-[2-[3-[(2,3-dihydro-1H-inden-2-yl)oxy]-4-methoxyphenyl]-2-hydroxyethyl]-1,3-dihydro-2H-imidazol-2-ilidene]cyanamide (compound 21).

In table. 1 lists the compounds of formula (I) who will receive one of the above examples.

C. Pharmacological examples

The C. example 1: Inhibition of recombinant human managerno lymphocytic (NL) phosphodiesterase type IV produced in insect cells with a baculovirus vector

Facilitate and/or therapeutic effect of certain compounds in allergic and atopic diseases is assessed through a system of in vitro tests to determine the inhibitory D. recombinant baculovirus cells insects collect and precipitate at 500 g for 5 minutes. Cells are lysed in 10 ml of buffer for lysis containing 20 mm Tris, 10 mm G, 2 mm Na2Add, 1% Triton-X-100, 1 mm PA3VO4, 10 mm NF, 2 μg/ml leupeptin, pepstatin and Aprotinin, 0.3 ág/ml of benzamidine and 100 μg/ml TFHK, pH 7.5. After a 5 minute exposure on ice dissolved cells are centrifuged at 4000 rpm for 15 minutes at 4oC. the resulting supernatant filtered through a 0,45 µm filter (illipore) and bring in S-buffer (50 mm Tris, 150 mm Nl, pH 7.4).

The supernatant containing the phosphodiesterase type IV In, then download a 5-ml column with gel with anti-FLG-M2affinity, previously activated with 5 ml 100 mm glycine, pH 3.5, and equilibrated with 20 ml of 50 mm Tris, 150 mm Nl, pH 7.4. After washing the column equilibrating buffer elute D IV in fractions of 1.5 ml containing of 37.5 μl of 1 M Tris, pH 8. Faction cialiswhat overnight against 20 mm Tris, 2 mm Na2Add and 400 mm Nl, pH 7.5 and experience on the activity D IV. The determination is carried out on the basis of SDS RADA and Western blotting (anti FLG-M2). The active fractions are combined placed in 10% glycerol and stored at -70oC.

The mixture incubation (pH 8) (200 ml) contains 20 mm Tris, 10 mm magnesium sulfate, 0.8 μm3H-camp (310 ICJ/mmol) and phosphodiesterase linear increase phosphodiesterase activity during the incubation period, a maximum of 10 minutes at 37oAnd when hydrolyzed less than 10% of the original substrate.

When testing the effects of various compounds on fosfodiesterazu activity environment without the camp incubated with compound (compounds) or its vehicle (DMSO, final concentration 1%) for 5 minutes. The enzymatic reaction is initiated by adding a3H-camp and stop after 10 minutes, transferring tetrazinni the microplate in a water bath at 100oWith in 5 minutes. After cooling to room temperature, add alkaline phosphatase (0.25 microgram/ml), and the mixture is incubated at 37oC for 20 minutes and Then 100 μl of the mixture is placed in tetrazinni a microtiter plate reader with a filter GF (illipore) filled with 300 μl of the suspension D-Sephadex-A25. The tablet is washed 3 times with 75 μl of 20 mm Tris, pH 7.5, and collect the filtrate for counting in a scintillation counter krd tor unt.

The inhibitory activity of the compounds of the present invention by recombinant human NL-phosphodiesterase D IV is determined at different concentrations of specific compounds. The value of the IC50(expressed in Meters) calculated graphically from the thus obtained indicators of inhibition and are presented in table. 2.

D. Examples of songs

Privedennogo or local injection of an animal or a person in accordance with the present invention.

The notation "Active ingredient" (and. I.) used in these examples relates to a compound of formula (I) or its pharmaceutically acceptable salt accession.

Example D. 1. Tablets, film-coated

Obtain core tablets

A mixture of 100 g and.and., 570 g lactose and 200 g starch is mixed well and then moisturize with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture is sieved, dried, and sift again. Then add 100 g microcrystalline cellulose and 15 g hydrogenated vegetable oil. All well mixed, pressed into tablets and get 10,000 tablets, each containing 10 mg of active ingredient.

Floor

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. Melt 10 g of polyethylene glycol and dissolved in 75 ml of dichloromethane. The last solution is added to the first, then to this add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye, and all homogenized. Core tablets cover the private use of

To a solution of 200 mg of hydroxypropyl--cyclodextrin in purified water is added under stirring 20 mg and.and. Add hydrochloric acid to dissolve, and then add sodium hydroxide to a pH of 6.0. Add with stirring 50 mg of glycerol and 35 mg of Polysorbate 60, the mixture is heated to 70oC, the resulting mixture with slow stirring to a mixture of 100 mg of mineral oil, 20 mg stearyl alcohol, 20 mg of cetyl alcohol, 20 mg glycerol monostearate and 15 mg sorbate 60 having a temperature of 70oC. After cooling to a temperature below the 25oTo add the remaining purified water, q.s. ad 1 g, and the mixture is stirred until homogeneous.

1. Derivatives of 2-renominate General formula I

< / BR>
their N-oxide form, pharmaceutically acceptable salt accession acid or base or their stereochemical isomeric form,

where R1and R2each independently represents hydrogen, C1- C6alkyl, deformity, trifluoromethyl, C3- C6cycloalkyl, saturated 5-membered heterocycle containing one oxygen atom, indanyl, 6,7-dihydro-5H-cyclopentadienyl or1- C6alkyl, substituted phenyl, indayla or3- C7qi 6alkyl, trifluoromethyl, or R4represents a radical of the formula-O-R7(a-1), where R7represents hydrogen;

R5represents hydrogen or R4and R5taken together may form a bivalent radical of formula-CH2-CH2-O-CH2-CH2- (b-2);

R6represents hydrogen or C1- C4alkyl;

-A-b represents a bivalent radical of the formula- (CR10= CR11- (s-1) or R10-R11- (p-2), where each R10and R11independently represents hydrogen or C1- C4alkyl;

L represents hydrogen, C1- C6alkyl, C1- C6allyloxycarbonyl; C1- C6alkyl, substituted by one or two fenelli.

2. Connection on p. 1, in which each R1and R2independently represents hydrogen; C1- C6alkyl, deformity, trifluoromethyl, C3- C6cycloalkyl, saturated 5-membered heterocycle containing one oxygen atom, indanyl or1- C6alkyl, substituted phenyl or3- C7cycloalkyl.

3. Connection on p. 1, in which each R1and R2independently represents C1- C6alkyl, C3- C6qi is C6alkyl, substituted phenyl, indayla or3- C6cycloalkyl.

4. The compound according to any one of paragraphs. 1-3, in which R4is1- C6alkyl.

5. The compound according to any one of paragraphs. 1-4, in which R1is cyclopentyl, tetrahydrofuranyl, cyclopropylmethyl, 5-phenylmethyl, 6,7-dihydro-5H-cyclopent [b] pyridinyl or indanyl; R2is methyl or deformity and R3, R5, R6, R10, R11and L represent hydrogen.

6. Connection on p. 1, which is a[1-[2-[4-(deformedarse)-3-[(tetrahydro-3-furanyl)oxy] phenyl] -propyl] -1,3-dihydro-2H-imidazol-2-ilidene] cyanamide and[1-[2-[4-(methoxy)-3-[(1,3-dihydro-2H-inden-2-yl)oxy] phenyl] -propyl] -1,3-dihydro-2H-imidazol-2-ilidene] cyanamide or its N-oxide form, its stereochemical isomeric form or its pharmaceutically acceptable salt of the merger.

7. The compound according to any one of paragraphs. 1-6, having inhibitory activity against phosphodiesterase IV.

8. Pharmaceutical composition having inhibitory activity against phosphodiesterase IV, containing a pharmaceutically acceptable carrier and as active ingredient a therapeutically effektivnim, what pharmaceutically acceptable carrier thoroughly mixed with a therapeutically effective amount of a compound according to any one of paragraphs. 1-6.

10. A method of obtaining a connection on p. 1, comprising the cyclization of the intermediate compounds of formula II

< / BR>
or its functional derivative,

in which R1-R6, R10and R11have the values listed in paragraph 1,

in an inert reaction solvent and in the presence of a suitable acid to obtain the compounds of formula I-a-1; and, if desired, converting compounds of the formula I from one to the other known methods of transformation and then, if desired, converting the compounds of formula I in a therapeutically active non-toxic salt accession acid by treatment with an acid, or into a therapeutically active non-toxic salt of attaching the base by treatment with a base, or, on the contrary, the transformation of salt accession acid free base by treatment with alkali, or the transformation of salt attaching the base to the free acid by treatment with acid; and, if desirable, getting their stereochemical isomeric forms or N-oxide forms.

11. A method of obtaining a connection on p. 1, comprising the cyclization of the intermediate soy is passed in p. 1;

R represents hydrogen or trimethylsilyl protective group,

or its functional derivative,

in an inert reaction solvent and in the presence of a suitable acid to obtain the compounds of formula I-a-1-1 and, if desired, converting compounds of the formula I from one to the other known methods of transformation and then, if desired, converting the compounds of formula I in a therapeutically active non-toxic salt accession acid by treatment with an acid, or into a therapeutically active non-toxic salt of attaching the base by treatment with a base, or, on the contrary, the transformation of salt accession acid free base by treatment with alkali, or the transformation of salt attaching the base to the free acid by treatment with an acid and, if desired, getting their stereochemical isomeric forms or N-oxide forms.

12. A method of obtaining a connection on p. 1, comprising the cyclization of the intermediate compounds of formula III

< / BR>
or its functional derivative,

in which R1-R6, R10and R11have the values listed in paragraph 1,

in an inert reaction solvent and in the presence of dimethylcarbamodithioato or diphenyl-N-cyan is in other known methods of transformation and then, if desired, the conversion of the compounds of formula I in a therapeutically active non-toxic salt accession acid by treatment with an acid, or into a therapeutically active non-toxic salt of attaching the base by treatment with a base, or, on the contrary, the transformation of salt accession acid free base by treatment with alkali, or the transformation of salt attaching the base to the free acid by treatment with an acid and, if desired, obtaining their stereochemical isomeric forms or N-oxide forms.

 

Same patents:

The invention relates to new substituted phenylimidazoline, to a method for their production and to their use in pharmaceutical compositions

The invention relates to organic chemistry, and more specifically to new connections - hydrochloridum 2-aminoimidazole and 2-aminothiazole General formula (1),

< / BR>
aryl, the substituent in position 4 and a disulfide bridge in the position 5, where X is alkylamino, for example, methylamino, and R1-R2is hydrogen; X-methylaminopropyl, and R1-alkyl, for example methyl and R2is hydrogen; X-methylaminopropyl, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X-methylaminopropyl, and R1-ethoxypropan and R2is hydrogen; X-methylaminopropyl, and R1halogen, for example chlorine and RF2is hydrogen; X-methylaminopropyl, and R1-R2-alkoxygroup, for example, methoxy; X-atramentaria, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-R2-alkoxygroup, for example, methoxy; X is sulfur, and R1halogen, for example fluorine and R2-hydrogen

The invention relates to a new derivative of imidazolidine, namely TRANS-4,5-guidemegreen-2-ONU formula (I) exhibiting fungicidal activity, and which may find application in agriculture
The invention relates to medicine, in particular to Allergology, to methods for treating allergies
The invention relates to medicine, in particular to Oncology, and concerns the application of the antidepressant amitriptyline as a means of having antiallergic action, for the correction of allergic status in patients with lung cancer

The invention relates to medicine and relates to methods for obtaining protein hydrolysate suppressive regulation of allergic reactions, methods of prevention or treatment of allergies

The invention relates to new ascomycin General formula I, where Y represents a phenylene; Z is selected from carboxyl and physiologically hydrolyzable of oxycarbonyl or alkyl, CNS, alkylamino or dialkylamino bearing from 1 to 4 carboxyl or physiologically hydrolyzable oxycarbonyl group; Q is O or S; R1Is H, alkyl or aryl; R2is hydrogen or hydroxyl; R3is methyl, ethyl, propyl or allyl; R4is hydroxyl or alkoxyl; R5-oxoprop or (H, OH), R6- oxoprop, H, HE H, alkoxyl); n is an integer 1 or 2, in free form or in the form of a pharmaceutically acceptable salt

The invention relates to previously unknown compounds, useful in medical and veterinary practice, to their pharmaceutically acceptable salts and biopremier derivatives, to methods for obtaining data of new compounds, to pharmaceutical compositions containing these new compounds, to a single dosage forms of these compositions and to methods of treating patients using these compositions and dosage forms

The invention relates to medicine, specifically to medicines, exhibiting anti-allergic, anti-asthma and anti-inflammatory effect

The invention relates to the field of medicine and is suitable for the treatment of seasonal and perennial allergic rhinitis, conjunctivitis, hay fever, urticaria, including chronic idiopathic urticaria, angioedema, psevdoallergicakie reactions caused by the release of histamine, itching dermatoses, allergic reactions to insect bites and itching of various etiology

The invention relates to solutions for surgical irrigation and methods of use thereof, in particular to anti-inflammatory, analgesic and anticonvulsant solutions

The invention relates to medicine and to the use of at least one peptide containing the C-end of the Tripeptide Lysine-Proline-Valine, in which a Proline residue is in the form of programalso optical isomer for the local treatment of inflammation
The invention relates to pharmaceutical industry and veterinary

The invention relates to cosmetology

The invention relates to the processing of larch wood with getting bioflavonoids, specifically dihydroquercetin (DQC), which finds application in medicine, food industry

The invention relates to new phenanthridine derivative of the General formula I and II and their salts, where R1represents an aromatic carbocyclic residue, which is derived from benzene or naphthalene, or represents a heterocyclic residue, which is derived from furan, thiophene or pyridine, and R1may have one or more substituents, and these substituents selected from monoamino, alkylamino, dialkylamino-, alkyl-, alkoxy-, alkylene and galactography, a R2and R3that may be the same or raznie, represent a hydrogen atom, CNS residue, accelerometry residue, a halogen atom or a nitro-group
Up!