Derivatives of amidine, the retrieval method and the drug based on them, have the property to inhibit the activity of the synthetase of nitric oxide (y)

 

(57) Abstract:

The proposed derivatives of amidine General formula I

,

in which D is phenyl or 5-membered heterocyclic aromatic ring containing 1 to 2 heteroatoms selected from O, S and N, one group of which is optionally substituted by a group selected from C1-C6-alkyl, halogen, or C1-C6-perfluoroalkyl;

R1represents hydrogen, halogen;

R2represents a group - X - (CH2)nZCONR3R4, -X - (CH2)nNHCO(CH2)sNR3R4;

-X - (CH2)pNR3R4, -X - (CH2)nNHCOR5or -(CH2)qNHC(NH)R6;

R3and R4represent hydrogen, C1-C4-alkyl, -(CH2)r-A, -(CH2)m-OA or CH(CH3)/CH2)t-A; or NR3R4together represent piperidylamine, piperidinyl, morpholinyl and others;

R5represents a C1-C6-alkyl, C1-C6-perfluoroalkyl, -(CH2)r-A or-O(CH2)w-A;

A represents A phenyl, pyridinyl, pyrimidinyl or 5-membered heterocyclic aromatic ring containing: (I heteroatom selected from O, S and N;

n and r = 0-4; p; w = 1-4;

m = 2-4; q and t = 0-4; S = 1-3;

X is O or a bond;

Z represents O, NR7or communication;

R7represents hydrogen or C1-C6-alkyl,

or its pharmaceutically acceptable salt. The method of obtaining the compounds of formula I or its pharmaceutically acceptable salt by interaction of the compounds of formula II

,

where L is a detachable group, and D are defined above,

with the compound of the formula III

,

where R1and R2defined above.

The drug has the property to inhibit the activity of the synthetase of nitric oxide (Y). 3 S. and 9 C.p. f-crystals.

This invention relates to derivatives of amidine, methods for their preparation, containing compositions and to their use in therapy.

As a neuroprotective means have been described certain nitrogen-containing compounds. In the international application WO 91/12797 (State Oregon) as a neuroprotective funds presents three-Tetra-substituted guanidine. In U.S. patent N 5266594 (Dawson et al.) (published after the earliest priority date of this application) describes the use of derivatives of arginine in the treatment of stroke and other neurodegenerative diseases. In addition to icenii immunological and other disorders.

Applying synthetase inhibitors of nitric oxide (V) in the treatment of diseases is also described, for example, in international patent applications WO 94/12163 (Abbott) and WO 94/12165 (Welcome) (both published after the earliest priority date of this application) and the application for the European patent 4446699 (Merell Dau).

Derivatives of amidine when used as herbicides are described in the application at the German patent DE-OS-2321330 (Leverkusen).

In U.S. patent N 3669974 (Pharmacetical Bldg. USV) and the application for patent in the UK 2226562 (football Boots) described as derivatives of N-phenylaniline used in the treatment of diabetes. In the application for international patent WO 92/04054 (University Origoni) described N',N ' -disubstituted amidine used to treat hypertension, depressive syndromes and hallucinogenic States. In UK patent N 1180629 (Delalande) described the use of certain symmetric bis-amidino as analgesic tools in the treatment of inflammation and hypertension.

In a number of patent documents describes how to get amidino or use amidino as intermediate products without disclosing the pharmaceutical use of these compounds. Simple derivatives of amidine as intermediate products Postfach N-aryl and N-heteroaryl amidino described in U.S. patent 3299081 (Merck), and fluorine-containing derivatives of amidine as chemical intermediates described in the patent application of Japan N 58057357 (Daikin).

We found a new group of derivatives of amidine, which have a suitable pharmaceutical activity.

In accordance with the first aspect of the invention we have provided a compound of formula I:

< / BR>
in which D represents phenyl, pyridinyl or 5-membered heterocyclic aromatic ring containing 1 to 4 heteroatoms selected from O, S and N, three groups of which are optionally substituted by one or more groups selected from C1-C6-alkyl, C1-C6-alkoxy, halogen and C1-C6-perfluoroalkyl; or C1-C6-perfluoroalkyl;

R1represents hydrogen, C1-C6-alkyl or halogen;

R2represents-X - (CH2)nZCONR3R4, -X - (CH2)nNHCO(CH2)3NR3R4, -X - (CH2)pNR3R4, -X - (CH2)nNHCOR5or -(CH2)qNHC(NH)R6;

R3and R4independently represent hydrogen, C1-C6-alkyl, (CH2)rA, -(CH2)mOA or CH(CH3)(CH2)tA; or NR3R4 is indolinyl; or piperazinil, optional 4-substituted C1-C6-alkyl;

R6represents C1-C6-alkyl, C1-C6-perfluoroalkyl, -(CH2)rA or-O(CH2)wA; A is phenyl, pyridinyl, pyrimidinyl or 5-membered heterocyclic aromatic ring containing 1 to 4 heteroatoms selected from O, S and N, four groups of which are optionally substituted by one or more groups selected from C1-C6-alkyl, halogen, nitro, cyano and trifloromethyl;

R6represents phenyl, pyridinyl or 5-membered heterocyclic aromatic ring containing 1 to 4 heteroatoms selected from O, S and N, three groups of which are optionally substituted by one or more groups selected from C1-C6-alkyl, C1-C6-alkoxy, halogen and C1-C6-perfluoroalkyl; or C1-C6-perfluoroalkyl,

n and r independently represent an integer from 0 to 6 inclusive;

p and w independently represent an integer in the range from 1 to 5 inclusive;

m represents an integer in the range from 2 to 5 inclusive;

g and t independently represent an integer in the range from 0 to 5 inclusive;

S submitted the BR>
R7represents hydrogen or C1-C6-alkyl; provided that:

(a) when D contains a heteroatom, it is not associated with the remainder of the compounds of formula I via a heteroatom;

(b) when R2represents-X - (CH2)nZCONR3R4and neither X nor Z does not represent a bond, then n is an integer in the range from 2 to 6, inclusive;

(c) when R2represents-X - (CH2)nNHCO(CH2)sR3R4or X(CH2)nNHCOR5and X is O, then n represents an integer in the range from 2 to 6, inclusive;

(d) when R2represents-X - (CH2)pNR3R4and X is O, then p represents an integer in the range from 2 to 5 inclusive;

(e) when R2represents -(CH2)gNHC(NH)R6, R1is hydrogen and D and R6have the same definition and represent phenyl, optionally substituted C1-C4-alkyl, or one or more groups C1-C3-alkoxy or one or more halogen atoms; or pyridinyl, then q is not equal to 0;

or its pharmaceutically acceptable salt.

Preferably, D is represented by a phenyl, pyridinyl or 5-membered GE the CSOs optionally substituted by one or more groups, selected from C1-C6-alkyl, C1-C6-alkoxy, halogen or C1-C6-perfluoroalkyl.

More preferably, D is represented by phenyl, thiophene, furan, pyrrole or thiazole, five groups of which are optionally substituted by one or more groups selected from C1-C6-alkyl, C1-C6-alkoxy, halogen or C1-C6-perfluoroalkyl.

Even more preferably, D is represented thiophene, pyrrole, furan or thiazole, four groups of which are optionally substituted C1-C6-alkyl or halogen.

Mainly it is preferable that D was the thiophene, furan or pyrrole, most preferably thiophene, D was 2-thiophene, R1was hydrogen.

When R2represents-X - (CH2)nZCONR3R4, -X - (CH2)nNHCO(CH2)sNR3R4or-X - (CH2)pNR3R4we prefer-NR3R4represented piperidinyl, morpholinyl, pyrrolidinyl, 1,2,3,4-tetrahydroisoquinoline or 1 indanyl, or to at least one of R3and R4represented (CH2)rA or -(CH2)mOA. We especially UP>3
and R4was represented by -(CH2)rA and the other was represented by hydrogen or methyl. We mainly preferred that one of R3and R4was represented by -(CH2)rA and the other was represented by hydrogen or methyl.

When R2represents-X - (CH2)nNHCOR5we prefer to R5was represented by -(CH2)rA.

When R2represents-X - (CH2)nZCONR3R4, -X - (CH2)nNHCO(CH2)sNR3R4,

-X - (CH2)pNR3R4or-X - (CH2)nNHCOR5we prefer to X was represented by the link.

When R2represents-X - (CH2)nZCONR3R4and Z represents NR7we prefer to R7was hydrogen.

When R2represents-X - (CH2)nZCONR3R4we prefer to Z was represented by the link.

When R2represents -(CH2)gNHC(NH)R6we prefer to R6represented phenyl or 5-membered heterocyclic aromatic ring containing 1 to 4 heteroatoms selected from O, S and N, two groups of which are optionally substituted by one or more groups, SEL is jet -(CH2)gNHC(NH)R6we especially preferred that R6represented phenyl or thiophene, two groups of which are optionally substituted by one or more groups selected from C1-C6of alkyl and halogen.

When R2represents -(CH2)qNHC(NH)R6we prefer that q was 0, 1 or 2.

We particularly prefer that q was 0 or 2, mainly 0.

When R2represents -(CH2)gNHC(NH)R6, g is O and R6represents phenyl, optionally substituted with halogen, C1-C6-alkyl or C1-C6-alkoxy, or R6is pyridinyl, then we prefer that D did not have the same definition as6.

When R2represents -(CH2)qNHC (NH)R6and g is 0, then we usually prefer to R6did not have the same definition as D.

When R2represents-X - (CH2)pNR3R4we prefer that p was an integer in the range from 1 to 4 inclusive, in particular 1, 2 or 3, mostly 1 or 2.

When R2represents-X - (CH2)nZCOHR3Rthe m to n was 1, 2 or 3, mostly 2 or 3.

When R3, R4or R5represent -(CH2)rA, we prefer that r was represented by an integer in the range from 0 to 4 inclusive, in particular 0, 1 or 2, more preferably 1 or 2, mostly 1.

When R3or R4represent -(CH2)mOA, we prefer that m was 2, 3 or 4.

When R5represents-O(CH2)wA, we prefer that w was represented by 2, 3 or 4.

When R3or R4is-CHMe(CH2)tA, we prefer to t was represented by 0, 1 or 2, mostly 0 or 1.

We prefer A represented phenyl, pyridinyl, pyrimidinyl, thiophenyl or furanyl, five groups of which are optionally substituted by one or more groups selected from C1-C6of alkyl and halogen. We particularly prefer that A represented phenyl, optionally substituted by one or more groups selected from C1-C6of alkyl and halogen.

When in D or R6submit C1-C6-perfluoroalkyl, we prefer to represent pentaborate or trifluoromethyl,>
R4or -(CH2)gNHC(NH)R6.

We prefer to R2was oriented in the meta - or paraprotein relative to the nitrogen atom amedieval component.

In accordance with the invention we also provide a method of obtaining compounds of formula I and its pharmaceutically acceptable salts, which includes:

(a) obtaining the compounds of formula I by reacting the corresponding compounds of formula II:

< / BR>
in which D is as defined above, and L is tsepliaeva group, with a compound of the formula (III),

in which R1and R2are as defined above;

(b) obtaining the compounds of formula I by reacting the corresponding compounds of formula IV

< / BR>
in which D is as defined above, with a compound of formula V

< / BR>
in which R1and R2are as defined above and HA is an acid;

(c) obtaining the compounds of formula I in which R2represents-X - (CH2)nZCONR3R4, -X - (CH2)nNHCO(CH2)sNR3R4or-X - (CH2)pNR3R4and at least one of R3and R4presented shimodate the corresponding compounds of formula I, in which one or both of R3and R4represent hydrogen, with a compound of formula VI

R8- L

in which R8represents C1-C6-alkyl, -(CH2)rA, -(CH2)mOA or-CH(CH3)-(CH2)tA, and L is tsepliaeva group;

(d) obtaining the compounds of formula I in which R2represents -(CH2)gNHC(NH)R6by interaction of the corresponding compounds of formula VII

< / BR>
in which D, R1and O are as defined above,

with the compound of the formula VIII

< / BR>
in which R6is the same as defined above, and L is tsepliaeva group;

(e) obtaining the compounds of formula I in which R2represents -(CH2)gNHC(NH)R6by interaction of the corresponding compounds of formula IX

< / BR>
in which D, R1q and HA are as defined above, with a compound of formula X

< / BR>
in which R6is as defined above;

(f) obtaining the compounds of formula I in which R2represents-X - (CH2)nZCONR3R4by interaction of the corresponding compounds of formula XI

< / BR>
in which D, R1, X, n, Z and L t R3and R4are as defined above;

(q) obtaining the compounds of formula I in which R2represents-X - (CH2)nNHCO(CH2)sNR3R4by interaction of the compounds of formula XIII

< / BR>
in which D, R1, X and n are as defined above, with a compound of formula XIV

R3R4N(CH2)sCOL,

in which R3, R4and S are as defined above, and L is tsepliaeva group;

(h) obtaining the compounds of formula I in which R2represents-X - (CH2)nNHCOR5by interaction of the compounds of formula XIII with a compound of formula XV

R5COL,

in which R5is the same as defined above, and L is tsepliaeva group;

(i) obtaining the compounds of formula I in which R2represents-X - (CH2)nZCONR3R4and Z represents NR7by interaction of the corresponding compounds of formula I in which R2represents-X - (CH2)nZCONR3R4and Z represents-NH, with a compound of formula XVI

R7- L

in which R7is the same as defined above, and L is tsepliaeva group;

(j is its than 2, by restoring the compounds of formula XVII

< / BR>
in which D, X, R1, R3, R4and p are as defined above;

(k) obtaining the compounds of formula I in which R2represents-X - (CH2)pNR3R4and both R3and R4represent hydrogen, by restoring the compounds of formula XVIII

< / BR>
in which R1, D, p and X are as defined above;

(l) obtaining the compounds of formula I in which R2represents-X - (CH2)sZCONR3R4Z is O or NR7and R3represents hydrogen, by reacting the compounds of formula XIX

< / BR>
in which R1, D, X and n are as defined above, and Z represents O or NR7with the compound of the formula XX

R4- N = C = O,

in which R4is as defined above;

(m) obtaining the compounds of formula I in which R2represents-X - (CH2)nNHCOR5and R5represents-O(CH2)wA, by reacting the compounds of formula XXI

< / BR>
in which R1, D, X and n are as defined above,

with the compound of the formula XXII

A(CH2)wOH,

in which A and w-X(CH2)nZCONR3R4and Z is O or NR7by interaction of the compounds of formula XIX with a compound of formula XXIII

< / BR>
in which R3and R4are as defined above;

(o) obtaining the compounds of formula I in which R2represents-X - (CH2)pNR3R4, R3represents hydrogen and p represents an integer from 2 to 5, by restoring the compounds of formula XXIV

< / BR>
in which R1, R4, D, X and p are as defined above;

(p) obtaining the compounds of formula I in which R2represents-X - (CH2)pNR3R4one of R3and R4represents hydrogen and the other represents -(CH2)rA, where r is an integer from 2 to 6, by restoring the compounds of formula XXV

< / BR>
in which R1A , D, r and p are as defined above;

(q) obtaining the compounds of formula I in which R2represents-X - (CH2)pNR3R4one of R3and R4represents hydrogen and the other represents -(CH2)mOA, by restoring the compounds of formula XXVI

< / BR>
in which R1A , D, p and m are as defined>one of R3and R4represents hydrogen and the other represents -(CH2)rA, where r is an integer from 2 to 6, by restoring the compounds of formula XXVII

< / BR>
in which R1A , D, p and r are as defined above;

(s) obtaining the compounds of formula I in which R2represents-X - (CH2)pNR3R4one of R3and R4represents hydrogen and the other represents -(CH2)mOA, by restoring the compounds of formula XXVIII

< / BR>
in which R1A , D, p and m are as defined above, and when it is desirable or necessary conversion of the compounds of formula I or its salts in its pharmaceutically acceptable salt or Vice versa.

In method (a) the reaction takes place under stirring mixture of reagent in an appropriate solvent, for example a lower alcohol, for example ethanol, isopropanol or tertiary butanol, at a temperature between room temperature and the temperature phlegmy solvent. The time of reaction will depend, among other things, and from nature tsepliaeva group and may take up to 48 hours, however, it is usually from 1 hour to 5 hours. Suitable otsepleniya group that is strong and aryl alcohols and tselnye group; others are listed in "Advanced Organic Chemistry", J. Merch (1985) 3rdEdition, McGrow-Hill on page 315, and are well known in this field.

In method (b) the reaction is preferably carried out by heating under reflux a mixture of two compounds in a few hours in the presence of an appropriate solvent, whereupon the reaction temperature is high enough to quickly occurred condensation, but not high enough for the decomposition of an educated amidine. The reaction temperature may vary from room temperature to about 250oC, although it is preferable to carry out the reaction at temperatures from about 100oC to 200oC. We have found that o-dichlorobenzene is particularly suitable solvent and that it is useful to add 4-dimethylaminopyridine as a catalyst. Upon cooling formed 2 layers, the solvent can be dementiava, and the reaction can be completed by adding water base. Alternatively, when the reagents are soluble in the solvent, the solvent can be evaporated under vacuum, and the reaction mixture gives a finished look by adding water.

Acid HA can be organic or personnel, lactic, succinic, fumaric, malic, maleic, tartaric, citric, benzoic or methansulfonate.

In method (c) the reaction is carried out under standard conditions, for example in the interaction of two materials in an inert solvent in the primary environment at room temperature in a period of time up to 12 hours. We repeatedly found that before the interaction with the compound of the formula II amine is desirable to process NaH. We prefer that L was represented by halogen, in particular bromine.

Method (d) can be performed under conditions similar to those described above for the method (a).

Method (e) can be performed under conditions similar to those described above for the method (b).

Methods (f), (q) and (h) can be performed under standard conditions, well known in this area for condensation of amine and carboxylic acid or activated carboxylic acid for the formation of the amide. The reaction of the compound for the formation of amide can be carried out, for example, when mixing of reagents within 12-24 hours at a temperature between 0oC and 25oC in water or in a mixture of water and a less polar solvent, for example dioxane, tetrahydrofuran or ethanol. We pre is whether sodium bicarbonate.

Method (i) can be performed under standard conditions similar to those described above for the method (c).

In method (j) recovery can be accomplished by treatment with DIBORANE in an inert solvent, for example THF.

Alternatively, although less preferred reagents that may be suitable include alumoweld lithium and reagents for catalytic hydrogenation, such as H2on Pd/C. for More information regarding the reaction conditions for these reactions can be obtained by accessing the reference J. March "Advanced Organic Chemistry", page 1099, including the references cited in this source.

In method (k) response recovery can be performed under various conditions such as those described in J. March "Advanced Organic Chemistry", pages 1103 - 1104. These conditions include catalytic hydrogenation, the use of Zn, Sn or Fe, AlH3-AlCl3, sulphides and other substances. We prefer to carry out the reaction by hydrogenation at atmospheric pressure for a period of 3-6 hours in the presence of palladium carbon catalyst.

In method (l) and (m) the reaction can be performed by stirring the reactants in the presence of an inert solvent, if P CLASS="ptx2">

Way (n) can be performed under conditions similar to those described above for the methods (f), (q) and (h).

In how (o), (p) and (q) the recovery can be accomplished by treating the compound with sodium borohydride under standard conditions.

In the methods (r) and (s) the reaction can be performed under conditions similar to those described above for the method (j).

Salts of compounds of formula I can be formed by reacting the free acid, base or salt, enantiomer, tautomer or protected derivative with one or more equivalents of the appropriate base or acid. The reaction can be performed in a solvent or medium in which the salt is insoluble, such as water, dioxane, ethanol, tetrahydrofuran or diethyl ether, or a mixture of solvents that can be removed under vacuum or freeze-drying. The reaction may represent a metabolic process or it can be performed on ion-exchange resin.

For specialists in this area it is obvious that it may be desirable to protect the hydroxyl group, amino group or other reactive group with a protective group, which is described in the manual "P is given C2-C7-allyloxycarbonyl, for example tert-butyloxycarbonyl, C8-C13-phenylalkylamines, such as benzyloxycarbonyl, or preferably triptorelin. The protective group is usually removed by treatment with an aqueous solution of the base.

The compounds of formula II are either known or can be obtained by known methods. For example, the compounds of formula II in which L represents thioalkyl, can be obtained by processing the corresponding teamed formula XXIX

< / BR>
in which D is as defined above,

with alkylation.

The compounds of formula (III) can be obtained by recovering the corresponding compounds of formula XXX

< / BR>
in which R1and R2are as defined above.

The reduction can be performed under conditions similar to those described above for the method (k).

Certain compounds of formula XXX are either known or can be obtained by conventional means, essentially known. Other compounds of formula XXX can be obtained from known compounds from simpler side chains by methods similar to those described for sposob obtain the compounds of formula III. The compounds of formula V can be converted into the corresponding compounds of formula III by treatment with base. The compounds of formula III can be converted into the corresponding compounds of formula V by treatment with the proton acid HA, for example one of the above.

The compounds of formula VII, IX, XI, XIII; XVII, XXVIII, XIX, XXI, XXIV, XXV, XXVI, XXVII and XXVIII can be obtained by methods similar to those described for preparing compounds of formula I.

The compounds of formula VIII are either known or can be obtained in a manner analogous to that described above to obtain compounds of formula II.

The compounds of formula IV, VI, X, XII, XVI, XX, XXII, XXIII and XXIX are known or can be obtained by conventional means, essentially known.

The compounds of formula XIV or XV are either known or can be easily obtained from the corresponding carboxylic acids, or which is known or can be obtained by conventional means, essentially, is known.

When necessary, hydroxyl group, amino group or other reactive group in the intermediate compounds can be protected with protective groups, which are described in rukovodi compounds may be isolated from their reaction mixtures by standard techniques.

The term "C1-C6-alkyl" includes straight chain, branched, saturated, unsaturated, aliphatic and cyclic alkyl groups containing from 1 to 6 carbon atoms.

The compounds of formula I may exist in tautomeric, enantiomeric or diastereoisomeric forms, all of which are included in the scope of the invention. By separation of the racemic mixture of the compounds using conventional techniques such as fractional crystallization or HPLC (high performance liquid chromatography) can be allocated to different optical isomers. Alternative individual enantiomers may be obtained by reacting the corresponding optically active starting materials under the reaction conditions which do not cause racemization.

Intermediate chemical compounds can exist in enantiomeric forms and can be used as purified enantiomers, diastereomers, racemates or mixtures.

Compounds of General formula I possess suitable pharmacological activity towards animals. In particular, they are suitable inhibitory activity against synthetase of nitric oxide (V) and it is expected that they b which is the synthesis or excessive synthesis of nitric oxide (V), for example, hypoxia, for example in cases of cardiac arrest and strokes, neurodegenerative disorders, including degeneration and/or death of nerve cells in such disorders as hypoxia, hypoglycemia, epilepsy, and in external wounds (such as spinal cord and head injuries, seizures associated with hyperbaria and toxicity, dementia, such as premature dementia, Alzheimer's disease and syndromes of acquired immune deficiency (AIDS), a relative with dementia, horei of Sydenham, Huntington's disease, amyotrophic lateral sclerosis, polyneuritis psychosis, mental disabilities associated with cerebral vascular disorders, carotid disease, schizophrenia, depression, emotional disorders associated with changes in the weather, depression or other symptoms associated with premenstrual syndrome (PMS), anxiety and septic shock. It can be expected that the compounds of formula I are active also in the prevention and cancellation of resistance to drugs and benzodiazepines in the treatment of addiction to the excessive use of drugs, the pain and the treatment of migraine and other vascular diseases of the brain. Compounds of this image is ractice inflammation, in the treatment of gastrointestinal disorders and induction of labor.

It is expected that compounds of the formula I is particularly suitable for the treatment of neurodegenerative disorders, migraines, or to prevent and cancellation of resistance to drugs and benzodiazepines or for the treatment of addiction to the excessive use of medicines and, mainly, in the treatment of neurodegenerative disorders.

Thus, in accordance with another aspect of the invention we have provided a compound of formula I or its pharmaceutically acceptable salt for use as a pharmaceutical product.

In accordance with another feature of the invention we provide the use of compounds of formula I, with no conditions (e), or its pharmaceutically acceptable salts in the manufacture of a medicinal product for the treatment of the aforementioned diseases or conditions.

For the above-mentioned therapeutic indications injected dose will, of course, vary depending on the compound, the route of administration of the medicinal product and on the desired treatment. However, when the compound is administered to humans at a daily dose of between 1 mg and 2000 mg (in terms of teski acceptable salts can be used alone or in the form of appropriate medications for intestinal or parenteral administration.

In accordance with the invention provided with the technology of preparation of a medicinal product, preferably containing less than 80%, more preferably less than 50% of the compounds of formula I or its pharmaceutically acceptable salt, in a mixture with a pharmaceutically acceptable diluent or carrier.

Provided also is a method of treatment of the aforementioned diseases or conditions, which includes the introduction of therapeutically effective amounts of compounds of formula I, with no conditions (e), or its pharmaceutically acceptable salt, a person suffering from such disease or condition.

Examples of such diluents and carriers are for tablets and coated tablets: lactose, starch, stearic acid; for capsules: tartaric acid or lactose; for injectable solutions, include water, alcohols, glycerol, vegetable oils; for suppositories: natural or hardened oils or waxes.

Composition in a form suitable for oral administration, i.e., the introduction into the esophagus include: tablets, capsules and pills; compositions for long-term pain relief include those in which the active ingredient is associated with ion exchange resins, which do not necessarily cover the diffusion barrier dlya formula I or their pharmaceutically acceptable salts can be tested for inhibitory activity against synthetase of nitric oxide (V) methods, based on those presented in Bredt and Snyder in Proc. Natl. Acad. Sci. (1990), 87, 682-685 and Forstermann et al. (1992 ) Für J. Pharm., 225, 161 to 165, as follows. Synthase-nitric oxide (V) turns 3H-L-arginine in3H-L-citruline, which can be separated by cation exchange chromatography and quantified by scintillation counter liquid.

Check A.

(A) Check for inhibitory activity against neural synthetase of nitric oxide (V).

The hippocampus or cerebellum in rats have identified the enzyme. The cerebellum or hippocampus of the rat male Sprague-Dawley (250-275 g) were removed by anesthesia of the animal CO2and decapitation. By homogenization in 50 mm Tris-HCl and decapitation. By homogenization in 50 mm Tris-HCl with 1 mm EDTA buffer ethylenediaminetetraacetic acid (pH of 7.2 at 25oC) and centrifugation for 15 minutes at 20000 q prepared supernatant of the cerebellum or hippocampus.

By sequential chromatography through a column of Dowex AG-50W-X8 in the sodium form and hydrogen form and centrifugation at 10000 q within 30 to removed residual L-arginine from the supernatant.

For analysis, 25 μl of the obtained supernatant dobaH-L-arginine) or 25 ál of the test buffer (50 mm HEPES, 1 mm EDTA, 1.5 mm CaCl2, a pH of 7.4) or 25 μl of the test compound in the buffer at 22oC. To each tube was added 75 μl final analyzed buffer (50 mm HEPES, 1 mm EDTA, 1.5 mm CaCl2, 1 mm DTT, 100 μm NaDPH, 10 μg/ml calmodulin, pH 7,4) for the beginning of the reaction and after 10 minutes the reaction was stopped by adding 2 ml of buffer solution to complete the reaction (20 mm HEPES, 2 mm EDTA, pH 5.5).

Labeled L-citruline separated from labeled L-arginine by chromatography through a column of Dowex AG-50W-X8 200-400. In a separate 1 ml column was added 1 ml of buffer solution, which is used to complete the reaction, and the eluent was combined with the eluent from two washes with 1 ml of distilled water and 16 ml of scintillation mixture. Then using a scintillation counter quantitatively determined L-citruline.

In a typical experiment, which used the supernatant of the cerebellum, the main activity has increased by 20,000 disintegrations per minute/ml of the sample relative to the reagent blank, which has activity 7000 disintegrations per minute/ml For test methods in the analysis were subjected to the test of comparative reference, N-nitro-L-Arinin, which gives a 60% inhibition of oxide synthetase AZ is makropoulou synthetase of nitric oxide (V).

From cultivated hydrochloric makropoulou cell line, J1774A-1 (obtained from the laboratories of the Imperial Cancer research Fund) after the induction of prepared enzyme. Cells J774A-1 was cultured in Dulbecco''s Modified Eagles Medium (DMEM), supplemented with 10% fetal bovine serum, 4 mm L-glutamine and antibiotics (100 units/ml penicillin G, 100 μg/ml streptomycin and 0.25 μg/ml amphotericin B). Cells were grown in the prescribed mode 225 cm3flasks containing 35 ml medium supported at 37oC and in a humidified atmosphere containing 5% CO2. The synthetase of nitric oxide (V) was produced by cells in response to interferon -(IFN-) and lipopolysaccharide (LPS).

From the flasks with culture was removed Wednesday and replaced it with 25 ml (flask) with fresh medium containing 1 μg/ml LPS and 10 units/ml of IFN-. Through 17-20 hours collected cells grown in culture by scraping the layer of cells from the surface of the flask in culture medium. Cells were collected by centrifugation (1000 g for 10 minutes) and by adding to the precipitate cells after centrifugation of the solution containing 50 mm Tris-HCl (pH 7.5 at 20oC). 10% (about. /about. ) glycerol, 0,1% vol. /about. Triton-X-100, 0.1 ám of dithiothreitol and a mixture of protease inhibitors containing lapatin (2 μg/ml), the inhibitor from rojalnoj plate with 96-th cells (pore size 0.45 µm), containing 25 μl solution of the test compound in 50 mm Tris-HCl, was added 25 μl of nutrient mixture (50 mm Tris-HCl, pH 7.5 at 20oC), 400 μm NaDPH, 20 μm flavinadeninnukleotid, 20 μm playmonopolyonline, 4 μm tetrahydrobiopterin, 12 μm L-arginine and 0.025 μm Cl L-[3H] arginine). The reaction was started by adding 50 μl of cell lysate (obtained as mentioned above) and after incubation for 1 hour at room temperature the reaction was completed by adding 50 μl of an aqueous solution, 3 mm nitroarginine and 21 mm EDTA.

Labeled L-citruline separated from labeled L-arginine using Dowex AG-50W. To analyze added 150 μl of a 25% aqueous suspension of Dowex 50W (Na+form), then the received filtered on plates containing 96 wells. Took 70 μl of the filtrate and added to the cell plates having 96 wells, which contained solid scintillant. After drying, samples L-citruline quantified by scintillation counter.

In a typical experiment, the main activity was 300 disintegrations per minute/70 ál of the sample, which increased to 1900 disintegrations per minute in the control reagent groups. To validate the technique as a standard had Aminogen the pKa C.

(C) Checking for inhibitory activity against endothelial synthetase of nitric oxide (V).

The enzyme can be isolated from umbilical vein endothelial cells (HUVECs) by a method based on that presented in Pollock et al., (1991) Proc., Nat. Acad. Sci., 88, 10480-10484, HUVEC were purchased from Clonetics Bldg. (San Diego, CA, USA) and were cultured until confluence. Cells can be preserved without significant loss of output synthetase of nitric oxide (V). When cells reached confluence, they re-suspended in phosphate buffer salt Dulbecco, centrifuged at 800 rpm for 10 minutes to precipitate the cells after centrifugation of the solution homogenized in 50 mm Tris-HCl, chilled with ice, 1 mm EDTA, 10% glycerol, 1 mm phenylmethylsulfonyl, 2 μm latina at a pH of 4.2. After centrifugation at 34000 rpm for 60 minutes, the precipitate was solubilizers in buffer containing 20 mm CHAPS. After 30 minutes incubation on ice, the suspension was centrifuged at 34000 rpm for 30 minutes.

The obtained supernatant was stored until use at -80oC.

For analysis in each of the 12 test tubes containing 25 μl of a solution of L-arginine (concentration of 12 μm1H-L is the CL of the test compound in the buffer solution at 22oC, was added 25 μl final analyzed buffer (50 mm HEPES 1 mm EDTA, 1.5 mm CaCl2, 1 mm DTT, 100 μm NaDPH, 10 μg/ml calmodulin, 12 mm tetrahydrobiopterin, pH 7,4), to cause the reaction, which after 10 minutes he finished by adding 2 ml of buffer for completion of the reaction (20 mm HEPES, 2 mm EDTA, pH 5.5).

Labeled L-citruline separated from labeled L-arginine by chromatography through a column of Dowex AG-50 X8 200-400. In a separate 1 ml column was added 1 ml of each reagent, the final reaction, and the eluent was combined with the eluent from two washes with 1 ml of distilled water and 16 ml of scintillation mixture. Then using a scintillation counter quantitatively determined L-citruline.

In a typical experiment the main activity increased by 5000 disintegrations per minute/ml of the sample relative to the reagent blank, which has an activity of 1500 disintegrations per minute/ml For test methods in the analysis were subjected to the test of comparative reference, N-nitro-L-arginine, which gives 70% to 90% synthetase inhibition of nitric oxide (V) at a concentration of 1 μm.

To determine the degree of penetration of the brain connections can be tested in the analysis of ex-vivo.

Check D.

(D) Analysis of ex-vivo in ing is - 275 g) were dosed out intravenous 10 mg/kg of the test compound, dissolved in 0.9% saline solution, or as a control only salt. In a predetermined time (usually 2-24 hours) after handling animals marshville, removed the cerebellum, prepared supernatant and analyzed for activity against synthetase of nitric oxide (V), as described in test A.

As an additional confirmatory test in 2'-5'-ADP Sephorose column (which connects synthase-nitric oxide (V)) has filed a fraction of the supernatant liquid of the cerebellum and then he suirable NADPH. Eluent was tested for activity against synthetase of nitric oxide (V), following the methodology of verification A.

Compounds that penetrate the rat brain and inhibit neural synthase-nitric oxide (V), lead to decreased activity of the synthetase of nitric oxide (V) as in the supernatant and in eluent of the 2'-5'-ADP Sephorose column.

In tests on inhibitory activity against synthetase of nitric oxide (V) the activity of the compounds was expressed as IC50(the concentration of the medicinal substance, which gives in the analysis of the inhibition of the enzyme by 50%). The values of the IC50for the tested compounds were initially evaluated on the basis of the inhibitory activity of 1,10 and 100 μm solutions using a more appropriate concentration with the in order to determine the IC50.

In test A above (tested for activity against neural synthetase isoforms of nitric oxide (V)) of the compound of example 1, below, gives the IC50less than 10 μm, which indicates that it is assumed suitable therapeutic activity.

In tests B and C (tested for activity against makropoulou and endothelial synthetase isoforms of nitric oxide (V)), the compound of example 1 gives the values of the IC50more than 10 times higher than those that were obtained in test A, which indicates that it shows the desired selectivity.

Compounds of examples 2-20, 21(a) - (n), 22(a) - (e), 23(a) - (f), 24-26, 27(a), (b), 28-47 and 49-71 experienced in test A, and they also gave value IC50less than 10 microns. The compound of example 48 was tested in test A and received the value of the IC50less than 100 microns. The compound of example 72 was tested in test A and got the inhibition by 17% at a concentration of 10 μm. Thus, it is assumed that these compounds have suitable therapeutic activity.

The compounds of formula I and their pharmaceutically acceptable salts have the advantage that they are less toxic, sick range of activities, are more potent, give fewer side effects, are more easily absorbed or have other suitable pharmacological properties than previously known compounds used in the above mentioned areas of therapy.

The compounds of formula I and their pharmaceutically acceptable salts can also take advantage of the fact that they are more selective for the neuronal isoform of the enzyme synthetase of nitric oxide (V) and, therefore, it is expected that they have a suitable therapeutic activity profile reduced side effects associated with inhibition of other isoforms.

The invention is illustrated by the following examples.

Example 1

N-(4-(2-((phenylmethyl)amino)ethyl)phenyl-2-thiophenecarboxylate.

(a) N-(2-(4-(4-nitrophenyl)ethyl)triptorelin.

To a stirred solution of 4-nitrophenylhydrazine (1.84 g, 9,10 mmol) and triethylamine (3,03 ml, 21,70 mmol) in methanol (12 ml) was added dropwise triperoxonane anhydride (1,51 ml, 20,66 mmol). After stirring for 1 minute under reduced pressure, the solvent was removed, and the remaining residue was mixed with water and was extracted with methylene chloride (solid substance, which recrystallize from methylene chloride/hexane to obtain N-(2-(4-nitrophenyl)ethyl)trifurcated in the form of a white solid: 1.92 g (yield 80%); melting point 103-104oC.

(b) N-(2-(4-nitrophenyl)ethyl)-N-(phenylmethyl)triptorelin.

To a stirred solution of the product of stage (a) (0,89 g, 3,40 mmol) in THF (5 ml) at 0oC was added NaH (60%, 0.18 g, was 4.42 mmol), then benzylbromide (0,50 ml, 4,10 mmol). The mixture was stirred at room temperature for 6 hours, sharply cooled water and extracted with ethyl acetate (3 30 ml).

Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and subjected to chromatography on silica gel (18% ethyl acetate/hexane) to obtain N-(2-(4-nitrophenyl)ethyl-N-(phenylmethyl)trifurcated in the form of a colorless oil (0.52 g, 44%); M. S. (M+H)+= 353.

(c) N-(2-(4-AMINOPHENYL)ethyl-N-(phenylmethyl)triptorelin.

To a stirred solution of the product of stage (b) (0.52 g, 1.48 mmol) in THF/MeOH (100 ml, 1:1) was added catalytic amount of 10% Pd/C. the Mixture was first made when the pressure 3,5155 kg/cm2within 1 hour, filtered through celite and concentrated to obtain N-(2-(4-AMINOPHENYL)ethyl)-N-(phenylmethyl)trifurcated that star> (d) S-methyl-2-theoreticalmethodological.

A solution of 2-thiophenecarboxylate (Maybridge chemical) (11.1 g) in 60 ml of acetone was treated with yadidamean (13,4 g). After 6 hours at 22oC the yellow particles were collected by filtration, washed twice with 25 ml of acetone and dried to provide of 18.45 g of S-methyl-2-theoreticalmethodological, melting point 195oC (decomposition).

(e) N-(4-(2-((phenylmethyl)amino)ethyl)phenyl-2-thiophene-carboxamide.

To a solution of N-(2-(4-AMINOPHENYL)ethyl-N-(phenylmethyl)trifurcated (0,48 g, 1.48 mmol) in isopropanol (6 ml) was added S-methyl-2-theoreticalmethodological (0,42 g, 1.48 mmol). The mixture was mixed for 4 hours, diluted with methanol (5 ml) and 2N NaOH (6 ml) and heated to 70oC for 1 hour. POI reduced pressure removed the solvent, and the residue was dumped in the water and was extracted with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to obtain a solid, which was recrystallized (ethyl acetate/hexane) to obtain N-(4-(2-((phenylmethyl)amino)ethyl)phenyl-2-thiophenecarboxaldehyde in the form of a white solid: (0.17 g, 34%); melting point 116-118oC.

Example 2

N-(4-(1-(LASS="ptx2">

To a stirred solution of 4-nitrobenzenesulfonamide (4,06 g, 21.5 mmol) and triethylamine (6,60 ml, with 47.4 mmol) in methylene chloride (30 ml) was added dropwise triperoxonane anhydride (3,34 ml, with 23.7 mmol). After stirring for 1 minute added water and separated layers. Then the aqueous layer was extracted with metilenhloride (3 20 ml) and combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to obtain a solid, which was recrystallize from methylene chloride/hexane to N-(4-((nitrophenyl)methyl)trifurcated in the form of a white solid: 3,9 g (yield 73%); melting point 97-98oC.

(b) N-(4-((nitrophenyl)methyl)-N-(phenylmethyl)triptorelin.

To a stirred solution of the product of stage (a) (1.0 g, a 4.03 mmol) in THF (10 ml) at 0oC was added NaH (60%, 0,21

g, of 5.24 mmol), then benzylbromide (to 0.72 ml, 4,84 mmol). The mixture was mixed at room temperature for 12 hours, sharply cooled water and extracted with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and subjected to chromatography on silica gel (16% ethyl acetate/hexane) to obtain N-((4-nitrophenyl)methyl-N-(phenylmethyl)cryptorchidectomy.

To a stirred solution of the product of stage (b) (1,76 g, 5,16 mmol) in THF/MeOH (100 ml, 1:1) was added catalytic amount of 10% Pd/C. the Mixture was first made when the pressure 3,51 kg/cm2for 0.5 hours, filtered through celite and concentrated to obtain N-((4-AMINOPHENYL)methyl-N-(phenylmethyl)trifurcated, which was homogeneous by TLC and used immediately in the next reaction.

(d) N-(4-(1-phenylethyl)amino)methyl)phenyl-2-thiophenecarboxylate.

To a solution of the product of stage (c) (1.60 g, 5,16 mmol) in isopropanol (6 ml) was added S-methyl-2-S-theoreticalmethodological (the product of example 1, stage (d) (1.47 g, 5,16 mmol). The mixture was stirred for 24 hours at 40oC, diluted with methanol (5 ml) 2 NaOH (15 ml) and was heated to 70oC for 1 hour. Under reduced pressure removed the solvent, and the residue was dumped in the water and was extracted with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and subjected to chromatography on silica gel (8% methanol/methylene chloride) to obtain a solid, which precrystallization (ethyl acetate/hexane) to yield N-(4-(1-((phenylmethyl)amino)methyl)phenyl)-2-thiophencarboxylic)amino)methyl)phenyl)-2-thiophencarboxylic.

(a) N-(2-phenylethyl)triptorelin.

To a stirred solution of phenethylamine (4,91 g, 40,5 mmol) and triethylamine (6,50 ml and 46.6 mmol) in methylene chloride (30 ml) was added dropwise triperoxonane anhydride (6.3 ml and 44.6 mmol). After stirring for 1 minute added water and the layers were separated. Then the aqueous layer was extracted with methylene chloride (3 40 ml), and combined extracts washed with water, dried over magnesium sulfate, filtered and concentrated to obtain a solid, which was recrystallized from methylene chloride/hexane to obtain N-(2-phenylethyl)trifurcated in the form of a white solid: (60 g, yield 69%); melting point 50-52oC.

(b) N-(2-phenylethyl)-N-(4-nitrophenyl)methyl)triptorelin.

To a stirred solution of the product of stage (a) (2.0 g, 9,26 mmol) in THF (10 ml) at 0oC was added NaH (60%, and 0.37 g, 9,26 mmol) then 4-nitrobenzylamine (1.0 ml, 4,63 mmol). The mixture was mixed at room temperature for 1 hour, sharply cooled water and extracted with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and subjected to chromatography on silica gel (16% ethyl acetate/hexane) to obtain N-(2-phenylethyl)-N-((4-microplates)-N-((4-AMINOPHENYL)methyl)triptorelin.

To a stirred solution of the product of stage (b) (1.60 g, of 4.54 mmol) in THF/MeOH (100 ml, 1:1) was added catalytic amount of 10% Pd/C. the Mixture was first made when the pressure 3,5155 kg/cm2for 0.75 hour, filtered through celite and concentrated to obtain N-(2-phenylethyl)-N-((4-AMINOPHENYL)methyl)trifurcated, which was homogeneous by thin-layer chromatography, and immediately used in the next reaction.

(d) N-(4-(1-((2-phenylethyl)amino)methyl)phenyl-2-thiophenecarboxylate.

To a solution of the product of stage (c) (1,17 g of 4.54 mmol) in isopropanol (5 ml) was added S-methyl-2-theoreticalmethodological (the product of example 1, stage (a) (1.30 grams, of 4.54 mmol). The mixture was mixed for 24 hours at 40oC, diluted with methanol (5 ml) and 2N NaOH (10 ml) and heated for 1 hour to 70oC. Under reduced pressure removed the solvent, the residue is dropped in the water and was extracted with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and subjected to chromatography on silica gel (10% methanol/methylene chloride) to obtain a solid, which precrystallization (ethyl acetate/hexane) to obtain N-(4-(1-((2-phenylethyl)amino)methyl)phenyl)-2-typenormal who yl)amino)ethyl)phenyl)-2-thiophencarboxylic

(a) N-(4-nitrophenyl)ethyl-N-((2-chlorophenyl)methyl) triptorelin.

To a stirred solution of N-(2-(4-nitrophenyl)ethyl)trifurcated (the product of example 1 stage (a) (2.0 g, 7,63 mmol) and catalytic amount of 15-cruan-5 in THF (10 ml) at 0oC was added NaH (60%, 0.18 g, was 4.42 mmol) then 2-Chlorobenzilate (1,49 ml of 11.45 mmol). The mixture was stirred at room temperature for 2 hours, sharply cooled water and extracted with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and subjected to chromatography on silica gel (18% etelaat/hexane) to obtain N-(2-(4-nitrophenyl)ethyl-N-((2-chlorophenyl)methyl)trifurcated in the form of a colorless oil: (2,31 g, 78%); M. S. (M+H)+= 353.

(b) N-(2-AMINOPHENYL)ethyl)-N-((2-chlorophenyl)methyl)triptorelin.

To a stirred solution of the product of stage (a) (231 g, 5,96 mmol) in THF/MeOH (100 ml, 1:1) was added catalytic amount of 10% Pd/C.

The mixture was first made under pressure 3,5155 kg/cm3within 1 hour, filtered through celite and concentrated to obtain N-(2-(4-AMINOPHENYL)ethyl)-N-(2-chlorophenyl)methyl)trifurcated, which was homogeneous by thin-layer chromatography, and immediately use the solution of the product of stage (b) (2.1 g, 5,96 mmol) in isopropanol (10 ml) was added S-methyl-2-theoreticalmethodological (the product of example 1, stage (d) (1.7 g, 5,96 mmol). The mixture was mixed for 24 hours, diluted with methanol (10 ml) and 2N NaOH (6 ml) and heated for 1 hour to 70oC. Under reduced pressure removed the solvent, the residue is dropped in the water and was extracted with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and subjected to chromatography on silica gel (10% methanol/methylene chloride) to obtain a solid, which was recrystallized (methylene chloride/hexane) to obtain N-(4-(2-(2-chloroformate)amino)ethyl)phenol)-2-thiophenecarboxaldehyde in the form of a white solid: (0.21 g, 10%); melting point 81-82oC.

Example 5 N-(4-(2-((3-performer)amino)ethyl)phenyl-2-thiophencarboxylic

(a) N-((3-forfinal)methyl-N-(2-(4-nitrophenyl)ethyl) triptorelin.

To a stirred solution of N-(2-(4-nitrophenyl)ethyl)trifurcated (the product of example 1, stage (a) (1.5 g, of 5.75 mmol) and catalytic amount of 15-crown-5 in THF (10 ml) at 0oC was added NaH (60%, 0.25 g, 6,34 mmol) then 3-florantyrone (1,40 ml of 11.45 mmol). The mixture was mixed at room temperature in the course is whether over magnesium sulfate, filtered, concentrated and subjected to chromatography on silica gel (18% ethyl acetate/hexane) to obtain N-((3-forfinal)methyl-N-(2-(4-nitrophenyl)ethyl)trifurcated in the form of a colorless oil (1.63 g, 77%); M. S. (M+H)+= 371.

(b) N-(2-(4-AMINOPHENYL)ethyl)-N-(3-forfinal)methyl)triptorelin.

To a stirred solution of the product of stage (a) (1.63 g, 4.40 mmol) in THF/MeOH (100 ml, 1:1) was added catalytic amount of 10% Pd/C. the Mixture was first made when the pressure 3,5155 kg/cm3within 1 hour, filtered through celite and concentrated to obtain N-(2-(4-AMINOPHENYL)ethyl)-N-(3-forfinal)methyl)trifurcated, which was homogeneous by thin-layer chromatography and immediately used in the next reaction.

(c) N-(4-(2-(3-forfinal)methyl)amino)ethyl)phenyl-2-thiophenecarboxylate.

To a solution of the product of stage (b) (1.5 g, 4.40 mmol) in methanol (10 ml) was added S-methyl-2-theoreticalmethodological (the product of example 1, stage (d) (1.3 g, 4.40 mmol). The mixture was mixed for 2 hours, diluted with methanol (5 ml) and 2N NaOH (8 ml) and heated for 1 hour to 70oC. Under reduced pressure removed the solvent, the residue is dropped in the water and was extracted with ethyl acetate (3 30 ml). Mixed extracts industrial recrystallized (methylene chloride/hexane) to obtain N-(4-(2-((3-forfinal)methyl)amino)ethyl)phenyl)-2-thiophenecarboxaldehyde in the form of a white solid: (0.14 g, 8%); melting point 130-131oC.

Example 6 N-(4-(2-(((2-were)methyl)amino)ethyl)phenyl-2-thiophenecarboxylate.

(a) N-((2-were)methyl-N-(2-(4-nitrophenyl)ethyl) triptorelin.

To a stirred solution of N-(2-(4-nitrophenyl)ethyl)trifurcated (the product of example 1, stage (a) (1.5 g, of 5.75 mmol) and catalytic amount of 15-crown-5 in THF (10 ml) at 0oC was added NaH (60%, 0.25 g, 6,34 mmol) then 2-methylbenzylamine (1,53 ml, 22,45 mmol).

The mixture was mixed at room temperature for 2 hours, sharply cooled water and extracted with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and subjected to chromatography on silica gel (18% ethyl acetate/hexane) to obtain N-((2-were)methyl-N-(2-(4-nitrophenyl)ethyl)trifurcated in the form of a white colorless oil: (1,76 g, 84%); M. S. (M+H)+= 367.

(b) N-(2-(4-AMINOPHENYL)ethyl)-N-((2-were)methyl)triptorelin.

To a stirred solution of the product of stage (a) (1,76 g, 4,82 mmol) in THF/MeOH (100 ml, 1:1) was added catalytic amount of 10% Pd/C. the Mixture was first made when the pressure 3,5155 kg/cm3within 1 hour, filtered through celite and concentrated to obtain N-(2-(4-omatography, and immediately used in the next reaction.

(c) N-(4-(2-(((2-were)methyl)amino)ethyl)phenyl)-2-thiophenecarboxylate.

To a solution of the product of stage (b) (1,62 g, 4,82 mmol) in methanol (10 ml) was added S-methyl-2-theoreticalmethodological (the product of example 1, stage (d) (1,37 g, 4,82 mmol). The mixture was mixed for 2 hours, diluted with 2N NaOH (8 ml) and heated for 1 hour to 70oC. Under reduced pressure removed the solvent, the residue is dropped in the water and was extracted with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated to obtain a solid, which was recrystallize (methylene chloride/hexane) to obtain N-4-(((2-were)methyl)amino)ethyl)phenyl-2-thiophenecarboxaldehyde in the form of a white solid: (0,46 g, 28%); melting point 105-106oC.

Example 7

N-(4-(2-(methylamino)ethyl)phenyl)-2-thiophenecarboxylate.

(a) N-methyl-N-(2-(4-nitrophenyl)ethyl)triptorelin.

To a stirred solution of N-(2-(4-nitrophenyl)ethyl)trifurcated (the product of example 1, stage (a)) (1.5 g, of 5.75 mmol) and catalytic amount of 15-crown-5 in THF (10 ml) at 0oC added NaF (60%, 0.25 g, to 6.43 mmol), then methyliodide (of 0.71 ml, 11 with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to obtain N-methyl-N-(2-(4-AMINOPHENYL)ethyl)trifurcated in the form of a white colorless oil (1.40 g, 88%); M. S. (M+H)+= 277.

(b) N-methyl-N-(2-AMINOPHENYL)ethyl)triptorelin.

To a stirred solution of the product of stage (a) (1.45 g, a 5.25 mmol) in THF/MeOH (100 ml, 1:1) was added catalytic amount of 10% Pd/C. the Mixture was first made when the pressure 3,5155 kg/cm3within 1 hour, filtered through celite and concentrated to obtain N-methyl-N-(2-(4-AMINOPHENYL)ethyl)trifurcated, which was homogeneous by thin-layer chromatography, and immediately used in the next reaction.

(c) N-(4-(2-(methylamino)ethyl)phenyl)-2-thiophenecarboxylate.

To a solution of the product of stage (b) (1,32 g, 5.37 mmol) in methanol (10 ml) was added S-methyl-2-theoreticalmethodological (the product of example 1, stage (d) (1,53 g, 5.37 mmol). The mixture was mixed for 2 hours, diluted with 2N NaOH (8 ml) and heated for 1 hour to 70oC. Under reduced pressure removed the solvent, the residue is dropped in the water and was extracted with ethyl acetate (3 30). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, and conc who-((2-methylphenylethyl)amino)ethyl)phenyl)-2-thiophenecarboxaldehyde in the form of a white solid: (0,43 g, 31%); M. S. (M+H)+= 260.

Example 8 N-(4-(2-amino-ethyl)phenyl)-2-thiophenecarboxylate.

(a) N-(2-AMINOPHENYL)ethyl)triptorelin.

To a stirred solution of N-(2-(4-nitrophenyl)ethyl-N-(phenylmethyl)trifurcated (the product of example 1, stage (a)) (1,00 g, 3,81 mmol) in THF/MeOH (100 ml, 1:1) was added catalytic amount of 10% Pd/C. the Mixture was first made when the pressure 3,5155 kg/cm2within 1 hour, filtered through celite and concentrated to obtain N-(2-(4-AMINOPHENYL)ethyl)trifurcated, which was homogeneous by thin-layer chromatography, and immediately used in the next reaction.

(c) N-(4-(2-amino-ethyl)phenyl)-2-thiophenecarboxylate.

To a solution of the product of stage (a) (0.88 g, 3,81 mmol) in methanol (10 ml) was added S-methyl-2-theoreticalmethodological (the product of example 1, stage (d)) (1,09 g, 3,81 mmol). The mixture was mixed for 12 hours, diluted with 2N NaOH (8 ml) and heated for 1 hour to 70oC. Under reduced pressure removed the solvent, the residue is dropped in the water and was extracted with ethyl acetate (3 30). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated to obtain a solid, which was recrystallize (ethyl acetate/meta is and melting 134-137oC.

Example 9 N-((4-morpholinylmethyl)phenyl-2-thiophenecarboxylate.

(a) 4-(4-nitrobenzyl)morpholine.

To a mixed solution (2.00 g, 0,0093 mol) of 4-nitrobenzaldehyde (Aldrich) and (0,736 g to 0.011 mol) of anhydrous potassium carbonate (Aldrich) 20,00 ml of DMF was added morpholine (coefficient was 0.796 ml, 0,0093 mol). The reaction mixture was heated to 50oC and mixed for 30 minutes, then added additional 0.1 equivalents of the research and potassium carbonate. After 30 minutes the reaction mixture is abruptly cooled 100 ml of water and was extracted (4 100 ml) with ethyl acetate. The organic layers were collected and dried over magnesium sulfate, and boiled away the solvent. The obtained solid was recrystallize from ethyl acetate and hexane to obtain 1.90 g of 4-(4-nitrobenzyl)of the research.

(b) 4-morpholinylmethyl)aniline.

A sample (1,00 g; 0,0045 mol) of 4-(4-nitrobenzyl)of the research were dissolved in 25 ml of THF and 25 ml of methanol in a thick-walled bottle for reactions under pressure. Added catalytic amount of 10% palladium on carbon and the reaction mixture was first made. When the absorption of hydrogen ceased, the catalyst was removed by filtration, and the solvent is boiled away. The solid was dissolved in 30 ml of ethyl acetate and 30 ml of water and 30 ml of 2N sodium hydroxide. Water layers ek is reali under vacuum. The obtained solid was recrystallize from ethyl acetate and hexane to obtain 0.68 g (4-morpholinylmethyl)aniline.

(c) N-((4-morpholinylmethyl)phenyl-2-thiophenecarboxylate.

To a stirred solution of the product of stage (b) (0.68 g, 0,0035 mol) and 150 ml of isopropyl alcohol was added S-methyl-2-theoreticalmethodological (the product of example 1, stage (d)) (0,99 g; 0,0035 mol). The mixture was mixed with 35oC. To this mixture, together with 2M hydrochloric acid in isopropyl alcohol, was added dropwise, was added 10.0 ml of methanol until then, until all reagents are in solution. Provided stirring the reaction mixture for 48 hours. Then the reaction mixture was diluted with 50 ml saturated sodium chloride and was extracted with ethyl acetate (3 75 ml). The organic layers were collected, dried over magnesium sulfate, and the solvent is boiled away. The crude product was separated on silicagel column with elution 10% methanol in methylene chloride. The solvent is boiled away and the crude solid was twice recrystallize from ethyl acetate and hexane to obtain 60 mg of N-((4-morpholinylmethyl)phenyl-2-thiophenecarboxaldehyde, melting point 148150oC.

Example 10

N-(3-(((phenylmethyl)amino)methyl)phenyl)-2-thiophenecarboxaldehyde mol) in solution in 50 ml of methylene chloride and 50 ml Polynesians aqueous solution of potassium carbonate at 0oC was added dropwise a solution of benzoyl chloride (2.1 g, 0,0149 mol) in 10 ml of methylene chloride. After complete addition, the reaction mixture was mixed for 2 hours at 0oC and then heated up to ambient temperature overnight. The organic layer was separated and successively washed with diluted hydrochloric acid and water. The dried organic phase (MgSO4) was concentrated in vacuo to obtain of 2.92 g (88%) of the named product, the melting point of 136-138oC.

b) N-benzyl-2,2,2-Cryptor-N-(3-nitrobenzyl)ndimethylacetamide.

To a solution of the product of stage (a) (2.85 g, 11.1 mmol) in 50 ml of anhydrous tetrahydrofuran at 0oC under nitrogen was added 18.6 ml of 1.0 M borane in THF solution (to 18.6 mmol). Then the reaction mixture for 5.5 hours was heated in a flask with reflux condenser. The solution was cooled in throughout the night and then abruptly cooled by successive addition of 2 ml of methanol and 10 ml of 6M hydrochloric acid. The reaction mixture is again heated in a flask under reflux for 1 hour. After cooling to ambient temperature increased the basicity of the reaction mixture and was extracted in a simple ether, dried (MgSO4) and concentrated to obtain oil. The oil was subjected to chromatography on forces is in the form of oil To the solution of crude benzyl-3/(nitrobenzyl)amine (1,95 g, with 8.05 mmol) and triethylamine (2.6 ml, 18 mmol) in 20 ml of methylene chloride under nitrogen at 0oC was added dropwise triperoxonane anhydride (3.4 g, 16 mmol). Before discharge into water, the reaction mixture was mixed for 10 minutes. Separated the organic layer and dried over magnesium sulfate. The solution was filtered and concentrated to obtain oil. Chromatography on silica gel using 20% ethyl acetate in hexane as eluent received of 1.46 g (54%) of product as an oil, mass spectrum m/e 339 (100%, M+H).

(c) N-(3-aminobenzyl)-N-benzyl-2,2,2-triptorelin.

To a solution of the product of stage (b) (1,21 g, 3.58 mmol), dissolved in a solution of 100 ml of methanol was added 20 ml of a saturated solution of hydrogen chloride in isopropanol and 0.1 g of 5% Pd/C. the resulting solution was first made in the course of 1 hour at a pressure of 3,5155 kg/cm2. Removed the catalyst by filtration, and the filtrate was concentrated in vacuo to obtain a solid substance. When crushed into powder solids with simple ether got to 1.15 g (93%) of the named compound in the form of cleaners containing hydrochloride salt, current melting 169-174oC.

(d) N-3-(((phenylmethyl)amino)methyl)phenyl-2-thiophenecarboxylate.

To a solution of 0.25 g (0,94 mmol) of S-methyl-2-Teoreticheskie the-trifurcated (obtained using cleaners containing hydrochloride salt, neutralization of 2.5 m NaOH and extraction in methylene chloride). The reaction mixture was mixed for 5 hours. Added a 2.5 M solution of sodium hydroxide (2 ml) and 5 drops of methanol, and the resulting solution was heated for 1 hour in a flask with reflux condenser. The solution was concentrated, and the product was extracted into ethyl acetate. The solution was dried and concentrated to obtain a solid substance. The solid is dissolved in ethanol and added the dihydrate of oxalic acid (0.16 g, 1.3 mmol). The obtained salt was collected and dried to obtain 0.26 g (55%) of the named compound in the form of biseksualnoy salt, melting point 178-183oC.

Example 11

An alternative synthesis of compounds of example 2.

N-(4-(((phenylmethyl)amino)methyl)phenyl)-2-thiophenecarboxylate.

(a) N-(4-nitrobenzyl)benzamide).

This compound is obtained by following the procedure of example 10, step (a). 4-nitrobenzylamine (2,45 g 0,031 mol) and benzolamide (2.1 g, 0,0149 mol) was allocated 2,56 g (77%) of the named product, melting point 150-153oC.

(b) N-benzyl-2,2,2-Cryptor-N-(4-nitrobenzyl)ndimethylacetamide.

This connection benzyl-(4-nitrobenzyl)amine was obtained using the procedure described in example 10, step (b) to obtain benzyl-3-(l-(4-nitrobenzyl)amine, which was used without further purification. This crude product was mixed with 4.3 ml of triethylamine in 40 ml of methylene chloride at 0oC under nitrogen. To this solution dropwise added 3.6 ml triperoxonane anhydride. This solution was mixed for 10 minutes, poured into water and separated. The organic phase was dried (MgSO4) and concentrated to obtain 3.1 g (94%) of the titled compound as oil.

(c) N-(4-aminobenzyl)-N-benzyl-2,2,2-triptorelin.

This compound is obtained using methods described in example 10, stage (c), to obtain N-(3-aminobenzyl)-N-benzyl-2,2,2-trifurcated.

From N-benzyl-2,2,2-Cryptor-N-(4-nitrobenzyl)ndimethylacetamide (3.1 g, 9.2 mmol) after hydrogenation got 2,46 g (78%) of the named compound in the form of cleaners containing hydrochloride salt. By recrystallization from isopropanol and simple broadcast received 1,74 g of pure material, melting point 115-119oC.

(d) N-(4-(((phenylethylamine)methyl)phenyl)-2-thiophenecarboxylate.

Out of 0.60 g (1.9 mmol) of free base N-(4-aminobenzyl)-N-benzyl-2,2,2-trifurcated and 0.42 g (1.6 mmol) of S-methyl-2-titaniumoxide (obtained using cleaners containing hydrochloride salt obtained by following the method similar to that of anola. The reaction mixture was mixed for 5 hours. Added a solution (2 ml) of 2.5 M sodium hydroxide and about 5 drops of methanol, and the resulting solution was heated in a flask under reflux for 1 hour. The solution was concentrated, and the product was extracted into ethyl acetate. The solution was dried and concentrated to obtain a solid substance. The solid is transformed into bis-oxalate in isopropanol and then recrystallize from 95% ethanol to obtain 110 mg (10%) of the named compound, melting point 209-213oC.

Example 12

Following the procedure of example 1, there are obtained the following compounds:

(a) N-(4-(2-(((2,6-dichlorophenyl)methyl)amino)ethyl)phenyl)- 2-thiophenecarboxylate, melting point 104-105oC.

(b) N-(4-(2-(((2-bromophenyl)methyl)amino)ethyl)phenyl)- 2-thiophenecarboxylate, melting point 81-82oC.

(C) N-(3-(2-((phenylmethyl)amino)ethyl)phenyl)-3 - thiophenecarboxaldehyde, melting point 145-147oC.

(d) Free base N-(4-(2-((2,6-dichlorophenyl)methyl)amino)ethyl)phenyl)-3 - thiophencarboxylic, melting point 109-110oC.

(e) N-(4-(2-amino-ethyl)-3-thiophenecarboxaldehyde, melting point 158-170oC (Razlog.).

(f) Free base N-() Free base N-(3-(3-(1-pyrrolidinyl)propyl)phenyl)-2 - thiophenecarboxylate, the melting point 110-111oC.

(h) N-(4-(2-amino-ethyl)phenyl)-2-procarboxypeptidase, melting point 162oC (Razlog.).

Example 13

Following the procedure of example 9, received the following connections:

(a) N-(4-((1-piperidinyl)methyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 277-278oC.

(b) N-(4-((1-pyrrolidinyl)methyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 248-250oC.

Example 14

Following the procedure of example 10, received the following connection:

N-(3-(((phenylmethyl)amino)methyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 171-173oC.

Example 15

Following the General method of example 1, carrying out stage (c) interaction S-methyl-2-theoreticalmethodological with 3-(methylamino)phenylamine, received the following connection:

N-(3-((amino)methyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 145-148oC.

Example 16

Following the procedure of example 10, received the following connection:

N-(3-(2-((phenylmethyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 132-134oC.

Example 17

N-(3-(2-(ethylamino)ethylphenyl)-2-thiophenecarboxylate.

(a) (3-nitrophenyl)ACML, 1.37 mol) was heated in a flask under reflux for 2 hours, then concentrated to yield 11.1 g (3-nitrophenyl)acetylchloride in the form of a reddish-brown solid.

(b) N-ethyl-(2-nitrophenyl)ndimethylacetamide.

To a mixed solution of 70 wt.% ethylamine in water (35 ml), cooled in a bath of ice, was added in one portion (3-nitrophenyl)acetylchloride (3 g, 15.0 mmol).

The resulting mixture was heated to achieve a clear solution, which was cooled. The precipitate was filtered, obtaining N-ethyl-2-(3-nitrophenyl)ndimethylacetamide in the form of a yellow solid: (2.2 g, 71%; melting point 115-117oC).

(c) Ethyl-(2-(3-nitrophenyl)ethyl)aminogidrohlorid.

To a stirred solution of the product of stage (b) (2.2 g, 10.6 mmol) in tetrahydrofuran under nitrogen was added dropwise 1.0 M borane-tetrahydrofuran (42 ml, 42 mmol). The reaction mixture was heated in a flask under reflux for 1.5 hours, cooled in a bath with ice, then added dropwise an aqueous solution of 6N HCl (75 ml). The resulting mixture was heated in a flask under reflux for 1 hour, increased basicity to pH 11 20% aqueous solution of sodium hydroxide, and was extracted twice with simple ether. Mixed extracts C and ethyl acetate, he recrystallize to yield ethyl-(2-(3-nitrophenyl)ethyl)americanled in the form of a light yellow solid: (1.7 g, 70%); melting point of 186-188oC.

(d) 3-(2-ethylaminomethyl)phenylaminopropane.

To a solution of the product of stage (c) (1.7 g, 7.0 mmol) in methanol (30 ml) was added catalytic amount of 10% palladium on carbon. The mixture was first made in the course of 30 minutes at a pressure of 3,5155 kg/cm2was filtered through celite, concentrated to yield 3-(2-ethylaminomethyl)fenilalaningidroksilazy as not quite white solids: (1.4 g, 100%); melting point 192-194oC.

(e) N-(3-(2-ethylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

To a solution of the product of stage (d) (1.4 g, 7.0 mmol) in isopropanol (20 ml) and dimethylformamide (20 ml) was added S-methyl-2-theoreticalmethodological (2.5 g, 8,8 mmol). The mixture was mixed for 16 hours, diluted 20% aqueous solution of sodium hydroxide and was extracted twice with ethyl acetate. Mixed extracts were twice washed with water, dried over magnesium sulfate, filtered and concentrated to obtain 2.7 g of oil. Dihydrobromide salt received from isopropanol and ethyl acetate, recrystallize from isopropanol, methanol and Atila solids: (1,72 g, 49%); melting point 192-194oC (Razlog.).

Example 18

N-(3-(3-((phenylethyl)amino)propyl)phenyl)-2 - thiophenecarboxaldehyde.

(a) 3-(3-phenylaminopropyl)phenylenedimethylene.

Got it, following the method similar to that described in example 17, steps (a) - (o).

(b) N-(3-(3-((phenylethyl)amino)propyl)phenyl)-2 - thiophenecarboxaldehyde.

To a solution of the product of stage (a) (3.0 g, 9,17 mmol) and S-methyl-2-theoreticalmethodological (3,3 g, 11.5 mmol) in propanol (25 ml) and dimethylformamide (25 ml) was added in one portion pyridine (0,74 ml, 9,17 mmol). The mixture was mixed for 16 hours, diluted 20% aqueous solution of sodium hydroxide and was extracted twice with ethyl acetate. Mixed extracts were twice washed with water, dried over magnesium sulfate, filtered and concentrated. Raw dioxalate salt obtained from ethanol and simple ether, recrystallize from ethanol to yield N-(3-(3-phenylethyl)amino)propyl)phenyl)-2 - thiophenecarboxylate in the form of a white solid: (2.3 g, 44%); melting point 102-105oC.

Example 19 N-(3-((2-(((2-bromophenyl)methyl)amino)ethyl)phenyl)-2 - thiophenecarboxylate.

(a) N-(2-bromobenzyl)-2-(3-mitrofanii (a) - (b).

(b) N-(2-bromobenzyl)-2-(3-AMINOPHENYL)ndimethylacetamide.

To a solution of the product of stage (a) (of 5.45 g, 15.6 mmol) in 85% glacial acetic acid (400 ml) was added in one portion zinc dust (10.2 g, 156 mmol). The reaction mixture was mixed for 30 minutes, filtered and concentrated. The residue was separated 20% aqueous sodium hydroxide solution and dichloromethane, the organic layer was dried over magnesium sulfate, filtered, concentrated to yield N-(2-bromobenzyl)-2-(3-AMINOPHENYL)ndimethylacetamide in the form of a white solid: (4.7 g, 94%); melting point 110-112oC.

(c) 3-(2-(2-bromobenzylamine)ethyl)phenylaminopropane.

Got it, following a technique similar to that presented in example 17, step (c).

(d) N-(3-(2-(((2-bromophenyl)methyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

Got it, following a technique similar to that presented in example 18, step (b), the melting point 175-178oC (decomp.).

Example 20

N-(3/(2-phenylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

(a) (2-(3-nitrophenyl)ethyl) - phenylamine.

Got it, following a technique similar to that presented in example 17, steps (a) - (c).

(c) 2,2,2-Cryptor-N-(2-(3-AMINOPHENYL)ethyl-N-phenylacetamide.

Got it, following a technique similar to that presented in example 1, stage (c).

(d) N-(3-(2-(phenylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

Got it, following the method similar to that described in example 1, stage (c). The melting point 235-240oC (Razlog.).

Example 21

Following a methodology similar to that described in example 17, received the following connections:

(a) N-(4-(2-ethylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 176-178oC.

(b) N-(4-(2-(2-propylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, the melting point of 240-242oC.

(c) N-(4-(2-(1-propylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 233-235oC.

(d) N-(4-(2-tert-butylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 241-242oC.

(e) N-(4-(2-(n-butylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, the melting point of 238-240oC.

(f) N-(3-(2-(methylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, point PLA melting 72-75oC (RASMAG.).

(h) N-(3-(2-tert-butylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 232-235oC (Razlog.).

(i) N-(3-(2-propylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 206-210oC (Razlog.).

(j) N-(3-(2-amino-ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 194-199oC (Razlog.).

(k) N-(3-(2-dimethylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 232-233oC (Razlog.).

(l) N-(3-(2-(diethylamino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 75-80oC (RASMAG.).

(m) N-(3-(2-(2-(1,2,3,4-tetrahydro)ethenolysis)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 172-175oC (Razlog.).

(n) N-(4-(3-(2-(1,2,3,4-tetrahydro)ethenolysis)propyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 138-142oC.

(o) Free base N-(4-(2-(3,5-bis-triftormetilfullerenov)amino)ethyl)phenyl)-2 - thiophenecarboxylate, melting point 98-100oC.

(p) the Free base N-(4-(2-diethylamino)ethyl)phenyl)-2 - thiophenecarboxylate, melting point 113-115oC.

(q) N-(4-(2-((3-chloroformate)amino)ethyl)phenyl) benzl)phenyl)-3 - chlorothiophene-2-carboxymenthyllulose, 257oC.

(s) N-(4-(2-((4-methylphenylethyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, 218-219oC.

(t) N-(4-(2-(piperidylamine)ethyl)phenyl)-2 - thiophenecarboxaldehyde, 205-206oC.

Example 22

Using a technique similar to that presented in example 18, received the following connections:

(a) N-(3-(2-(((2-chlorophenyl)methyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 155-157oC (Razlog.).

(b) N-(3-(3-((phenylmethyl)amino)propyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 138-141oC (Razlog.).

(c) N-(4-(2-(((3-chlorophenyl)methyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 216-217oC.

(d) N-(4-(2-(((4-chlorophenyl)methyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 203-204oC.

(e) N-(4-(2-(((3-chlorophenyl)methyl)amino)ethyl)phenyl)-3 - chlorothiophene-2-carboxymenthyllulose, melting point 257-258oC.

(f) N-(4-(3-ethylamino)propyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 98-100oC.

Example 23

Using a technique similar to that presented in example 19, received the following connections:

(a)SUP>oC.

(b) the Free base N-(4-(2-((N-phenylmethyl-N-methyl)amino) ethyl)phenyl)-2-thiophenecarboxylate, melting point 110-112oC.

(c) N-(3-(2-(((3-chlorophenyl)methyl)amino) ethyl)phenyl)-2-thiophenecarboxaldehyde, melting point 185-188oC (Razlog.).

(d) N-(3-(2-(((forfinal)methyl)amino) ethyl)phenyl)-2-thiophenecarboxaldehyde, melting point 183-184oC.

(e) N-(4-(3-(((3-chlorophenyl)methyl)amino) propyl)phenyl)-2-thiophenecarboxaldehyde, melting point 212-215oC.

(f) N-(4-(3-(((3-phenylmethyl-N-methyl)amino) propyl)phenyl)-2-thiophenecarboxaldehyde, melting point 228-232oC (Razlog.).

(g) the Free base N-(4-(2-((ethyl)(phenylmethyl)amino) ethyl)phenyl)-2-thiophenecarboxylate, melting point 87-89oC.

(n) Free base N-(4-(2-((propyl)(phenylmethyl)amino)ethyl) phenyl)-thiophencarboxylic, the melting point of 100-102oC.

(i) Free base N-(4-(2-((1,1-dimethylethyl)(phenylmethyl)amino)ethyl) phenyl-2-thiophenecarboxylate, melting point 145-148oC.

(j) Free base N-(4-(2-(((3,4-dichlorophenyl)methyl)amino)ethyl) phenyl)-2-thiophenecarboxylate, melting point 111-114oC.

Example 24 N)aniline.

The stirred solution of 4-(4-nitrophenyl)butyric acid (5.0 g, is 0.023 mol) in 20 ml of thionyl chloride was heated in a flask under reflux for 4 hours. The solvent is evaporated and to the stirred solution of aniline (2.0 g, 0.02 mol) in 30 ml of tetrahydrofuran and 10 ml of triethylamine dropwise added 2.5 g of crude acid chloride, and then the reaction mixture was stirred for 18 hours. Filtration removed trietilenglikole, and the organic phase was added 50 ml of ethyl acetate. The organic phase is washed 1 100 ml of 1N hydrochloric acid and dried over magnesium sulfate. The solvent is boiled away to obtain a yellow solid. The solid is dissolved in 100 ml of methanol and added 5200 mg of 10% palladium on carbon, the reaction mixture was first made within 4 hours. It was found that the product has not recovered and then dissolved in 100 ml of methanol. Added 10 ml of a saturated solution of HCl in isopropanol, then 250 mg of 10% palladium on carbon. The mixture was first made within 4 hours. Removed the catalyst by filtration, and boiled away the solvent. The residue was dissolved in 100 ml of hot water with a minimal amount of methanol and then 50% solution of sodium hydroxide increased the basicity of the solution. The mixture was extracted with 150 ml ethylacetat 1.0 g, a single spot in thin-layer chromatography.

(b) N-(4-(3-((phenylamino)carbonyl)propyl)phenyl)-2 - thiophenecarboxylate.

To a stirred suspension of the product of stage (a) (1,00 g, 0,0037 mol) in approximately 5 ml of isopropanol was added S-methyl-2-theoreticalmethodological (the product of example 1, stage (d) (1.01 g, 0,0035 mol).

This mixture was heated for 1 hour in a flask under reflux and then cooled to obtain solid particles. The product was filtered, dried under vacuum overnight, receiving N-(4-(3-((phenylamino)carbonyl)propyl)phenyl)-2 - thiophenecarboxylate, the output of 1.76 g, melting point 229-231oC.

Example 25

Using a technique similar to that presented in example 24, received the following connections:

(a) N-(4-(3-((phenylethylamine)carbonyl)propyl)phenyl)-2 - thiophenecarboxylate, melting point 169-171oC.

(b) N-(4-(3-((1-pyrrolidyl)carbonyl)propyloxy)phenyl)-2 - thiophenecarboxylate, melting point 191-194oC.

(c) N-(4-(3-morpholinyl)carbonyl)propyloxy)phenyl)-2 - thiophenecarboxylate, the melting point of 136-138oC.

(d) N-(4-(2-((phenylethylamine)carbonyl)ethyl)phenyl)-2 - thiophenecarboxylate, melting point 63-65oCLASS="ptx2">

(f) N-(4-(3-((phenylamino)carbonyl)propyl)phenyl)-2 - errorcorrecting, melting point 195-196oC.

(g) N-(4-(3-((phenylamino)carbonyl)propyl)phenyl)-2 - procarboxypeptidase, melting point 197-199oC.

(h) N-(4-(3-((phenylamino)carbonyl)propyl)phenyl)-3 - chloro-2-thiophencarboxylic, melting point 141-144oC.

(i) N-((3-((phenylamino)carbonyl)propyl)phenyl)-1 - methylpyrrole-2-carboxamide, melting point 154-155oC.

(j) N-(4-(3-(1-(4-methylpiperazine)carbonyl)propyl)phenyl)-2 - thiophenecarboxylate, melting point 132-134oC.

Example 26

N-(4-(3-(1-pyrrolidyl)carbonyl)propyl)phenyl)thiophene-2 - carboxymethylated

(a) N-(4-(3-((1-pyrrolidinyl)carbonyl)propyl)aniline.

4-(4-nitrophenyl)butyric acid (2.25 g, 0,01076 mol) was dissolved in 40 ml dichloromethane and cooled to -5oC in a bath containing a mixture of ice / acetone. Added triethylamine (1,09 g, 0,01076 mol) and ethylchloride (1,17 g, 0,01076 mol), the mixture was mixed for 10 minutes and added dropwise maintaining the temperature below 0oC added pyrrolidine (0,92 g, 0,01291 mol). After 10 minutes, the cold bath was removed and the reaction mixture was mixed for 16 hours at room temperature. The dichloromethane solution was washed on the od vacuum boiled away the solvent, receiving 2,19 g of light brown oil. Light brown oil was restored under pressure 3,5155 kg/cm2, the solvent was ethanol, and was used as the catalyst 10% palladium on carbon. After 4 hours the catalyst was filtered under vacuum boiled away the solvent, thus providing 4-(3-((1-pyrrolidinyl)carbonyl)propyl)aniline oil, which was aterials when standing (it was used in the form as it is).

(b) N-(4-(3-((1-pyrrolidyl)carbonyl)propyl)phenyl)-2 - thiophenecarboxaldehyde.

The product of stage (a) (1.50 g, 0,00646 mol) in 6 ml of isopropanol was added S-methyl-2-thiophenecarboxaldehyde (the product of example 1, stage (d)) (1,53 g, 0,00538 mol) and mixed for 16 hours at room temperature. The resulting suspension of solid particles was diluted with 50 ml of isopropanol, and the solids were collected by filtration, receiving N-(4-(3-((1-pyrrolidyl)carbonyl)propyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 213-216oC.

Example 27

Using a technique similar to that presented in example 26, received the following connections:

(a) N-(4-(3-((4-morpholinyl)carbonyl)propyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 189-192oS="ptx2">

(c) N-(4-(2-(((4-morpholinyl)carbonyl)ethyl)phenyl)-2-methylthiazole - 4-carboxamide, melting point 280-281oC.

Example 28 N-(4-(2-(((4-morpholinyl)carbonyl)amino)ethyl)phenyl) thiophene-2-carboxymethylated.

(a) 4-(2-(((4-morpholinyl)carbonyl)amino)ethyl)analysekontoret.

To a stirred solution of 4-nitrophenylhydrazine (4.0 g, 0.24 mol) in 50 ml of tetrahydrofuran was added 10 ml of triethylamine. To this mixture dropwise added 4-morpholinylcarbonyl (3.6 g, 0,0024 mol) in 20 ml of tetrahydrofuran, and the reaction mixture was mixed for 6 hours. Filtering removed triethylamine salt, and the organic phase is washed 1 100 ml of 1N hydrochloric acid. The organic phase was dried over magnesium sulfate; after evaporation of solvent received crude oil. Then the crude oil was dissolved in 250 ml of methanol, was added 250 mg of 10% palladium on carbon and the reaction mixture was first made within 4 hours. Filtration removed the catalyst and boiled away the solvent. To the residue was added 150 ml of ethyl acetate, to obtain the salt then added hydrochloric gas. When cooling, the crystallized 4-(2-(((morpholinyl)carbonyl)amino)ethyl)bilingualised, solid 4.4 g, which was collected by filtration.

(c) N-(4-(2-(((4-morpholinyl)carbonyl)amino)ethyl)phenyl-2 - thiophenecarboxaldehyde.

The product of stage (b), 1.0 g, and S-methyl-2-thiophenecarboxaldehyde (the product of example 1, stage (d)), 1,09 g mixed with a minimum amount of isopropanol. The mixture was heated in a flask under reflux for 1 hour. The resulting solution was cooled, besieged solids and gathered their filtering, receiving 0.95 g N-(4-(2-(((4-morpholinyl)carbonyl)amino)ethyl)phenyl-2 - thiophenecarboxaldehyde, melting point 209-211oC.

Example 29 N-(4-(3-(((phenyl)amino)carbonyl)propyloxy)phenyl-2 - thiophenecarboxaldehyde.

(a) 4-(4-nitrophenoxy)butyric acid.

Ethyl-4-bromobutyrate, 9,9 g, 4-NITROPHENOL, 7.0 g, and sodium carbonate, 6.0 g, were mixed in 50 ml of DMF, and the mixture was heated at 100oC tile for four hours. Filtration removed the solid particles and the industry is Aksana. The obtained organic layer was washed 3 200 ml of 0.2 M potassium carbonate to remove unreacted NITROPHENOL. The obtained organic layer was boiled away in a vacuum to obtain 11 g of a yellow oil. The crude yellow oil was diluted with 200 ml of methanol was treated with 25 ml of 2M sodium hydroxide and stirred overnight at room temperature. The mixture is boiled away in vacuum and diluted with water to 250 ml Solution ostelli telicom and then was acidified with 20 ml of 4M hydrochloric acid. The obtained solids were collected by filtration, washed with water and dried in vacuo to obtain 4-(4-nitrophenoxy)butyric acid, melting point 116-118oC.

(b) N-(4-(3-(((phenyl)amino)carbonyl)propyloxy)aniline.

A solution of 4-(4-nitrophenoxy)butyric acid, 4.0 g in 20 ml of thionyl chloride was heated in a flask under reflux for 4 hours, and then excess thionyl chloride are boiled away into the vacuum. The crude acid chloride was added to a solution of 1.68 g of aniline and 10 ml of triethylamine in 30 ml of THF, and the reaction mixture was mixed for 18 hours. Filtering removed solids, and the filtrate was diluted with 50 ml ethyl acetate. The solution was washed with 100 ml of 1N hydrochloric acid, dried with magnesium sulfate and boiled away to obtain a solid substance. The solid was dissolved in 100 ml IU is yloxy)aniline, white solids. M. S. (M+H)+= 271.

(c) N-4-(3-(((phenyl)amino)carbonyl)propyloxy)phenyl-2 - thiophenecarboxaldehyde.

The product (b) 1.0, and S-methyl-2-theoreticalmethodological (the product of example 1, stage (d)), 1.01 g were mixed in a minimum amount of isopropanol and the mixture was heated in a flask under reflux for 1 hour. The obtained clear solution is cooled, the solid was besieged and was collected by filtration, receiving 1,76 g N-(4-(3-(((phenyl)amino)carbonyl)propyloxy)phenyl)-2 - thiophenecarboxaldehyde, melting point 229-231oC.

Example 30 N-(4-(2-(((triterpenes)carbonyl)amino)ethyl)phenyl)-2 - thiophencarboxylic.

(a) 4-(2-(((triterpenes)carbonyl)amino)ethyl) - nitrobenzene.

To a stirred solution of 4-nitrophenylhydrazine (1.84 g, 9,10 mmol) and triethylamine (3,03 ml, 21,70 mmol) in methanol (12 ml) was added dropwise triperoxonane anhydride (1,51 ml, 10,66 mmol). After stirring for 1 minute under reduced pressure, the solvent was removed, and the remaining residue was mixed with water and was extracted with methylene chloride (3 20 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to yield a solid veetil)nitrobenzene in the form of a white solid; 1.92 g (yield 80%); melting point 103-104oC.

(b) 4-(2-(((trifluoromethyl)carbonyl)amino)ethyl)aniline.

To a stirred solution of the product of stage (a) (0.52 g, to 1.98 mmol) in THF/MeOH (100 ml, 1:1) was added catalytic amount of 10% Pd/C. the Mixture was first made in the course of 1 hour at a pressure of 3,5155 kg/cm2was filtered through celite and concentrated to obtain 4-(2-(((trifluoromethyl)carbonyl)amino)ethyl)aniline, which was homogeneous by thin-layer chromatography, and immediately used in the next reaction.

(c) N-4-(2-(((trifluoromethyl)carbonyl)amino)ethyl)phenyl)-2 - thiophenecarboxylate.

To a solution of the product of stage (b) (0,30 g, 1,29 mmol) in isopropanol (6 ml) was added S-methyl-2-theoreticalmethodological (the product of example 1 (stage d) (0,37 g, 1,29 mmol). The mixture was mixed for 4 hours, transferred into a solution of saturated NaCl (50 ml) and 50% NaOH (4 ml) and was extracted with ethyl acetate (3 20 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to a solid, which was recrystallize from hexane/ethyl acetate to yield N-4-(2-(((trifluoromethyl)carbonyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde in the form of a yellowish solid: 0,19 g (yield 43%), the doctor

(a) 4-(2-(((methyl)carbonyl)amino)ethyl) - nitrobenzene.

The above compound was obtained by the method of example 30 stage (a), except that triperoxonane anhydride was replaced by acetic anhydride. Got 1,28 pale yellow solid, which was immediately used in the next reaction.

(b) 4-(2-(((methyl)carbonyl)amino)ethyl)aniline.

To a stirred solution of the product of stage (a) (0,82 g of 3.94 mmol) in THF/MeOH (100 ml, 1:1) was added to 4 ml of 1N HCl and a catalytic amount of 10% Pd/C. the Mixture was first made in the course of 4 hours at a pressure of 3,5155 kg/cm2was filtered through celite and concentrated to obtain a solid substance. The solid was transferred into a solution of saturated NaCl (50 ml) and 50% NaOH (4 ml) and was extracted with ethyl acetate (3 20 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to a solid, which was immediately used in the next reaction.

(c) N-4-(2-(((methyl)carbonyl)amino)ethyl)phenyl)-2 - thiophenecarboxylate.

The above compound was obtained by following the procedure of example 30, step (c). After recrystallization from ethyl acetate/methanol was obtained 0.56 g of reddish-brown solid, melting point 18 CLASS="ptx2">

(a) 4-(2-(((methyl)carbonyl)amino)ethyl) - nitrobenzene.

The above compound was obtained by following the procedure of example 30, step (a), except that triperoxonane anhydride was replaced by phenylacetylcarbinol. Received 1.42 g of pale yellow solid, which was immediately used in the next reaction.

(b) 4-(2-(((phenylmethyl)carbonyl)amino)ethyl)aniline.

The above compound was obtained in a manner analogous to that described in example 8, step (b). The oil obtained was immediately used in the next reaction.

(c) N-(4-(2-(((phenylmethyl)carbonyl)amino)ethyl)phenyl)-2 - thiophenecarboxylate.

The above compound was obtained by following the procedure of example 30, step (c). After recrystallization from ethyl acetate/methanol obtained 0.45 g of tan solid, melting point 210-211oC.

Example 33 N-(4-(2-((phenyl)carbonyl)amino)ethyl)phenyl)-2 - thiophencarboxylic

(a) 4-(2-(((phenyl)carbonyl)amino)ethyl) - nitrobenzene.

The above compound was obtained by following the procedure of example 30, step (a), except that triperoxonane anhydride was replaced by benzoyl chloride. Got to 1.77 g of pale yellow solid, the cat who

The above compound was obtained in a manner analogous to that described in example 8, step (b). The oil obtained was immediately used in the next reaction.

(c) N-(4-(2-((phenyl)carbonyl)amino)ethyl)phenyl)-2 - thiophenecarboxylate.

The above compound was obtained by following the procedure of example 30, step (c). After recrystallization from ethyl acetate/methanol received 1.10 g tan solid, melting point 196-197oC.

Example 34 N-(4-(((phenyl)aminocarbonyl)amino)ethyl)phenyl)-2 - thiophenecarboxylate.

(a) N-(4-nitrophenyl)benzoperoxide.

To a stirred solution of benzonitrile (25 ml) was added a catalytic amount of 4-dimethylaminopyridine. To this mixture was added 4-nitroanilide (10.0 g, of 0.57 mol) and the reaction mixture was heated for six hours to 190oC. the Reaction mixture is cooled and added to 25 ml of isopropanol. The solid is collected by filtration, receiving 8.6 g of N-(4-nitrophenyl)benzoquinoneimine, melting point 240-241oC.

(b) N-(4-AMINOPHENYL)benzoperoxide.

In a thick-walled flask for reactions under pressure, downloaded the product of stage (a) (8.6 g, 0,024 mol) in 200 ml of meta and hours; filtration removed the catalyst and boiled away the solvent. To the residue was added 50 ml of isopropanol and 100 ml of ethyl acetate, the solid suspended and then collected by filtration, receiving 10.6 g of N-(4-AMINOPHENYL)benzonorbornadiene. N-(4-AMINOPHENYL)benzonorbornadiene dissolved in 100 ml of water and 20 ml of 50% sodium hydroxide. The aqueous phase was extracted with ethyl acetate (3 100 ml) and dried over magnesium sulfate. After evaporation of the solvent obtained solid product N-(4-AMINOPHENYL)benzoperoxide, the output of 7.6 g

(c) N-(4-(((phenyl)aminocarbonyl)amino)phenyl)-2 - thiophenecarboxylate.

To a stirred suspension of the product of stage (b) (1.1 g, 0,0052 mol) in 5 ml of isopropanol was added S-methyl-2-theoreticalmethodological (the product of example 1, stage (o) (1.5 g, 0,0054 mol) and the reaction mixture was stirred for 48 hours. The solid was collected by filtration, dissolved in a solution containing 100 ml of water and 10 ml of 50% sodium hydroxide, and the aqueous phase was extracted three times with ethyl acetate (100 ml). The organic phase was dried over magnesium sulfate and subsequent evaporation of solvent received crude oil. The crude oil was dissolved in 20 ml of methanol and added hydrochloric gas; when standing, vikri the l)-2-thiophenecarboxylate, were dried for 24 hours over magnesium sulfate, melting point 317-318oC.

Example 35

Using a technique similar to that described in example 34, received the following connections:

(a) N-N ' -(1,4-phenylene)bis-2-thiophenecarboxaldehyde, melting point 278-279oC.

(b) N-N ' -(1,3-phenyl)bis-2-thiophenecarboxaldehyde, melting point 219-220oC.

(c) N-N'-(1,3-phenylene)bis-2-chlorophenyl-carboxypenicillins, melting point 200-201oC.

(d) the Free base N-N-(1,4-phenylene)bis-3-chlorothiophene-2-carboxamide, melting point 247-248oC.

(e) the Free base N-(4-(((2-methoxyphenyl)aminocarbonyl)amino)phenyl-2-thiophenecarboxylate, melting point 187-188oC.

(f) the Free base of N-4-(((phenyl)aminocarbonyl)amino)phenyl)-3-chlorothiophene-2 - carboxamide, melting point 213-214oC.

(q) N-(4-(((phenyl)aminocarbonyl)amino)phenyl)-3 - thiophenecarboxaldehyde, melting point 323-324oC.

(h) N-(3-(((phenyl)aminocarbonyl)amino)phenyl)-2 - thiophenecarboxylate, melting point 295-296oC.

(i) N-(4-(((4-chlorophenyl)aminocarbonyl)amino)phenyl)-2 - thiophenecarboxaldehyde, tomedical, the melting point of 166-167oC.

(k) N-(4-(((4-bromophenyl)aminocarbonyl)amino)phenyl)-2 - thiophenecarboxaldehyde, melting point 236-237oC.

(l) N-(4-(((3-chloro-4-were)aminocarbonyl)amino)phenyl)-2 - thiophenecarboxaldehyde, melting point 294oC.

(m) N-(4-(((3,5-acid)aminocarbonyl)amino)phenyl)-2 - thiophenecarboxaldehyde, melting point 226-227 of theoC.

(n) N-(4-(((3,5-dichlorophenyl)aminocarbonyl)amino)phenyl)-2 - thiophenecarboxaldehyde, melting point 237-238oC.

(o) N-(4-(((phenyl)aminocarbonyl)amino)phenyl)-2-furan - carboxymethyloxime, melting point 210-211oC.

(p) the Free base N-(4-(((3-were)aminocarbonyl)amino)phenyl)-2 - thiophenecarboxylate, the melting point of 205-206oC.

(q) Free base N-(4-(((3-methoxyphenyl)aminocarbonyl)amino)phenyl)-2 - thiophenecarboxylate, melting point 194-195oC.

(r) N-(4-(((3-bromophenyl)aminocarbonyl)amino)phenyl)-2 - thiophenecarboxaldehyde, melting point 293-294oC.

(s) - N-(4-(((3-chlorophenyl)aminocarbonyl)amino)phenyl)-2 - thiophenecarboxaldehyde, melting point 310-311oC.

(t) N-(4-(((P CLASS="ptx2">

(u) N-(4-(((4-chlorophenyl)aminocarbonyl)amino)phenyl)-2 - errorconnectiontimeout, melting point 228-229oC.

Example 36 N-(4-(2-((phenylamino)carbonyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

(a) N-(2-(4-nitrophenyl)ethyl-N'-phenylacetone.

Before the start of the reaction sample to 3.09 g of 4-nitrophenylhydrazine dissolved in 20 ml of water and treated with 30 ml of 2N NaOH. The free base was extracted with 2 75 ml diethyl ether. The ether layer was dried over magnesium sulfate and the volume of ether was reduced under vacuum to ~60 ml. of this solution was added dropwise 1,81 g phenylisocyanate. The white solids that have precipitated when added, mixed for 3 hours, then collected by filtration and washed with simple ether. Air drying has got to 3.67 g of N-(2-(4-nitrophenyl)ethyl)-N'-phenylacetone, melting point 170-172oC.

(b) N-(2-(4-AMINOPHENYL)ethyl)-N'-prilocaine/

In a thick-walled flask for reactions under high pressure loaded to 3.67 g of N-(2-(4-nitrophenyl)ethyl)-N'-prilocaine in 100 ml of a mixture of methanol (THF 50/50 vol.%), added a catalytic amount of 5% Pd/C. the Mixture was first made under hydrogen pressure 3,5155 kg/cm2within 24 hours, the catalyst was filtered, and thin-layer chrom and the obtained solid was combined with methanol and added an excess of oxalic acid. The solution is abruptly cooled by a simple ether, and the precipitated white solids were collected by filtration. The solid was treated with 100 ml 2N NaOH, and was extracted with ethyl acetate free base; the organic layer was dried with magnesium sulfate and boiled away, getting a yellow solid, N-(2-(4-AMINOPHENYL)ethyl-N'-phenylacetone (430 mg).

(c) N-(2-(((phenylamino)carbonyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

To a solution of 430 mg of N-(2-(4-AMINOPHENYL)ethyl-N'-phenylacetone, suspendirovanie in 3 ml of isopropyl alcohol was added 435 mg S-methyl-2-theoreticalmethodological (the product of example 1, stage (d)). The mixture was stirred for 16 hours at room temperature. The suspension was diluted in 25 ml of isopropyl alcohol, and the solids were collected by filtration, receiving a yellow-tan solid. The solid was recrystallize from methanol/simple ether. Two portions were collected and combined to obtain 470 g N-(4-(2-(((phenylamino)carbonyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 216-219oC.

Example 37

In a manner analogous to that shown in example 36, received the following connection:

N-(4-(2-(((phenylamino)carbonyl)oxy)SEEIT)methyl)phenyl)-2 - thiophenecarboxylate.

(a) 4-((bis(phenylmethyl)amino)methyl)nitrobenzene.

To 4-nitrobenzylamine (1,61 g, or 10.60 mmol) in DMF (25 ml) was added potassium carbonate (3,32 g, 23,30 mmol), then benzylbromide (2,64 ml, 22,30 mmol). The mixture was mixed for 2 days, dropped in the water and was extracted with ethyl acetate (3 50 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and subjected to chromatography on silica gel (20% ethyl acetate/hexane) to yield 4-((bis(phenylmethyl)amino)methyl)nitrobenzene: (1.64 g, 47%); M. S. (M+H)+= 333.

(b) 4-((bis(phenylmethyl)amino)methyl)aniline.

The product of stage (a) (0.56 g, was 1.69 mmol) in AcOH (15 ml) was added chloride dihydrate tin (II) (2.00 g, of 19.03 mmol), and then concentrated HCl (5 ml). The mixture was mixed for 20 hours, cooled to 0oC, abruptly cooled 50% NaOH and was extracted with ethyl acetate (3 50 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and subjected to chromatography on silica gel (30% ethyl acetate/hexane) to yield 4-((bis(phenylmethyl)amino)methyl)aniline: (0,29 g, 57%); M. S. (M+H)+= 303.

(c) N-(4-((bis(phenylmethyl)amino)methyl)phenyl)-2 - thiophenecarboxylate.

To a solution of the product of stage (b) (0.28 g, of 0.93 mmol) was isopropanolamine within 14 hours abruptly cooled 2N NaOH (2 ml) and was extracted with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to get a solid, which was recrystallize from ethyl acetate/hexane to yield N-(4-((bis(phenylmethyl)amino)methyl)phenyl)-2 - thiophenecarboxaldehyde in the form of a white solid (86 mg, 22%); melting point 127-128oC.

Example 39

Following the method similar to that presented in example 8, received the following compound: N-(4-(2-aminomethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 188-189oC.

Example 40

N-(3-(1,2,3,4-tetrahydroisoquinoline-2-ylmethyl)phenyl-2 - thiophenecarboxaldehyde.

(a) 3-(1,2,3,4-tetrahydroisoquinoline-2-yl-methyl)nitrobenzene.

To 3-nitrobenzylamine (2.00 g, 11,66 mmol) in DMF (25 ml) was added potassium carbonate (1,93 g, 13,96 mmol), then tetrahydroisoquinoline (1.55 g, 11,66 mmol). The mixture was mixed for 4 hours, dropped in the water and was extracted with ethyl acetate (3 50 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to obtain oil. The oil was dissolved in a simple ether and treated 1PA/HCl to obtain 3-(1,2,3,4-b) 3-(1,2,3,4-tetrahydroisoquinoline-2-yl-methyl)religitard.

To a stirred solution of the product of stage (a) (1,00 g, 3,29 mmol) in THF/MeOH (100 ml, 1:1) was added catalytic amount of 10% Pd/C. the Mixture was first made in the course of 0.5 hour at a pressure of 3,5155 kg/cm2was filtered through celite and concentrated to obtain 3-(1,2,3,4-tetrahydroisoquinoline-2-yl-methyl)bilingualised, which was homogeneous by thin-layer chromatography, and immediately used in the next reaction.

(c) N-(3-(1,2,3,4-tetrahydroisoquinoline-2-yl-methyl)phenyl)-2 - thiophenecarboxylate.

To a solution of the product of stage (b) (0,90 g, 3,29 mmol) in isopropanol (3 ml)/DMF (1 ml) was added S-methyl-2-theoreticalmethodological (the product of example 1, stage (d)) (0,94 g, 3,29 mmol). The mixture was mixed for 14 hours, sharply cooled 2N NaOH (2 ml) and was extracted with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered and subjected to chromatography on silica gel (8% methanol/methylene chloride) to yield the named compound as free base. Processing 1PA/HBr received N-(3-(1,2,3,4-tetrahydroisoquinoline-2-yl-methyl)phenyl)-2 - thiophenecarboxylate in the form of a white solid: (0.26 g, 16%); melting point (Razlog.) > 179oC.

Example 41

N-(4-(4-((fenil is.

A sample of 4-(4-nitrophenyl)butyric acid, 2,09 g, dissolved in 20 ml of dichloromethane was treated with benzylamine, 1.07 g, having suspended solid particles. The mixture was treated with diphenylphosphorylacetate, 2,75 g, and 20 ml of dioxane, and after stirring for 4 hours, it became transparent. The mixture was diluted with 100 ml ethyl acetate and washed twice with 100 ml of 2M potassium carbonate, then with 100 ml of 1M hydrochloric acid. The organic layer was dried with magnesium sulfate and boiled away to obtain solid particles. The solids were dissolved in 150 ml of cyclohexane and 50 ml of ethyl acetate and cooled to obtain white solids; the solids were collected by filtration and dried in air to obtain 4-(4-nitrophenyl)-N-(phenylmethyl)butylamide, the melting point of 133-135oC.

(b) 4-(4-AMINOPHENYL)-N-(phenylmethyl)butylimidazole.

A sample of the product of stage (a), 0,80 g, in 20 ml ethanol and 20 ml of ethyl acetate was treated with 0.4 g of 5% palladium on carbon and subjected to hydrogen pressure 3,5155 kg/cm2. After 1 hour, thin layer chromatography showed a new spot, P 0.2 with 15% acetone in methylene chloride. The mixture is boiled away dryness and then treated with 30 ml of toluene. The residue was dissolved in 10 ml) and treated with 4 ml of 1M lithium aluminum hydride in TNG, receiving transparent R is sodium sulfate. After stirring for 30 minutes the mixture was filtered and treated with hydrochloric gas, formed oil. The mixture was treated with 3 ml of isopropanol and then hydrochloric gas, got a solid particle. The mixture was cooled to -20oC for 2 hours, then filtered and air-dried to obtain 4-(4-AMINOPHENYL)-(phenylmethyl)butylimidazole.

Analysis of chloride: calculated 20,78; found 20,64.

(c) 4-(4-((phenylmethyl)amino)butyl)aniline)dihydrochloride.

A sample of the product of stage (b) suspended in 5 ml TNG (Aldrich), receiving a clear solution. The mixture was heated in a flask under reflux for 5 hours, then cooled. The obtained solid mass was diluted with diethyl ether 20 ml) and then dropwise added 1 ml of 2M sodium hydroxide, then 4 cm2anhydrous sodium sulfate. After stirring for 15 minutes the mixture was filtered and the solids washed with 20 ml of diethyl ether. Mixed filtrate was treated with hydrochloric gas and kept at room temperature. The resulting solids were collected by filtration and dried in vacuo to obtain 4-(4-((phenylmethyl)amino)butyl)aniline)dihydrochloride; analysis of chloride: calculated: 2P> A sample of the product of stage (c) 0.50 g and S-methyl-2-thiophenecarboxaldehyde (the product of example 1, stage (d)) of 0.44 g were mixed in 4 ml of isopropanol and heated to 60oC. After 2 hours, thin-layer chromatography using 15% methanol in chloroform on silica showed that the starting aniline was mostly spent and that there was a new spot lower Rf. The mixture was diluted with 20 ml of 1M potassium carbonate and was extracted with ethyl acetate. The ethyl acetate extract was dried 10 g of potassium carbonate and treated 0,150 g of maleic acid, getting a sticky residue. Thin layer chromatography of sediment in comparison with the supernatant liquid showed that the precipitate was a mixture of the original amine and the product and that the supernatant contained mainly the product. Then the supernatant was processed again 0,150 g of maleic acid, getting a sticky residue, and the remaining supernatant was decanted. The solids were dissolved in 5 ml of methanol and besieged 100 ml diethyl ether. The obtained adhesive residue was treated with 1 ml of water, diluted with acetone to 200 ml and receive a clear solution was diluted with diethyl ether to 275 ml and cooled to -20oC. filtering the collected solids washed is amygdaleta, the melting point of 104-106oC.

Example 42 N-(4-(((2-thiophenyl)iminomethyl)amino)methyl)phenyl)-2 - thiophenecarboxaldehyde.

(a) 4-aminotetralin.

To a solution of 4-nitrobenzenesulfonamide (9.0 g, 0,0477) in methanol (200 ml) was added 20 ml of 1PA/HCl and a catalytic amount of 10% palladium on carbon.

The mixture was first made in the course of 4 hours at a pressure of 3,5155 kg/cm2was filtered through celite, concentrated to solids. Then the solid is dissolved in 300 ml of water and 20 ml of 2N sodium hydroxide and was extracted into methylene chloride (3 100 ml). Mixed extracts were dried over magnesium sulfate, filtered and concentrated to obtain 4-aminomethylpyridine in the form of oil (6,1 g).

(b) N-(4-(((2-thiophenyl)iminomethyl)amino)methyl)phenyl)-2 - thiophenecarboxaldehyde.

To a stirred solution of 4-aminomethylpyridine (1.6 g, 0,0013 mmol) in dimethylformamide (10 ml) and isopropanol (10 ml) was added N-methyl-2-theoreticalmethodological (the product of example 1, stage (d)) (4.4 g, 0.015 mmol). The mixture was heated for 72 hours before the 40oC. the Reaction mixture was diluted with 20% aqueous solution of sodium hydroxide and filtering the collected particulate matter (2.5 g). Of isopropanol and methanol is opencomponentlibraryts, the melting point of 200-201oC.

Example 43

In a manner analogous to that shown in example 17, received the following connections:

(a) N-(3-(3-(1-pyrrolidinyl)propyl)phenyl)-phenylcarbonylamino, melting point 138-139oC.

(b) the Free base N-(4-(2-((4-methoxyphenethyl)amino)ethyl)phenyl)-2-thiophenecarboxylate, the melting point of 144-145oC.

(c) N-(4-(2-((4-methylphenylethyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 225-226oC.

(d) N-(3-(2-((3-phenylpropyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 183-186oC.

(e) Free base N-(3-(2-(2-methylphenylethyl)amino) ethyl)phenyl)-2-thiophenecarboxylate, melting point 114-116oC.

(f) N-(4-(2-((1-indanyl)ethyl)amino) phenyl)-2-thiophenecarboxaldehyde, melting point 95oC (Razlog.).

(g) N-(4-(2-(((4-pyridyl)methyl)amino)ethyl) phenyl)-2-thiophenecarboxaldehyde, melting point > 250oC.

(h) N-(4-(2-(((2-thienyl)methyl)amino)ethyl) phenyl)-2-thiophenecarboxaldehyde, melting point 226-227 of theoC.

Example 44 N-(3-(2-((2-phenylethyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde heated in a flask under reflux in 25 ml of thionyl chloride. The solvent was boiled away, and the rest before adding dropwise at 0oC 3.51 g (0,290 mol) of phenethylamine placed in 50 ml of THF. The mixture was stirred for 48 hours and filtered cleaners containing hydrochloride salt of the amine as a white solid. Boiled away the wash water, while leaving N-(2-phenylethyl)-3-nitrophenylacetate, dull orange oil, 4,48, the Product was analyzed M. S. (mass spectrometry) and NMR (nuclear magnetic resonance).

(b) N-(2-phenylethyl)-2-(3-nitrophenyl)ethylamine.

To a stirred solution of the product of stage (a), 4,48 g (0,0158 mol) in 80 ml of dry THF was added 47,7 ml of 1M borane/THF. The mixture was heated in a flask under reflux for 3 hours, cooled and carefully added 10 ml of methanol, followed by 20 ml of 4N HCl. The solution was concentrated by evaporation under vacuum, this was a reddish liquid. 2M NaOH increased the basicity of oil, and the product was extracted with 3 50 ml EtOAc. The organic layers were combined, dried over magnesium sulfate and boiled away, leaving the oil. The oil was dissolved in a solution of HCl/isopropanol. Formed white solids, which were collected by filtration, receiving N-(2-phenylethyl)-2-(3-nitrophenyl)ethylamine, melting point 196-200oC.

(c) N-(2-phenylethyl)-N-(2-(3-nedobili 1,99 g (0,0197 mol) of triethylamine and before adding dropwise 21,34 g (0,111 mol triperoxonane anhydride mixture cooled. After 45 minutes the mixture is abruptly cooled 50 ml of water, and the product was extracted with 3 50 ml dichloromethane. Organic layers were mixed, dried over magnesium sulfate and boiled away, leaving the 3.3 grams of N-(2-phenylethyl)-N-(2-(3-nitrophenyl)ethyl)trifurcated in the form of butter.

(d) N-(2-phenylethyl)-N-(2-(3-AMINOPHENYL)ethyl)triptorelin.

To a solution of the product of stage (c), 3.3 grams in 75 ml of THF and 75 ml of methanol was added a catalytic amount of 10% Pd on carbon. After 1 hour under pressure 3,5155 kg/cm2the reaction was completed. The catalyst was filtered, and boiled away the solvent, leaving the 2,88 g of N-(2-phenylethyl)-N-(2-(3-AMINOPHENYL)ethyl) trifurcated in the form of butter.

(e) N-(3-(2-((2-phenylethyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

To a solution of product (d) is 2.88 g (0,00857 mol) in 15 ml of isopropanol was added to 2.94 g of S-methyl-2-theoreticalmethodological (the product of example 1, stage (d)). The mixture was mixed at room temperature for 16 hours, then the solid yellow precipitate was filtered and threw. Wash water has boiled away, and the residue was dissolved in minimum quantity of methanol; 2M NaOH increased the basicity of the solution and heating it for 30 minutes prior to the 50oC. the Product was extracted with 3 50 ml of ethyl acetate, about the lo. The free base was dissolved in isopropanolate solution of HBr. Solid particles formed by adding ethyl acetate and cooled, collected by filtration, receiving 102 mg N-(3-(2-((2-phenylethyl)amino)ethyl)phenyl)- 2-thiophenecarboxaldehyde salt, the melting point of 137-139oC.

Example 45

Following a methodology similar to that presented in example 44, received the following connections:

(a) N-(4-(2-(aminoethyl)phenyl)-2 - errorconnectiontimeout, melting point 145oC (Razlog.).

(b) (S)-N-(4-(2-((1-phenylethyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 197oC (Razlog.).

(c) the Free base of (R)-N-(4-(2-((1-phenylethyl)amino)ethyl)phenyl)-2 - thiophenecarboxylate, melting point 92-94oC.

(d) N-(3-(2-((4-phenylbutyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 136-139oC.

Example 46

N-(4-(((phenylmethoxy)carbonyl)aminomethyl)phenyl)-2 - thiophenecarboxaldehyde.

(a) 4-(((phenylmethoxy)carbonyl)aminomethyl)nitrobenzene.

Sample 4-nitrobenzimidazole, 5 g, and 200 ml of water was treated with 10 g of sodium bicarbonate. The mixture was treated with 50 ml of ethyl acetate and then 4 is a walkie-talkie. The crude product was dissolved in 150 ml of hot methanol, filtered, diluted with 250 ml of water and cooled. The obtained solids were collected, receiving 4-(((phenylmethoxy)carbonyl)aminomethyl)nitrobenzene, melting point 92-93oC.

(b) 4-(((phenylmethoxy)carbonyl)aminomethyl)aniline.

The product of stage (a), 6.0 g, was treated with 10 ml of acetic acid and 100 ml of methanol. The mixture was treated with platinum sulfide on carbon, 0.97 g, when the hydrogen pressure 3,5155 kg/cm2; after 20 hours the mixture was filtered and boiled away in a vacuum. The residue was dissolved in 50 ml of simple ether and diluted with hexane to 200 ml. of the mixture is Then mixed for five days and filtered to obtain 4-(((phenylmethoxy)carbonyl)aminomethyl)aniline, melting point 60-64oC.

(C) N-4-(((phenylmethoxy)carbonyl)aminomethyl)phenyl)-2 - thiophenecarboxaldehyde.

The product of stage (b), 0,89 g, and S-methyl-2 - theoreticalmethodological (the product of example 1, stage (d)), 1.0 g, was mixed in 6 ml of isopropanol and mixed with 30oC. After 4 hours the mixture was besieged by a simple ester, got a sticky solid particles that are placed in 100 ml of hot water, treated with telicom and filtered. The mixture was cooled, having an adhesive solid particles, Kili to -20oC. the mixture is Then treated with hexane. The mixture is boiled away in vacuum and the crude free base, 0.7 g, was dissolved in 40 ml of warm isopropanol and treated with 0.26 g of oxalic acid dihydrate. Upon cooling and processing 150 ml simple ether formed a sticky residue. After stirring for overnight at room temperature the obtained solids were collected by filtration, receiving N-((4-((phenylmethoxy)carbonyl)aminomethyl)phenyl)-2 - thiophenecarboxaldehyde, the melting point of 150-160oC.

Example 47

N-(4-((2-(phenylmethyl)amino)ethoxy)phenyl)-2 - thiophenecarboxaldehyde.

(a) 4-(nitrophenoxy-N-(phenylmethyl)ndimethylacetamide.

A sample of 4-(nitrophenoxy-N-(phenylmethyl)ndimethylacetamide acetic acid (Lancaster), 4,22 g, was treated with 20 ml of 1M aqueous HCl and 200 ml of ethyl acetate. The mixture was cooled to 10oC and then for 2 minutes added to 1.38 g of sodium nitrate in 20 ml of water. The mixture was mixed for 5 minutes, salt separated, and the ethyl acetate layer was dried with sodium sulfate. The ethyl acetate solution was treated with 5 ml of benzylamine that led to the rapid formation of sludge. After 20 minutes the mixture was washed with 100 ml saturated sodium carbonate, then with 100 ml 1M HCl (aqueous solution). Then boiled away the word what, the ri has received 3,76 g of 4-(nitrophenoxy-N-(phenylmethyl)ndimethylacetamide, melting point 125-126oC.

(b) 4-(aminophenoxy-N-(phenylmethyl)ndimethylacetamide.

A sample of the product of stage (a), 3,74 g, was placed in 100 ml of methanol and 100 ml of ethyl acetate. The mixture was treated with 0.4 g of 10% palladium on carbon and subjected to hydrogen pressure 3,5155 kg/cm2. After 1 hour the mixture was filtered and concentrated in vacuum, while crude 4-(aminophenoxy-N-(phenylmethyl)ndimethylacetamide; calculated: C 70,29; H 6,29; N of 10.93; found: C 69,97; H 6,3; N 10,90.

(c) 4-(2-((phenylmethyl)amino)ethoxy)aniline.

A solution of 3.2 g of the product of stage (b) in 40 ml of dry THF under nitrogen was treated with 40 ml of 1M DIBORANE in THF. The mixture was heated in a flask under reflux for 3 hours, treated with 40 ml of 6M aqueous HCl and heated in a flask under reflux for 2 hours. The filtrate was concentrated under vacuum to 150 ml of Turbid mixture was treated with 100 ml of crushed ice and neutralized with 50% NaOH, and the resulting finely ground solids were collected, washed with water and dried by infrared radiation to obtain 4-(2-((phenylmethyl)amino)ethoxy)aniline, MS = 243,98%, as was found by capillary electrophoresis.

(d) N-(4-(2-((phenylmethyl)amino)ethoxy)hair dryer is anticorrosivematerial (the product of example 1, stage (d)), 1.42 g, were mixed in 100 ml of isopropanol and mixed for 7 hours at room temperature. The obtained white solids were collected by filtration, washed with 10 ml of isopropanol and dried in vacuum, while white solid N-(4-(2-((phenylmethyl)amino)ethoxy)phenyl-2 - thiophenecarboxaldehyde, the melting point of 193-195oC.

Example 48

N-[4-(((diphenylamino)carbonyl)amino)phenyl] -2 - thiophenecarboxaldehyde.

(a) 4-[diphenylamino(carbonyl)amino]aniline.

To a stirred solution of 1,4-phenylenediamine (1,00 g, a 9.25 mmol) and triethylamine (1,29 ml, a 9.25 mmol) in methylene chloride (50 ml) was added diphenylcarbamate (2.14 g, a 9.25 mmol). After stirring for 14 hours, the mixture was dumped into water and extracted with methylene chloride (3 20 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered, concentrated and plunged chromatography on silica gel (80% ethyl acetate/hexane) to yield 4-[diphenylamino(carbonyl)amino]aniline: (0,49 g, 17%); M. S. (M+H)+= 304.

(b) N-[4-(((diphenylamino)carbonyl)amino)phenyl] -2 - thiophenecarboxaldehyde.

To a solution of the product of stage (a) (0,49 g of 1.62 mmol) in isopropanol (10 ml) was added S-methyl-2 - thiophene is 48 hours dropped in alkaline water and was extracted with ethyl acetate (3 30 ml). Mixed extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to obtain oil. Processing 1PA/HCl was obtained N-[4-(((diphenylamino)carbonyl)amino)phenyl]-2 - thiophenecarboxaldehyde in the form of a white solid: (24 mg, 3.3 percent); melting point 210-211oC.

Example 49

N-(3-(benzoyl)amino)phenyl)-2-thiophenecarboxaldehyde.

(a) N-(3-nitrophenyl)benzamide.

To a solution of 7.5 g (54 mmol) of 3-nitroaniline in two-phase solution consisting of 100 ml of methylene chloride and 100 ml of 20% potassium carbonate was added dropwise to 6.0 ml (52 mmol) of benzoyl chloride in 25 ml of methylene chloride. The reaction mixture stood overnight, and the organic phase is separated and washed with diluted hydrochloric acid. The solvent was concentrated to obtain a 3.83 g (32%) of the named compound, MS: 243 (M+H).

(b) N-(3-AMINOPHENYL)benzamide.

This compound was obtained following the method similar to that presented in example 30, step (b), MS 213 (M+H).

(c) N-(3-benzoyl)amino)phenyl)-2 - thiophenecarboxaldehyde.

This compound is obtained by following the procedure of example 30, step (b). The free base prevrat criminalidade.

(a) N-(3-nitrophenyl)benzamide.

This compound was obtained following the method similar to that presented in example 49, step (a), MS: 243 (M+H).

(b) N-(4-AMINOPHENYL)benzamide.

This compound was obtained following the method similar to that presented in example 30, step (b), MS 213 (M+H).

(c) N-(4-((benzoyl)amino)phenyl)-2 - thiophenecarboxaldehyde.

This compound is obtained by following the procedure of example 26, step (b) and recrystallize from water, the melting point 234-235oC.

Example 51

N-(3-(((phenylamino)carbonyl)amino)phenyl)-2 - thiophenecarboxaldehyde.

(a) N-phenyl-N'-(3-nitrophenyl)urea.

To a solution of 54.0 g (36 mmol) of m-nitroaniline in 40 ml of simple ether was added 5.0 ml (47 mmol) of phenylisocyanate. The solution was mixed for 6 hours. The product was filtered to obtain 9.2 grams (99%) of the named compound, MS: 258 (M+H).

(b) N-phenyl-N'-(3-AMINOPHENYL)urea.

This compound was obtained following the method similar to that presented in example 30, step (b). The suspension of the selected product in a simple ether resulted in the formation of solid product, melting point 199-202oC.

(c) N-(3-(((fenelli the e of example 30, stage (c). The free base was converted into the oxalate salt in isopropanol, 208-210oC.

Example 52 N-(3-(((4-phenoxybutyl)amino)carbonyl)phenyl)-2 - thiophenecarboxaldehyde.

(a) 3-nitro-N-(4-phenoxybutyl)benzamide.

This compound was obtained following the method similar to that presented in example 49, step (a), MS 315 (M+H).

(b) N-((3-(4-phenoxybutyl)amino)carbonyl)religitard.

A solution of 7.8 g (25 mmol) of N-4-phenoxybutyl-3-nitrobenzamide and 1 g of 5% palladium on carbon in 120 ml of isopropanol with the addition of hydrogen chloride was first made in the course of 3 hours at a pressure of 3,164 kg/cm2. The catalyst was filtered, and the solvent was concentrated, receiving 6.7 g (84%) of the named compound, MS: 285 (M+H).

(c) N-(3-(((4-phenoxybutyl)amino)carbonyl)-2 - thiophenecarboxaldehyde.

The above compound was first converted into the free base and, using the method of example 30, step (c), has been named connection. Then the free base of the titled compound was converted into the oxalate salt in isopropanol, MS: 349 (M+H), melting point 154-156oC.

Example 53

N-(3-(((4-phenylbutyl)amino)carbonyl)phenyl)-2 - thiophenecarboxylate, similar to the one presented in example 49, step (a), MS: 299 (M+H).

(b) 3-amino-N-(4-phenylbutyl)benzenedithiol.

This compound was obtained following the method similar to that presented in example 52, step (b), 273 MS (M+H).

(c) N-3-(((4-phenylbutyl)amino)carbonyl)phenyl)-2 - thiophenecarboxaldehyde.

This compound is obtained by following the procedure of example 30, step (c), except that in addition has added the equivalent of triethylamine. The free base was converted into the oxalate salt in isopropanol, MS: 376 (M+H), melting point 118-120oC.

Example 54

N-4-(((benzyl)amino)carbonyl)methyl)phenyl)-2 - thiophenecarboxylate.

(a) N-benzyl-(4-nitro)phenylacetamide.

This compound was obtained following the method similar to that presented in example 49, step (a), the melting point 172-182oC.

(b) N-benzyl-(4-amino)phenylacetamido.

This compound is obtained by following the procedure of example 17, step (d), melting point 137-140oC.

(c) N-(4 -(((( benzyl)amino)carbonyl)methyl)phenyl)-2 - thiophenecarboxylate.

This compound is obtained by following the procedure of example 30; stage (c), the melting point 257-161oC.

To a solution of 3.12 g (43,9 mmol) pyrrolidine in two-phase solution consisting of 100 ml of methylene chloride and 100 ml of 20% potassium carbonate was added dropwise to 7.3 g (to 36.5 mmol) of 4-nitrophenylacetonitrile in 25 ml of methylene chloride. The reaction mixture stood overnight, and the organic phase is separated and washed with diluted hydrochloric acid. The solvent was concentrated to obtain of 6.26 g (73%) of the named compound, melting point 103-105oC.

(b) 4-(2-(1-pyrrolidinyl)ethyl) - nitrobenzene.

This compound is obtained by following the procedure of example 17, step (c), MS: 221 (M+H).

(c) 4-(2-(1-pyrrolidinyl)ethyl)aniline.

This compound is obtained by following the procedure of example 34, stage (c), MS 191 (M+H).

(d) N-(4-(2-(1-pyrrolidinyl)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

This compound is obtained by following the procedure of example 18, step (b). Dihydrobromide salt crystallized from isopropanol and simple ester, MS: 300 (M+H).

Example 56

N-(4-(2-(1-piperidinyl)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

(a) N-piperidinyl-(4-nitrophenyl)acetic acid.

This compound is obtained by following the procedure of example 55, step (a), the melting point of 105-107oC.

(b) N-(4-(2-(1-PI

(c) N-(4-(2-(1-piperidinyl)ethyl)aniline.

This compound is obtained by following the procedure of example 34, stage (c). Cleaners containing hydrochloride salt was converted to free base in the form of oil, MS 205 (M+H).

(d) N-(4-(2-(1-piperidinyl)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

This compound is obtained by following the procedure of example 34, stage (d). Dihydrochloride salt crystallized from propanol and simple ester, melting point 256-261oC.

Example 57

N-(4-(3-(1-pyrrolidinyl)propyl)phenyl)-2 - thiophenecarboxaldehyde.

(a) N-pyrrolidinyl-(4-nitrophenyl)propenamide.

This compound is obtained by following the procedure of example 55, step (a), MS 247 (M+H).

(b) 4-(2-(1-((pyrrolidinyl)carbonyl)ethyl)aniline.

This compound is obtained by following the procedure of example 34, stage (c), MS 219 (M+H).

(c) 4-(3-(pyrrolidinyl)propyl)aniline)dihydrochloride.

This compound is obtained by following the procedure of example 17, step (c). Dihydrochloride salt crystallized from ethanol, the melting point 262-265oC.

(d) N-(4-(3-(1-pyrrolidinyl)propyl)phenyl)-2 - thiophenecarboxaldehyde.

This compound is obtained by following the procedure of example 18, step (b). Dioxalate who drank)phenyl)-2 - thiophenecarboxaldehyde.

(a) N-piperidinyl-(4-nitrophenyl)propenamide.

This compound is obtained by following the procedure of example 55, step (a). The melting point 168-171oC.

(b) 4-(2-(1-((piperidinyl)carbonyl)ethyl)aniline.

This compound is obtained by following the procedure of example 34, stage (c), MS 233 (M+H).

(c) 4-(2-1-((piperidinyl)propyl)aniline.

This compound is obtained by following the procedure of example 17, step (c), the melting point 180-185oC.

(d) N-(4-(3-(1-((piperidinyl)propyl)phenyl)-2 - thiophenecarboxaldehyde.

This compound is obtained by following the procedure of example 17, step (e). From ethanol and ethyl acetate received dioxalate salt, MS: 328 (M+H).

Example 59

N-(4-(2-(2-(1,2,3,4-tetrahydro)ethanolic)ethyl)phenyl-2 - thiophenecarboxaldehyde.

(a) 4-nitro-N-(2-ethanolic)phenylacetamide.

To a solution of 4-nitrophenylarsonic acid (5,43 g, 930 mmol) and 1,2,3,4-tetrahydroisoquinoline (5.6 g, 42 mmol) in methylene chloride (200 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (6,13 g, 32 mmol). The reaction mixture was mixed for 18 hours. The reaction mixture is washed with diluted hydrochloric acid and dilute sodium hydroxide, dried, and the solvent koncentrirane the melting points 137-139oC.

(b) N-(4-(2-(2-(1,2,3,4-tetrahydro)ethanolic)ethyl) - nitrobenzene.

This compound is obtained by following the procedure of example 17, step (c), the melting point 97-102oC.

(c) N-(4-(2-(2-(1,2,3,4-tetrahydro)ethanolic)ethylaniline.

This compound is obtained by following the procedure of example 34, stage (c), melting point 300oC (Razlog.).

(d) N-(4-(2-(2-(1,2,3,4-tetrahydro)ethanolic)ethyl)phenyl)-2 - thiophenecarboxaldehyde

This compound is obtained by following the procedure of example 18, step (b). From ethanol and ethyl acetate received dihydrobromide salt, MS: 362 (M+H).

Example 60

Free base N-(4 -(((( phenylmethyl)amino)methyl - carbonyl)amino)phenyl)-2-thiophenecarboxylate.

(a) N-(4-nitrophenyl)-2-chloracetamide.

4-nitroaniline (13.8 g) in ethyl acetate (200 ml) was treated with triethylamine (15 ml) and then portions processed by chloroacetylation (8 ml). The resulting mixture was mixed for 10 minutes. The mixture is then treated with water (200 ml) and ethyl acetate (100 ml). The mixture was heated up until dissolve all solids, and the layers were separated. Then layer acetylacetone was concentrated to 100 ml by heating and cooled to room temperature. The next day, the mixture Hotfile is tumida, the melting point of 183-185oC.

(b) 4 -(((( phenylmethyl)amino)methylcarbamoyl)amino)nitrobenzene.

Connection stage (a) (4,28 g) and benzylamine (2.5 ml) were mixed in DMF with potassium carbonate (3.2 g) was mixed at room temperature for 3 hours. Was filtered solids and washed with methanol (2 10 ml). Mixed filters slowly diluted with water to 150 ml, receiving yellow solids, which were collected by filtration and dried in the air, receiving 4 -(((( phenylmethyl)amino)methylcarbamoyl)amino)nitrobenzene, MS 286 (M + H).

(c) 4 -(((( phenylmethyl)triptoreline)amino)methylcarbamoyl)amino) nitrobenzene.

Connection stage (b) (4.9 g), triperoxonane anhydride (2.5 ml) and triethylamine (2.5 ml) were mixed in ethyl acetate (50 ml) and the mixture with suspended particles heated up all night until 50oC. the mixture is Then washed with water (50 ml), filtered to remove solids, and boiled away the layer of ethyl acetate. The residue was placed in a simple ester (151 ml) and cooled to -20oC all night. The solids were collected by filtration, receiving 4 -(((( phenylmethyl)trifluoromethyl)carbonyl)amino)methylcarbamoyl)amino) nitrobenzene, MS (M+H) = 282.

(d) 4 -(((( phenylmethyl)triptoreline)amino) was methylcarbazole when the pressure 3,5155 kg/cm2within 4 hours of palladium on carbon. The mixture was filtered and boiled away in vacuum, obtaining the white solids 4 -(((( phenylmethyl)trifluoromethyl)carbonyl)amino)methylcarbamoyl)amino) aniline, MS (M+H) = 352.

(e) the Free base of N-4 -(((( phenylmethyl)amino)methylcarbamoyl)amino)phenyl)-2 - thiophenecarboxylate.

Connection stage (d) (1,05 g) and S-methyl-2 - theoreticalmethodological (the product of example 1, stage (o)) of 0.85 g) was treated with methanol (2 ml). After 15 minutes, the solids were dissolved, and the mixture was purged with nitrogen to remove methanethiol. Thin layer chromatography using 10% isopropanol in chloroform on silica showed a new spot lower Rf and that the starting amine had been consumed.

The mixture was dissolved in methanol (6 ml) and treated with potassium carbonate (1.1 g). Thin-layer chromatography using 15% methanol in chloroform on silica showed that the hydrolysis is not complete, so I added an additional amount of potassium carbonate, 1,1, After 2 hours the conversion was completed and the mixture to remove solid particles filtered out. The next day, the filtrate was treated with 0.65 g of maleic acid, diluted simple ether and stirred overnight. The collected TV the layer was treated with 1M potassium carbonate and was extracted with ethyl acetate. The ethyl acetate was boiled away in vacuum, and the residue was placed in 20 ml of methanol.

The solution was slowly treated with water to until dissolved solids. The solids were collected by filtration and dried under vacuum at 40oC to obtain the free base of N-4 -(((( phenylmethyl)amino)methylcarbamoyl)amino)phenyl)-2 - thiophenecarboxaldehyde, melting point 161-163oC.

Example 61

N-(4-(2-(((2-furanyl)methyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

(a) 4-nitrophenylacetylene.

To 4-nitrophenylarsonic acid (30 g) was added thionyl chloride (100 ml). The mixture was heated in a flask with reflux condenser under nitrogen and was stirred for 2 hours. The excess thionyl chloride are boiled away under vacuum and the remaining oil azeotrope dried toluene. Got a 4-nitrophenylacetylene (35 g).

(b) 4-(2-(((2-furanyl)methyl)amino)ethyl)nitrobenzonitrile.

To a stirred solution of furfurylamine (1,32 g) in methylene chloride (125 ml) was added triethylamine (2,36 ml) and then dropwise added a solution of compound of stage (a) (3.0 g) in methylene chloride (10 ml). The mixture was mixed at 0oC for 15 minutes. The mixture was poured into water (150 ml), and methylene chloride (2 100 ml) ekstragirovanie particles was placed in a solution of 7% methanol/methylene chloride and purified on silicagel column during elution with the same solvent. The product was collected and concentrated. The solid was placed in THF (50 ml) and treated with 1M borane/THF (50 ml). The solution was heated in a flask under reflux for 15 hours. The mixture was cooled to 0oC and slowly added 4N hydrochloric acid. The mixture was re-heated in a flask with reflux condenser and mixed for 4 hours. Excess acid and THF boiled away under vacuum and the remaining suspension was placed in water (100 ml) and ethyl acetate (100 ml), 50% sodium hydroxide increased the basicity and were extracted with ethyl acetate (3 125 ml). The organic layers were collected, dried (MgSO4), filtered and concentrated. The crude product was dried in silicagel column during elution with 10% methanol/methylene chloride. The product was collected and concentrated. The remaining solids were placed in isopropyl alcohol (25 ml) and treated with saturated 1PA/HCl (10 ml). White particles was filtered and washed with isopropyl alcohol, receiving 4-(2-(((2-furanyl)methyl)amino)ethyl)nitrobenzonitrile (2.9 g).

(c) 4-(2-(((2-furanyl)methyl)amino)ethyl)religitard.

To a stirred solution of compound of stage (b) (2,46 g) in acetic acid (100 ml) was added in one portion (3.3 grams) of zinc dust. The mixture was mixed for 10 minutes. Zinc AHP crystal growth is acetate (100 ml), 50% sodium hydroxide increased the basicity and were extracted with ethyl acetate (3 125 ml). The organic layers were collected, dried (MgSO4), filtered and concentrated. The remaining oil was placed in isopropyl alcohol (25 ml) and treated with saturated 1PA/HCl (10 ml). The white solids were filtered and washed with isopropyl alcohol, receiving 4-(2-(((2-furanyl)methyl)amino)ethyl) anyindividual (1.50 g).

(d) 4-(2-(((2-furanyl)methyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

To a stirred suspension of the compound of stage (c) (1.5 g) in DMF (15 ml) was added pyridine (0,42 ml), then S-methyl-2 - theoreticalmethodological (the product of example 1, stage (d)) (1.51 g). The mixture was heated to 50oC and mixed for 48 hours. The mixture is then diluted in 100 ml of water and excess 50% sodium hydroxide increased the basicity. The crude product was extracted with ethyl acetate (3 100 ml). The organic layers were collected and washed with water. The organic layer was dried (MgSO4), filtered and concentrated. The crude product was purified on silicagel column during elution with 20% methanol/methylene chloride. The product was collected and concentrated to obtain oil, which was placed in isopropyl alcohol and treated with 2.5 equivalents of oxalic )amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde (580 g), the melting point (Razlog.) > 220oC.

Example 62

Following a methodology similar to that used in example 61, received the following connections:

(a) N-(4-(2-(((2-pyridyl)methyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, the melting point (Razlog.) > 250oC.

(b) N-(4-(2-(((2-thiophenyl)methyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, the melting point (Razlog.) > 226oC.

Example 63

N-(4-((amino)carbonyl)phenyl)-2-thiophenecarboxaldehyde.

This compound is obtained by following the procedure of example 26, step (b). Sol recrystallize from 30% isopropanol in water, melting point 236oC (Razlog.).

Example 64

N-(4-(2-(((2-thienyl)carbonyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

(a) N-(4-nitrophenyl)-2-thiophencarboxylic.

This compound is obtained by following the procedure of example 26, step (a), MS: 249 (M+H).

(b) N-(4-amino)aniline-2-thiophencarboxylic.

This compound is obtained by following the procedure of example 17, step (d), 219 MS (M+H).

(c) N-(4-(((2-thienyl)carbonyl)amino)phenyl-2 - thiophenecarboxaldehyde.

This compound is obtained by following the procedure of example 7, step (c). Free OS N-[4 -(((( diphenylamino)carbonyl)amino)methyl)phenyl] -2 - thiophenecarboxaldehyde.

(a) 4 -(((( diphenylamino)carbonyl)amino)methyl)nitrobenzene.

To a stirred solution of 4-nitrobenzenesulfonamide (1.04 g, 5.51 mmol) and triethylamine (1,56 ml, 11,22 mmol) in methylene chloride (10 ml) was added diphenylcarbamate (1.40 g, 6,07 mmol). After stirring for 5 hours the mixture was dumped into water and the layers were separated. Then the aqueous layer was extracted with methylene chloride (3 20 ml). Mixed extracts were washed with water, dried (MgSO4), filtered and concentrated to yield a solid substance, which was recrystallize ie ethyl acetate/hexane/methanol to obtain 4 -(((( diphenylamino)carbonyl)amino)methyl)nitrobenzene in the form of a white solid: 1,37 g (yield 72%); melting point 137-138oC.

(b) 4 -(((( diphenylamino)carbonyl)amino)methyl)aniline.

To a stirred solution of compound of stage (a) (1,37 g of 3.94 mmol) in THF/MeOH (100 ml, 1:1)) was added catalytic amount of 10% Po/C. the Mixture was first made when the pressure 3,5155 kg/cm2within 1 hour, filtered through celite and are condensed to obtain 4 -(((( diphenylamino)carbonyl)amino)methyl)aniline, which was homogeneous by thin-layer chromatography, and immediately used in the next reaction.

(c) N-[4 -(((( diphenylamino)to mmol) in isopropanol (10 ml) was added S-methyl-2 - theoreticalmethodological (1.06 g, 3,70 mmol). The mixture was mixed for 18 hours, dropped in alkaline water and was extracted with chloroform (3 30 ml). Mixed extracts were washed with water, dried (MgSO4), filtered, concentrated and subjected to chromatography on silica gel (6% methanol/methylene chloride) to obtain the oil, which tordillos when standing. A small amount was allocated in the form of the oxalate salt (48 mg); melting point (Razlog.) 150oC.

Example 66

N-[4-((((2-thiophenyl)iminomethyl)amino)methyl)phenyl] -2 - thiophenecarboxaldehyde.

(a) 4-(aminomethyl)aniline.

To a solution of 4-nitrobenzenesulfonamide (9.0 g, 4.7 mmol) in methanol (200 ml) was added catalytic amount of 10% palladium on carbon. The mixture was first made in the course of 4 hours at a pressure of 3,5155 kg/cm2was filtered through celite and concentrated to obtain crude oil. The oil was dissolved in water (100 ml) and 20% sodium hydroxide (20 ml), was extracted twice with dichloromethane, the organic layer was dried (MgSO4), filtered and concentrated to yield (6,1 g) 4-(aminomethyl)aniline.

(b) N-(4-((((2-thiophenyl)iminomethyl)amino)methyl)phenyl)-2 - thiophenecarboxaldehyde.

A mixture of compound of stage (a) (1.6 g, 1.3 mmol) and S-methyl-2-thio is e 72 hours. Then the mixture was diluted with 20% aqueous sodium hydroxide solution, and the solid was collected by filtration, receiving 2.5 g of crude N -(((( 2-thiophenyl)iminomethyl)amino)methyl)phenyl)-2 - thiophenecarboxaldehyde. From methanol and isopropanol got difumarate salt, melting point 200-201oC.

Example 67

Following a methodology similar to that presented in example 66, received the following connection:

(a) N-(4-((((2-thiophenyl)iminomethyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 200-201oC.

Example 68

N-(4-((((3-were)iminomethyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

(a) N-(4-(2-amino-ethyl)phenyl)-2-thiophencarboxylic.

To a solution of 4-aminoethylethanolamine (1.4 g, 6.6 mmol) and S-methyl-2-theoreticalmethodological (the product of example 1, stage (d)) (2,2 n, 7.6 mmol) in DMF (10 ml) was added pyridine (0.52 g, 6.6 mmol). The mixture was mixed at 40oC for 24 hours, diluted with 20% aqueous sodium hydroxide solution, and was twice extracted with dichloromethane, dried (MgSO4), filtered and concentrated to obtain N-(4-(2-amino-ethyl)phenyl)-2-thiophenecarboxaldehyde (4.1 g) in the form of butter.

(b) N-(4-(((3-were)iminomethyl)amino)ethyl)phenyl-is ethylphenyl)dicarboxaldehyde (2.8 g, 9.2 mmol) in isopropanol (10 ml). The mixture was mixed at 40oC for 18 hours, diluted with 20% aqueous sodium hydroxide solution and was extracted twice with ethyl acetate. The organic layer was washed with water (100 ml), dried (MgSO4), filtered and concentrated to obtain oil. From methanol, isopropanol and ethyl acetate received difumarate salt, N-(4-((((3-were)iminomethyl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde: melting point 200-201oC.

Example 69

Following a methodology similar to that presented in example 68, received the following connection:

(a) N-(3-((((2-thiophenyl)iminomethyl)amino)ethyl)phenyl)- -2-thiophenecarboxaldehyde, melting point 211-212oC.

Example 70

N-(4-(2-(pyrimidine-2-yl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

(a) [2-(4-nitrophenyl)ethyl]pyrimido-2-ylamine.

To a solution of 4-nitrophenylhydrazine (2.0 g, 9.8 mmol) in dimethylformamide (20 ml) was added potassium carbonate (10 g) and 2-chloropyrimidine (1.6 g, 1.4 mmol). The mixture was heated for 24 hours to 100oC, diluted with water (300 ml), and was twice extracted with ethyl acetate, dried (MgSO4), filtered and concentrated to obtain a crude solid. Of e is (2.4 g).

(b) [2-(4-AMINOPHENYL)ethyl]pyrimidine-2-ylamine.

To a solution of compound of stage (a) in acetic acid (100 ml) was added zinc dust (3.0 g). The reaction mixture was mixed for 30 minutes, filtered and concentrated. The remainder was divided 20% aqueous sodium hydroxide solution and dichloromethane and the organic layer was dried (MgSO4), filtered and concentrated to yield 1.3 g of [2-(4-AMINOPHENYL)ethyl]pyrimido-2-ylamine.

(c) N-(4-(2-(pyrimidine-2-yl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde.

To a solution of the compound (b) (1.3 g, 6.6 mmol) in dimethylformamide (10 ml) was added S-methyl-2-theoreticalmethodological (the product of example 1, stage (d)). The reaction mixture was mixed for 72 hours, diluted with 20% sodium hydroxide solution and was extracted twice with ethyl acetate. Mixed extracts washed twice with water, dried (MgSO4), filtered and concentrated.

From methanol and isopropanol received cleaners containing hydrochloride salt of N-(4-(2-(pyrimidine-2-yl)amino)ethyl)phenyl)-2 - thiophenecarboxaldehyde, melting point 191-192oC.

Example 71

N-(4-(2-((phenylmethyl)amino)ethoxy)-2-forfinal)-2 - thiophenecarboxylate.

(a) 3-fluoro-4-nitrophenoxyacetic acid.

oC. After 2 hours the mixture was treated with methanol (20 ml) and water (40 ml) and mixed. After another 2 hours the mixture was diluted with water to 200 ml and filtered solids. The filtrate was acidified, collected solid particles, receiving 3-fluoro-4-nitrophenoxyacetic acid, melting point 90-92oC.

(b) N-(phenylmethyl)-3-fluoro-4-nitrophenoxyacetic.

Sample connection stage (a) (2,84 g) was dissolved in dry THF (100 ml), then added methylmorpholin (1,45 ml) and the mixture was mixed at 0oC. was Added ethylchloride (1,26 ml) and the mixture was mixed for 2 minutes. Added benzylamine (1,45 ml) and the mixture was mixed at 0oC. After 15 minutes the mixture is slowly diluted with water to 22 ml and mixed at 0oC. the Obtained solids were collected and washed with water, then air-dried to obtain N-(phenylmethyl)-3-fluoro-4-nitrophenoxyacetic, melting point 128,5-130oC.

(c) N-(4-(2-((phenylmethyl)amino)ethoxy)-2-forfinal)-2 - thiophenecarboxylate.

The product of stage (b) was converted into the free base N-(4-(2-((phenylmethyl)amino)ethoxy)-2-forfinal)-2 - thiophenecarboxylate, following a methodology similar to that presented in example 19, steps (c) and (d)), the point plavleniya">

4-(2-((phenylmethyl)(methyl)amino)ethyl)anyindividual (obtained according to the method of example 19, steps (a) - (c)) (1,03 g), was dissolved in water (25 ml) was treated with 50% aqueous sodium hydroxide solution (5 ml) and was extracted with ethyl ether. The extract was dried (NaOH) and evaporated to provide the free base, 0,72, Then the free base was treated with triptoreline and heated to 100oC. After 1 hour, to improve the mixing of added toluene (5 ml). After 2 hours the mixture was cooled, added water (30 ml) and the mixture stirred it up. After 15 minutes with a formed semi-solid reddish-brown residue was decanted water. The residue was recrystallize from methanol and water mixture (125 ml), receiving N-(4-(2-((phenylmethyl)(methyl)amino)ethyl)phenyl)-triptorelin in the form of a reddish-brown solid, melting point 105-107oC.

1. Derivative amide of General formula I

< / BR>
in which D represents phenyl, 5-membered heterocyclic aromatic ring containing 1 to 2 heteroatoms selected from O, S and N, one group of which is optionally substituted by a group selected from C1-C6-alkyl, halogen; or C1-C6-perfluoroalkyl;

R1is hydrogen the SUB>sNR3R4, -X - (CH2)pNR3R4, -X - (CH2)nNHCOR5or -(CH2)qNHC(NH)R6;

R3and R4independently represent hydrogen, C1-C4-alkyl, -(CH2)rA, -(CH2)mOA or CH(CH3)(CH2)t-A; or NR3R4together represent piperidylamine, piperidinyl, morpholinyl, pyrrolidinyl, 1,2,3,4-tetrahydroisoquinoline; or piperazinil, optional 4-substituted C1-C6-alkyl;

R5represents C1-C6-alkyl, C1-C6-perfluoroalkyl, -(CH2)rA or-O(CH2)wA; A is phenyl, pyridinyl, pyrimidinyl, or 5-membered heterocyclic aromatic ring containing 1 heteroatom selected from O, S and N, two groups of which are optionally substituted by one or more groups selected from C1-C6-alkyl, halogen, and triptorelin;

R6represents phenyl or 5-membered heterocyclic aromatic ring containing 1 heteroatom selected from O, S and N, two groups of which are optionally substituted by one or two groups selected from C1-C6-alkyl, C1-C6-alkoxy, halogen;

n and r are independently presented the flax;

m represents an integer in the range 2 to 4 inclusive;

q and t independently represent an integer in the range 0 to 4 inclusive;

s represents an integer of 1 to 3 inclusive;

X is O or a bond;

Z represents O, NR7or communication;

R7represents hydrogen or C1-C6-alkyl, provided that (a) when D contains a heteroatom, it is not associated with the remainder of the compounds of formula (1) via a heteroatom; (C) when R2represents-X - (CH2)nZCONR3R4and neither X nor Z does not represent a bond, then n is an integer in the range 2 to 4 inclusive; (C) when R2represents-X - (CH2)nNHCO(CH2)sNR3R4or-X - (CH2)nNHCOR5X is O, then n represents an integer in the range from 2 to 4 inclusive; (d) when R2represents-X - (CH2)pNR3R4and X is O, then p represents an integer in the range from 2 to 4 inclusive; (e) when R2represents -(CH2)qNHC(NH)R6, R1is hydrogen and D and R6have the same definition and represent phenyl, optionally substituted C1-C4-alkyl, or one or more groups C

2. Connection on p. 1, wherein D is phenyl, thiophene, pyrrole, furan or thiazole, one group of which is optionally substituted by a group selected from C1-C6-alkyl, halogen; or C1-C6-perfluoroalkyl.

3. Connection under item 1 or 2, characterized in that D is thiophene, furan or pyrrole.

4. The compound according to any one of paragraphs.1 to 3, wherein R2represents-X - (CH2)pNR3R4or -(CH2)qNHC(NH)R6.

5. Connection to any one of paragraphs.1 to 4, wherein R2represents-X - (CH2)pNR3R4X represents a bond and any-NR3R4represents 1,2,3,4-tetrahydroisoquinoline, or one of R3and R4represents -(CH2)rA and the other represents hydrogen or methyl.

6. Connection to any one of paragraphs.1 to 5, wherein R2represents-X - (CH2)pNR3R4p represents an integer in the range 1 to 3 inclusive, one of R3and R4represents -(CH2)rA and the other represents hydrogen or methyl, r represents 1 or 2 and A represents A phenyl, optionally substituted by one or more grtlakes fact, what R2represents -(CH2)qNHC(NH)R6, q represents 0, 1 or 2 and R6represents phenyl or thiophene, two groups of which are optionally substituted by one or more groups selected from C1-C6of alkyl and halogen.

8. Connection to any one of paragraphs.1 - 4, 7, characterized in that R2represents -(CH2)qNHC(NH)R6and q is 0.

9. The compound of formula I under item 1, which is

N-(4-(2-((phenylmethyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(1-((phenylmethyl)amino)methyl)phenyl)-2-thiophenecarboxylate,

N-4-(1-((phenylethyl)amino)methyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-((2-chloroformate)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-((3-performer)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-((2-were)methyl)amino)ethyl)-phenyl)-2-thiophenecarboxylate,

N-(4-(2-((methyl)amino)ethyl)-phenyl)2-thiophencarboxylic,

N-(4-(2-amino-ethyl)phenyl)-2-thiophenecarboxylate,

N-((4-morpholinylmethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(((phenylmethyl)amino)methyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-(((2,6-dichlorophenyl)methyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-(((2-bromophenyl)methyl who,

N-(4-(2-((2,6-dichlorophenylethyl)amino)ethyl)phenyl)-3-thiophencarboxylic,

N-(4-(2-amino-ethyl)phenyl)-3-thiophenecarboxaldehyde,

N-(4-(2-((2,6-dichlorophenylethyl)amino)ethyl)phenyl)-2-furancarboxylic,

N-(3-(3-(1-pyrrolidinyl)propyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-amino-ethyl)phenyl-2-procarboxypeptidase,

N-(4-((1-piperidinyl)methyl)phenyl)-2-thiophenecarboxylate,

N-(4-((1-pyrrolidinyl)methyl)phenyl)-2-thiophenecarboxylate,

N-(3-(((phenylmethyl)amino)methyl)phenyl)-2-thiophenecarboxylate,

N-(3-((amino)methyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-((phenylmethyl)amino)ethyl)phenyl)-2-thiophencarboxylic,

N-(3-(2-(ethylamino)ethylphenyl)-2-thiophenecarboxylate,

N-(3-(3-((phenylethyl)amino)propyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-(((2-bromophenyl)methyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-phenylamino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-ethylamino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-(2-propylamino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-(1-propylamino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-tert-butylamino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-(n-butylamino)ethyl)phenyl)-2-thiophenecarboxylate,
midmid,

N-(3-(2-(tert-butylamino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-(2-propylamino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-amino-ethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-(dimethylamino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-dimethylamino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-(1,2,3,4-tetrahydro)ethenolysis)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(3-(2-(1,2,3,4-tetrahydro)ethanolic)propyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-(((2-chlorophenyl)methyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(3-((phenylmethyl)amino)propyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-(((3-chlorophenyl)methyl)amino)ethyl)phenyl)-2-thiophencarboxylic,

N-(4-(2-(((4-chlorophenyl)methyl)amino)ethyl)phenyl)-2-thiophencarboxylic,

N-(4-(2-(((3-chlorophenyl)methyl)amino)ethyl)phenyl)-3-chlorothiophene-2-carboxamide,

N-(3-(2-((N-phenylmethyl-N-methyl)amino)ethyl)phenyl-2-thiophenecarboxylate,

N-(4-(2-((N-phenylmethyl-N-methyl)amino)ethyl)phenyl-2-thiophenecarboxylate,

N-(3-(2-(((3-chlorophenyl)methyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(3-(((3-forfinal)methyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-(((3-chlorophenyl)methyl)amino)propyl)phenyl)-2-thiophenecarboxylate,

N-(4-(3-((phenylmethyl-N-mate Itemid,

N-(4-(3-((phenylethylamine)carbonyl)propyl)phenyl-2-thiophenecarboxylate,

N-(4-(3-((1-pyrrolidyl)carbonyl)propyl)oxy)phenyl)-2-thiophenecarboxylate,

N-(4-(3-((4-morpholinyl)carbonyl)propoxy)phenyl)-2-thiophenecarboxylate,

N-(4-(2-((phenylethylamine)carbonyl)ethyl)phenyl)-2-thiophenecarboxylate,

N-3-(2-((phenylamino)carbonyl)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(3-((phenylamino)carbonyl)propyl)phenyl)-2-errorcorrecting,

N-(4-(3-((phenylamino)carbonyl)propyl)phenyl)-2-procarboxypeptidase,

N-(4-(3-((phenylamino)carbonyl)propyl)phenyl)-3-chloro-2-thiophencarboxylic,

N-((3-((phenylamino)carbonyl)-propyl)phenyl)-1-methylpyrrole-2-carboxamide,

N-(4-(3-(1-(4-methylpiperazine)carbonyl)propyl)phenyl-2-thiophenecarboxylate,

N-(4-(3-((1-pyrrolidyl)carbonyl)propyl)phenyl)-2-thiophenecarboxylate,

N-(4-(3-((4-morpholinyl)carbonyl)propyl)phenyl)-2-thiophenecarboxylate,

N-(4-((phenylamino)carbonyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-((4-morpholinyl)carbonyl)ethyl)phenyl)-2-methylthiazole-4-carboxamide,

N-(4-(2-(((4-morpholinyl)carbonyl)amino)ethyl)phenyl)thiophene-2-carboximidic,

N-(4-(3-(((phenyl)amino)carbonyl)propyloxy)phenyl-2-thiophenecarboxylate,

N-(4-(2-(((triphtalocyaninine,

N-(4-(2-((phenylmethyl)carbonyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-((phenyl)carbonyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-((phenyliminomethyl)amino)phenyl)-2-thiophenecarboxylate,

N-N ' -(1,4-phenylene)bis-2-thiophencarboxylic,

N-N ' -(1,3-phenylene)bis-2-thiophencarboxylic,

N-N'-(1,3-phenylene)bis-2-chlorophenyl-carboximidic,

N-N'-(1,4-phenylene)bis-3-chlorothiophene-2-carboxamide,

N-(4-(((2-methoxyphenyl)aminocarbonyl)amino)phenyl)-2-thiophenecarboxylate,

N-(4-(((phenyl)aminocarbonyl)amino)phenyl)-3-chlorothiophene-2-carboxamide,

N-(4-(((phenyl)aminocarbonyl)amino)phenyl)-3-thiophencarboxylic,

N-(3-(((phenyl)aminocarbonyl)amino)phenyl)-2-thiophenecarboxylate,

N-(4-(((4-chlorophenyl)aminocarbonyl)amino)phenyl-2-thiophenecarboxylate,

N-(4-(((2-chlorophenyl)aminocarbonyl)amino)phenyl-2-thiophenecarboxylate,

N-(4-(((4-bromophenyl)aminocarbonyl)amino)phenyl-2-thiophenecarboxylate,

N-(4-(((3-chloro-4-were)aminocarbonyl)amino)phenyl-2-thiophenecarboxylate,

N-(4-(((3,5-dimethoxyphenyl)aminocarbonyl)amino)phenyl-2-thiophenecarboxylate,

N-(4-((3,5-dichlorophenyl)aminocarbonyl)amino)phenyl)-2-thiophenecarboxylate,

N-(4-(((phenyl)aminocarbonyl)BR>N-(4-(((3-methoxyphenyl)aminocarbonyl)amino)phenyl-2-thiophenecarboxylate,

N-(4-(((3-bromophenyl)aminocarbonyl)amino)phenyl-2-thiophenecarboxylate,

N-(4-(((3-chlorophenyl)aminocarbonyl)amino)phenyl)-2-thiophenecarboxylate,

N-(4-(((3-were)aminocarbonyl)amino)phenyl)-2-errorcorrecting,

N-(4-(((4-chlorophenyl)aminocarbonyl)amino)phenyl-2-errorcorrecting,

N-(4-(2-((phenylamino)carbonyl)amino)ethyl)phenyl)-2-thiophencarboxylic,

N-(4-(2-((phenylamino)carbonyl)oxy)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-((bis(phenylmethyl)amino)methyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-aminomethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(1,2,3,4-tetrahydroisoquinoline-2-ylmethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(4-((phenylmethyl)amino)butyl)phenyl)-2-thiophenecarboxylate,

N-(4-((((-2-thiophenyl)iminomethyl)amino)methyl)phenyl)-2-thiophenecarboxylate,

N-(3-(3-(1-pyrrolidino)propyl)phenyl)-phenylcarbamate,

N-(4-(2-((4-methoxyphenethyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-((4-methylphenylethyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-((3-phenylpropyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-((2-methylphenylethyl)amino)ethyl)phenyl)-2-thiophencarboxylic)-2-thiophenecarboxylate,

N-(4-(2-(((2-thienyl)methyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-((2-phenylethyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-amino-ethyl)phenyl)-2-errorcorrecting,

(S)-N-(4-(2-((1-phenylethyl)amino)ethyl)phenyl-2-thiophenecarboxylate,

(R)-N-(4-(2-((1-phenylethyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(3-(2-((4-phenylbutyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(((phenylmethoxy)carbonyl)aminomethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-((phenylmethyl)amino)ethoxy)phenyl)-2-thiophenecarboxylate,

N-[4-(((diphenylamino)carbonyl)amino)phenyl]-2-thiophenecarboxylate,

N-(3-(benzoyl)amino)phenyl-2-thiophencarboxylic,

N-(4-((benzoyl)amino)phenyl-2-thiophenecarboxylate,

N-(3 -(((( phenylamino)carbonyl)amino)phenyl)-2-thiophenecarboxylate,

N-(3-(((4-phenoxybutyl)amino)carbonyl)phenyl-2-thiophenecarboxylate,

N-(3-(((4-phenylbutyl)amino)carbonyl)phenyl-2-thiophenecarboxylate,

N-(4-(((benzyl)amino)carbonyl)methyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-(1-pyrrolidinyl)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-(1-piperidinyl)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(3-(1-pyrrolidinyl)propyl)phenyl)-2-thiophenecarboxylate,

N-(4-(3-(1-piperidineacetic,

N-(4-(((phenylmethyl)amino)methylcarbamoyl)amino)phenyl)-2-thiophenecarboxylate,

N-(4-(2-(((2-furanyl)methyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-(2-pyridyl)methyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-(((2-thiophenyl)methyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-((amino)carbonyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-(((2-thienyl)carbonyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4 -(((( diphenylamino)carbonyl)amino)methyl)phenyl)-2-thiophencarboxylic,

N-(4-((((2-thiophenyl)iminomethyl)amino)methyl)phenyl)-2-thiophencarboxylic,

N-(4-((((2-thiophenyl)iminomethyl)amino)ethyl)phenyl)-2-thiophencarboxylic,

N-(4-((((3-were)iminomethyl)amino)ethyl)phenyl)-2-thiophencarboxylic,

N-(3-((((2-thiophenyl)iminomethyl)amino)ethyl)phenyl)-2-thiophencarboxylic,

N-(4-(2-(pyrimidine-2-yl)amino)ethyl)phenyl)-2-thiophencarboxylic,

N-(4-(2-((phenylmethyl)amino)ethoxy)-2-forfinal)-2-thiophenecarboxylate,

N-(4-(2-((phenylmethyl)(methyl)amino)ethyl)phenyl)-triptoreline,

N-(4-(2-((ethyl)(phenylmethyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-((propyl)(phenylmethyl)amino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-((1,1-dimethylethyl)phenylmethyl)amino)ethyl)phenyl)-2-thiophenecarbonitrile)amino)ethyl)phenyl-2-thiophenecarboxylate,

N-(4-(3-((ethylamino)propyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-((diethylamino)ethyl)phenyl)-2-thiophenecarboxylate,

N-(4-(2-((3-chloroformate)amino)ethyl)phenyl)-benzoperoxide,

N-(4-(2-((4-methylphenylethyl)amino)ethyl)phenyl)-2-thiophencarboxylic,

N-(4-(2-((2-piperidylamine)ethyl)phenyl)-2-thiophencarboxylic,

or pharmaceutically acceptable salt of any of these compounds.

10. The drug that has the property to inhibit the activity of the synthetase of nitric oxide (V) comprising the active ingredient in a mixture with a pharmaceutically acceptable diluent or carrier, wherein as the active ingredient it contains a compound of the formula I, which is defined in paragraph 1, or its pharmaceutically acceptable salt.

11. The method of obtaining the compounds of formula I on p. 1 or its pharmaceutically acceptable salts, characterized in that conduct the interaction of the corresponding compounds of formula II

< / BR>
in which D is as defined in paragraph 1;

L is tsepliaeva group

with the compound of the formula III

< / BR>
in which R1and R2are as defined in paragraph 1.

12. A method of inhibiting the act of the I on p. 1, no conditions (e) or its pharmaceutically acceptable salt.

Priority points:

12.08.93 - PP.2, 3, 9 (connection 51, 52, 62, 63, 63-71), 10, 11, 12;

25.09.93 - p. 9 (connections 72-74);

11.12.93 - PP. 1 and 4 (where R2= -X(CH2)pNR3R4), 5, 6, 9 (compound 1-12, 19-21);

27.01.94 - PP.1 and 4 (where R2= -(CH2)qNHC(NH)R4), 7, 8, 9 (connections 75-79);

10.06.94 - p. 9 (connections 22-38, 40-43, 45-46).

 

Same patents:

The invention relates to dimethylpolysiloxene General formula

< / BR>
in which the radicals R1and R2may be the same or different, represents hydrogen, C2-C6- alkyl, C3-C6-cycloalkyl, C3-C6alkenyl,

C2-C6-quinil, C1-C3-halogenated, benzoyloxy group containing substituents, benzoylamino, which can also contain one or two Deputy, C2-C6-alkanolamines, C3-C6-cycloalkylcarbonyl, benzyl group which may contain substituents, the phenyl group with possible alternates, and other substituents, provided that at the same time R1and R2are not hydrogen atoms, the second condition is that one of R1and R2is not unsubstituted phenyl group when the other one represents a hydrogen atom, and the third condition is one of R1and R2in anthopology is not an aniline ring, C2-C6-alkyl, C3-C6-cycloalkyl or C2-C6-alkoxygroup when the other one represents a hydrogen atom

The invention relates to new methods of obtaining salt orthocarbonate acids or alcoholate hem-triolo having the structural formula R-Me where R is phenyl, furyl, R1-CH= CH-, CH3-(CH= CH)2- CH= C-CH3; Me - Na, K; Rlis phenyl, furyl, used as an intermediate reagents in organic synthesis, as well as in the printing industry for the regeneration of aluminum plates

The invention relates to new nitrogen-containing chemical compounds which possess valuable biological properties, in particular to new derivatives of amidine, which may constitute the active principle of the pharmaceutical composition having an antagonistic action on leukotriene4

The invention relates to methods for the stable solution of isetionate of pentamidine, which can be used to produce aerosols based on it

The invention relates to medicine, specifically to gynecology

The invention relates to veterinary medicine, namely to means of combating psoroptes farm animals

The invention relates to medicine, specifically to pharmacology

The invention relates to biochemistry, in particular to substances that have protective or normalizing effect on cells and cellular systems in terms of adverse environmental factors or pathology of development of the organism and can be used in industrial biotechnology, medicine, veterinary medicine and other related fields

The invention relates to new chemical substances that can be used as an inhibitor of cell adhesion, and more particularly to derivatives of 3-alkyloxy, aryloxy or arylalkylamine-benzo[b]thiophene-2-carboxamide, their pharmaceutically acceptable salts and pharmaceutical compositions with activity, inhibiting the adhesion of leukocytes to vascular endothelium

The invention relates to certain disubstituted acids benzenaminium

The invention relates to pharmaceutical compositions on the basis of benzothiophenes and to use the latter for treating or preventing osteoporosis by inhibiting bone rarefaction

Amidinopropane // 2130014
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