Derivatives of 5-substituted-1,2,4-thiadiazolyl, the retrieval method (variants), pharmaceutical composition, intermediate product and method thereof

 

(57) Abstract:

The invention relates to a derivative of 1,2,4-thiadiazole, substituted in the 5-position of General formula I, in which X Is N; R1- C1-6alkyl; R2is hydrogen, R3, R4and R5each independently selected from hydrogen; trifloromethyl; is Ar2, Ar2CH2or Het2; AG2is phenyl; Het2is a monocyclic heterocycle selected from thiadiazolyl, pyridinyl, pyrimidinyl or pyrazinyl, their N-oxide forms, the pharmaceutically acceptable acid additive salts and stereochemical isomeric forms. Also described methods of making the compounds and intermediates used in the synthesis, and method for producing the intermediate product. The compounds act as inhibitors of angiogenesis, which allows you to find them used in the treatment of diseases such as diabetic retinopathy, angiofibroma, psoriasis, osteoarthritis and other 7 c. and 3 C.p. f-crystals, 3 PL.

The invention relates to new derivatives of 5-substituted-1, 2, 4-thiadiazolyl acting as inhibitors of angiogenesis, and to receive them; in addition, it refers to the containing compositions and to their use as lekarstvennoyj in various physiological and pathophysiological processes. The development of a blood supply is essential for growth, maturation and maintenance of normal tissues. It is also necessary for wound healing. Angiogenesis plays a crucial role in the growth of solid tumors and metastases and is involved in various other painful pathological conditions such as neovascular glaucoma, diabetic retinopathy, psoriasis and rheumatoid arthritis. These pathophysiological state characterized by increased angiogenesis, during which usually in a resting endothelial cells become active, reduce extracellular matrix barriers, multiply rapidly and moved, forming new blood vessels. To fight against angiogenesis-related diseases will be very useful compounds with the properties of inhibiting angiogenesis.

In this area there are several compounds, inhibiting angiogenesis, also called angiostatin, angioinvasion or antagonists of angiogenic. For example, hydrocortisone is a well-known inhibitor of angiogenesis (Folkman et al., Science 230:1375, 1985' "A new class of steroids inhibits angiogenesis in the presence of heparin fragment"; Folkman et al., Science 221:719, 1983. "Angiogenesis inhibition and tumor regression causer by heparin fragment in the presence of cortisone").

In European the 0435381, published July 3, 1991, describes pyridazinone with antipaternalism activity. In the European patent 0429344, published may 29, 1991, discloses derivatives aminopyridazine as cholinergic agonists.

Compounds of the present invention differ from the compounds known in the prior art, the fact that they are always replaced thiadiazolidine fragment and in particular the fact that the data connection unexpectedly possess angiogenesis-any abscopal properties.

This invention relates to compounds of the formula

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their N-oxide forms, the pharmaceutically acceptable acid additive salts and stereochemical isomeric forms, where X represents CH or N;

R1represents hydrogen, C1-6alkyl, C1-6alkyloxy, C1-6alkylthio, amino, mono - or di (C1-6alkyl) amino, AG1, Ar1-NH-, C3-6cycloalkyl, hydroxymethyl or benzoyloxymethyl;

R2represent hydrogen, C1-6alkyl, amino, aminocarbonyl, mono - or di (C1-6alkyl) amino, C1-6allyloxycarbonyl, C1-6alkylcarboxylic, hydroxy or C1-6alkyloxy;

R3, R4and R5each independently selected /SUB> alkyloxy,1-6of alkyl, C1-6alkylthio, C1-6allyloxycarbonyl or Het1;

is AG2, Ar2CH2or Het2;

AG1represents phenyl; phenyl substituted with 1, 2 or 3 substituents, each of which is independently selected from halogen, C1-6of alkyl, C1-6alkyloxy, trihalomethyl, amino or nitro;

AG2represents phenyl; phenyl substituted with 1, 2 or 3 substituents, each of which is independently selected from halogen, C1-6of alkyl, C1-6alkyloxy, trihalomethyl, amino or nitro;

Het1represents a monocyclic heterocycle selected from oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazoline, thiadiazolyl or oxazoline; each monocyclic heterocycle optionally may be substituted on the carbon atom WITH1-4by alkyl; and

Het2represents a monocyclic heterocycle selected from furanyl, thiopurine, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl or pyrazinyl; each monocyclic heterocycle optionally may be substituted on carbon atom 1 or 2 substituents, each of which is independently selected from halogen, C1-4of alkyl, C1-4alkyloxy is a generic name for fluorine, chlorine, bromine and iodine; C1-4alkyl defines a linear or branched saturated hydrocarbon radicals containing from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, etc.; assume that C1-6alkyl includes WITH1-4alkyl and the higher homologues containing from 5 to 6 carbon atoms, such as, for example, pentyl, 2-methylbutyl, hexyl, 2-methylpentyl etc.;

Examples of the fragment are

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In any case, when a represents a radical of the formula Ar2CH2CH2the fragment in the specified radical preferably linked to the nitrogen atom piperidine fragment, if X represents CH, or piperazinilnom fragment, if X represents nitrogen.

Assume that the above pharmaceutically acceptable acid additive salts include therapeutically active non-toxic acid additive salt form, which can form compounds of formula (I). The compounds of formula (I) have basic properties can be converted into their pharmaceutically acceptable acid additive salt by processing the above-mentioned main form with a suitable acid. Suitable DNA or bromatologia acid; sulfuric; nitric; phosphoric and the like acids; or organic acids, such as acetic acid; propionic; hydroxyestra; dairy, pyramidographia, oxalic, malonic, succinic (i.e. batandjieva acid), maleic, fumaric, malic, tartaric, citric, methansulfonate, econsultancy, benzolsulfonat, p-toluensulfonate, ciclamino, salicylic, p-aminosalicylic, AMOVA and the like acids.

The term acid additive salt also comprises the hydrates and forms representing adducts with the solvent that can form the compounds of formula (I). Examples of such forms, for example, are hydrates, alcoholate, etc.,

The term stereochemical isomeric forms of the compounds of formula (I), as he used earlier in this description, defines all possible compounds formed from the same atoms connected by the same sequence of relationships, but having different three-dimensional structures which are not interchangeable, which can form compounds of formula (I). If not marked or not specified other, the chemical name of the compound includes a mixture of all possible stereochemical isomeric forms, which may make the primary molecular structure of the compounds. All stereochemical isomeric forms of the compounds of formula (I), both in pure form and in the form of a mixture with each other, also included in the scope of this invention.

Some compounds of formula (I) may also exist in tautomeric forms. It is assumed that these forms, although they are not marked in detail in the above formula, is also included in the scope of this invention.

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

Regardless of where next will use the term "compounds of formula (I), it is understood that it also includes pharmaceutically acceptable acid additive salts and all stereoisomeric forms.

A group of compounds of interest consists of those compounds of formula (I) in which one or more of the following restrictions:

a) X represents N;

in R1represents hydrogen, C1-6alkyl, amino, or di (C1-6alkyl) amino;

c) R2represents hydrogen;

d) R3, R4and R5each independently selected from hydrogen, halogen, C1-6dinani are such compounds of formula (I), in which X is N; R1represents hydrogen, C1-4alkyl or di (C1-4alkyl) amino; R2is hydrogen; R3, R4and R5each independently selected from hydrogen, halogen, C1-4of alkyl, C1-4alkyloxy or trifloromethyl; and bivalent radical is AG2, AG2CH2or Het2where AG2represents phenyl or phenyl substituted with 1 or 2 substituents, each of which is independently selected from halogen, C1-6of alkyl, C1-6alkyloxy, trihalomethyl, amino or nitro; and Het2is thiadiazolyl, pyridinyl, pyrimidinyl or pyrazinyl.

A preferred group of compounds are those compounds of formula (I) in which X is N, R1is methyl, R2is hydrogen, R3and R4represent hydrogen and R3represents trifluoromethyl.

A more preferred group of compounds are those preferred compounds in which R5represents trifluoromethyl, located in the 3-position.

Most preferred:

1-[4-(3-methyl-1,2,4-thiadiazole-5-yl)phenyl]-4-[3-(trifluoromethyl)phenyl]piperazine and 1-[5-(3-methyl-1, 2, 4-thiadiazole-5-yl)rosamaria forms or N-oxides.

Compounds of the present invention can be generally obtained by the interaction of the intermediate compounds of formula (II) with an intermediate compound of formula (III)

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In the preceding and subsequent reaction schemes W represents an appropriate reactive delete the group, such as, for example, halogen, for example fluorine, chlorine, bromine, iodine, or in some instances W may also be sulfonyloxy, for example, methanesulfonate, benzosulfimide, tripterocalyx and the like removed by reactive group. This interaction is carried out in accordance with well-known in this field means, such as, for example, mixing the two reactants in a reaction-inert solvent, such as N,N-dimethylformamide, acetonitrile, isobutyl ketone, etc., preferably in the presence of a base, such as sodium bicarbonate, sodium carbonate or triethylamine. The interaction can be conveniently carried out at a temperature in the range from room temperature to the boiling temperature of the reaction mixture under reflux.

The compounds of formula (I) in which R1is CH3moreover , these compounds, prestipino-O-sulfonic acid in a reaction-inert solvent, such as, for example, methanol or ethanol, in the presence of a base, such as pyridine.

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The compounds of formula (I) can be additionally obtained by converting compounds of the formula (I) into each other according to well-known in this field reactions of transformation groups.

The compounds of formula (I) can also be converted into the corresponding N-oxide forms in accordance with known in this area by way of turning trivalent nitrogen into its N-oxide form. These reactions of N-oxidation can, in General, to carry out the interaction of the parent substance of the formula (I) with a suitable organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, peroxides of alkali or alkaline earth metal, such as sodium peroxide, potassium peroxide; appropriate organic peroxides may include peroxyacids, such as, for example, benzonorbornadiene, or halogensubstituted benzonorbornadiene, for example 3-chlorobenzalmalononitrile, phenoxyalkanoic acid, for example peroxidasa acid, alkylhydroperoxide, for example tert-butylhydroperoxide. Suitable solvents PREDSTAVITEL, 2-butanone, halogenated hydrocarbons such as dichloromethane and mixtures of such solvents.

The initial substance and some intermediate compounds are known compounds and are commercially available or can be obtained according to conventional methods of carrying out the reaction, generally known in the art. For example, some of the intermediate compounds of formula (II), such as 5-(4-forfinal)-3-methyl-1, 2, 4-thiadiazole, were described by Yang-i Lin et al in J. Org. Chem., 45(19), p. 3750-3753 (1980) and some of the intermediate compounds of formula (III), such as 1-[3-(trifluoromethyl)phenyl] piperazine commercially available.

Intermediate compounds of formula (II) can be obtained by the interaction of the compounds of the formula (V) in which W represents a suitable removable group, as described above, with an intermediate compound of formula (VI), optionally in the form of its acid salt additive

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Intermediate compounds of formula (IV) can be obtained as described in scheme (I) (see the end of the description).

In scheme I, an intermediate compound of formula (VII), in which W1provides a suitable removable group, such as halogen or sulfonyloxy, and Z represents cyano or aminocarbonyl, the s, as described above for the synthesis of compounds of formula (I). The resulting intermediate compound of formula (VIII) is treated with a reagent Losson (Lawesson) in a suitable solvent, such as, for example, toluene or pyridine, or handle H2S in a suitable solvent, such as, for example, N, N-dimethylformamide, optionally in the presence of triethylamine. Subsequently, the intermediate compounds of formula (IX) is treated with N,N-dimethylacetamide by dimethylacetal in a reaction-inert solvent such as, for example, toluene or dichloromethane, thereby obtaining an intermediate compound of formula (IV).

The compounds of formula (I) and some intermediate compounds can have one or more stereogenic centers in their structure, having R or S configuration. For example, R1, R2, R3, R4or R5may be C1-6the alkyl having a stereogenic center.

The compounds of formula (I) obtained by the above methods, can be synthesized as racemic mixtures of enantiomers which can be separated from each other by means well known in the field of separation techniques. Racemic compounds of the formula (I) can be converted into the corresponding f is x salts subsequently share, for example, selective or fractional crystallization, and the enantiomers separated from them by treatment with alkali. An alternative method of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using chiral media. Suitable chiral media are, for example, polysaccharides, in particular cellulose or amylose derivative. Commercially available chiral media based on polysaccharides are ChiralCel SA, OA, OM, OS, OD, OF, OG, OJ and OK, and Chiralpak AD, AS, OP(+) and(+). Suitable suenami or mobile phases used in combination with the above polysaccharide chiral media are hexane, etc., which are modified by alcohol, such as ethanol, isopropanol, etc., the Above-mentioned pure stereochemical isomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting compounds, provided that the reaction was held stereospetsifichno. Preferably, if you want a specific stereoisomer, the above compound is synthesized stereospecifically methods of getting. In these methods, it is advantageous to use enantiomerically pure source materials.

Connection fterolaka in pharmacological example C. 1.

From the point of view of their pharmacological activity of the compounds of formula (I), their pharmaceutically acceptable acid additive salt, stereochemical isomeric forms, or their N-oxide forms are inhibitors of angiogenesis.

Therefore, inhibitors of angiogenesis are useful for combating or treating diseases angiogenesis-dependent, such as, for example, ocular neovascular disease, neovascular glaucoma, diabetic retinopathy, retrolental fibroplasia, hemangioma, angiofibroma, psoriasis, osteoarthritis and rheumatoid arthritis. Also inhibitors of angiogenesis useful to combat the growth of solid tumors, such as breast cancer, prostate cancer, melanoma, kidney cancer, cancer of the colon, cervical cancer and so on; and metastases.

Therefore, in the present invention are disclosed compounds of the formula (I) for use as a medicinal product, and the use of compounds of formula (I) for obtaining a medicinal product for the treatment of dependent angiogenesis diseases.

From the point of view of usefulness of the considered compounds for the treatment or prevention of angiogenesis-dependent diseases in the present from the persons includes the systematic introduction of therapeutically effective amounts of compounds of formula (I), its N-oxide or pharmaceutically acceptable acid additive salt.

Taking into account their useful pharmacological properties, the compounds being considered can be included in the formulation of various pharmaceutical forms for their use. To obtain pharmaceutical compositions according to this invention an effective amount of a compound in the form of a base or an acid additive salt, as an active ingredient, is mixed into a homogeneous mixture with a pharmaceutically acceptable carrier, such carrier may have various forms depending on the required for the introduction of forms of cooking. These pharmaceutical compositions are optimal in the form of a unit dosage forms, preferably suitable for administration orally, rectally or parenterally injection. For example, upon receipt of the compositions in oral dosage forms may be used any conventional pharmaceutical environment, such as, for example, water, glycols, oils, alcohols, etc., in the case of oral liquid preparations such as suspensions, syrups, elixirs or solutions; or solid carriers such as starches, sugars, kaolin, lubricants, wag the tablets and capsules represent the most advantageous oral unit dosage forms, in the case of which usually are solid pharmaceutical carriers. For parenteral compositions, the carrier typically includes, at least in the main part, sterile water, although you may be used and other ingredients, for example, in order to facilitate solubility. For example, can be obtained solutions for injection, in which the medium contains a salt solution, a glucose solution or a mixture of saline and glucose solution. Can also be obtained suspension for injection in this case may apply appropriate liquid carriers, suspendresume agents, etc. In compositions suitable for subcutaneous injection, the carrier may optionally include an agent that improves the penetration and/or a suitable wetting agent, optionally in combination in smaller proportions with acceptable additives of any nature, with such additives, which do not have a significant harmful impact on the skin. These additives can promote penetration through the skin and/or may be useful for obtaining the target composition. These compositions can be administered in various ways, for example, in the form of a transcutaneous patch, spot, in the form of ointment. An acid additive salt (I) because of their high soluble is">

In particular, it is convenient to make the recipe above pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used in the description and the claims refers to physically discrete units suitable as unit dosage forms, each unit contains a predetermined quantity of active ingredient calculated to obtain the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including tablets, scored and coated tablets), capsules, granules, packets of powders, pellets, solutions or suspensions for injection, measuring spoons, measuring spoons, etc., and separate multiple doses.

For oral administration the pharmaceutical compositions may be in the form of solid dosage forms such as tablets (like forms only for swallowing and chewing), capsules or gel capsules obtained by conventional means with pharmaceutically acceptable excipients such as binding agents (for example, clusterseven is, microcrystalline cellulose and calcium phosphate); lubricating agents such as magnesium stearate, talc or silica); disintegrators (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g. sodium lauryl sulphate). Tablets can be coated by methods well known in the art.

Liquid preparations for oral administration can be in the form of, for example, solutions, syrups or suspensions, or may be a dry product that can be connected to water or other acceptable media before use. Such liquid preparations can be obtained by conventional methods, optionally with pharmaceutically acceptable additives such as suspendresume agents (for example, morbity syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats); emulsifying agents (e.g. lecithin or Arabian gum); non-aqueous vehicles (e.g. almond oil, oily esters or ethyl alcohol); and preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid).

Pharmaceutically acceptable sweeteners include preferably at least one intensive podla hydroalcoholic sweetener monellin, stevioside, or Sucralose (4,1', 6'-trichloro-4,1', 6'-tridyakisicosahedron), preferably saccharin, saccharin sodium or calcium, and optionally a bulk sweetener, such as sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel or honey.

Intense sweeteners are commonly used in low concentrations. For example, in the case of saccharin sodium concentration may vary in the range from 0.04 to 0.1% (weight/volume) depending on the total volume of the final composition, and preferably is approximately 0.06% in the compositions with low dose and approximately 0,08% in formulations with a high dose. Bulk sweeteners can be effectively used in high concentrations, ranging from about 10 to about 35%, preferably from about 10% to 15% (weight/volume).

Pharmaceutically acceptable odorants that can mask the bitter taste of the ingredients in compositions with low doses, preferably represent fruit flavors, such as cherry, raspberry, blackcurrant or strawberry flavoring. The combination of the two fragrances can lead to very good results. For compositions with a high concentration is such pharmaceutically acceptable strong fragrances. Each odorant may be present in the final compositions in concentrations varying from 0.05 to 1% (weight/volume). It is advantageous to use a combination of these strong perfumes. Preferably use the perfume, for which in the acidic environment of the composition change is not happening or loss of flavor and color.

Compounds according to this invention can be introduced into the formulation as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. So, for example, the compounds can be incorporated together with suitable polymeric or hydrophobic materials (for example, in the form of an emulsion in a suitable oil) or ion exchange resins, or as sparingly soluble derivatives, for example in the form of sparingly soluble salts.

Compounds according to this invention can be introduced into the compositions for parenteral administration by injection, usually intravenous, intramuscular or subcutaneous injection, for example bolus injection or continuous intravenous infusion. Formulations for injection can be a single dosage form, such as capsules or containers with multiple gosalia in water or an oil medium, and may contain agents for the preparation of compounds such as isotherwise, suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for mixing before use with a suitable vehicle, e.g. sterile water, not containing bacterial toxins.

Compounds according to this invention can also be introduced into the compositions for rectal compositions such as suppositories or kept enemas, e.g. containing conventional bases for suppositories, such as cocoa butter or other glycerides.

Compounds according to the invention can be used for intranasal, for example, in the form of liquid aerosol, in the form of powder or in the form of a drop.

Specialists in this field can easily determine the effective amount on the basis of the results of the experiments presented below. In General, it is assumed that the effective amount will be from 0.001 to 10.0 mg/kg of body weight, especially from 0.01 to 1.0 mg/kg of body weight. It may be convenient to provide the required dose in the form of two, three, four or more sub-doses at appropriate intervals throughout the day. The above sub-doses may be the about 200.0 mg of the active ingredient in a unit dose.

The following examples are given for purposes of illustration.

Experimental part

Hereinafter, "DMF" means N,N-dimethylformamide, "DHM" means dichloromethane, "DIPE" refers to diisopropyl simple ether and "THF" means tetrahydrofuran.

A. the production of intermediate compounds

Example A. 1

a) a Mixture of 2-Chloro-4-methylpyrimidyl (0.07 mol) in thionyl chloride (100 g) was stirred and heated at the boil under reflux for 16 hours. The solvent was evaporated, obtaining 2-chloro-4-[dichloro(Horti)methyl]pyrimidine (intermediate compound 1).

C) a Mixture of the hydrochloride of 1-aminoethylamino (1:1) (0.08 mol) was added at 0oWith under stirring to a mixture of intermediate compound 1 (0.07 mol) in DHM (300 ml). Sodium hydroxide (50%, 20 ml) was added dropwise at 0oC. the Mixture was stirred at 5oC for 1 hour. Was added water (300 ml) and DHM (300 ml). The mixture was separated into layers. The aqueous layer was washed twice DHM. The combined organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: DHM). Collected pure fractions, the solvent was evaporated, obtaining 3.5 g of 2-chloro-4-(3-methyl-1,2,4-thiadiazolyl-5-yl) pyrimidine (PR is ormetal) phenyl] piperazine (0.11 mol) and sodium carbonate (0.22 mol) in DMF (300 ml) was stirred overnight at 120oC. the Mixture was poured into ice water (600 ml) and was stirred for 1 hour. The precipitate was filtered and dried. Part of this fraction (4 g) was dissolved in DHM and aqueous solution of NaHCO3. The mixture was separated into layers. The aqueous layer was extracted with DHM three times. The combined organic layer was dried, filtered and the solvent was evaporated to small volume. The precipitate was filtered and dried, obtaining 3.2 g of 6-[4-[3-(trifluoromethyl)phenyl] -1-piperazinil] -3-pyrimidinecarboxylic (intermediate compound 3).

C) a Mixture of intermediate compound 3 (0,013 mol) and reagents Losson (to 0.007 mol) in toluene (130 ml) was stirred and heated at the boil under reflux for 2 hours. The mixture was cooled. Was added water (100 ml). The mixture was stirred for 1 hour and the layers were separated. The aqueous layer was extracted with toluene three times and once DHM. The combined organic layer was dried, filtered and the solvent was evaporated, getting to 7.3 g of 6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinil]-3 - pyrimidinediamine (intermediate compound 4).

Example A. 3

A mixture of intermediate compound 4 (0,013 mol) and 1,1-dimethoxy-N,N-dimethylethanamine (0,021 mol) was left overnight and then used without further purification, with receipt shall Obedinenie 5).

In table I. 1 lists the intermediate compounds, which were obtained according to example A. 3.

C. obtain the final compounds

Example C. 1

A mixture of 5-(4-forfinal)-3-methyl-1, 2, 4-thiadiazole (0.012 mol), 1-[3-(trifluoromethyl)phenyl] piperazine (0.014 mol) and sodium carbonate (0,024 mol) in DMF (10 ml) was stirred at 140oC for 24 hours, then at 150oC for 24 hours, cooled, poured into ice water (200 ml) and stirred. The precipitate was filtered, absorbed DHM, dried, filtered and evaporated the solvent. The precipitate was led from DIPE. The precipitate was filtered and dried, obtaining 2.5 g(52%) 1-[4-(3-methyl-1, 2, 4-thiadiazole-5-yl)phenyl]-4-[3-(trifluoromethyl)phenyl]piperazine (compound 2).

Example Century. 2

A mixture of hydroxylamine-O-sulfonic acid (to 0.011 mol) in methanol (15 ml) was added at once to a mixture of intermediate compound 5 (0.01 mol) and pyridine (0.02 mol)in ethanol (40 ml). The mixture was stirred at room temperature for 90 minutes. The solvent was evaporated. The precipitate was stirred at room temperature DHM, washed with water and aqueous 0.1 N. NaOH solution, dried, filtered and evaporated the solvent. The residue was absorbed by the methanol, was filtered and dried. The residue was absorbed by azet the Zadok was filtered and dried, getting 1.4 g(35%) 1-[5-(3-methyl-1, 2, 4-thiadiazole-5-yl)-2-pyridinyl]-4-[3- (trifluoromethyl)phenyl]piperazine (compound 8).

In table F. 1 lists the compounds that were obtained according to one of the above examples and in table F. 2 shows the experimental (column entitled "ex.") and theoretical (column entitled "theory. the data of elemental analysis for carbon, hydrogen, and nitrogen compounds, obtained previously in the experimental part.

C. Pharmacological examples

Example C. 1

The activity of inhibiting angiogenesis was measured in vitro using a model of angiogenesis in the aortic rings of rats described Nicolas, R. F. and Ottinetti in "Laboratory Investigation, vol. 63, R. 115, 1990. The ability of compounds to inhibit the formation of microvessels compared with the control rings processed by the media. Quantitative assessment (region MicroSCADA) after 8 days in culture was performed using a system image analysis, consisting of a light microscope, CCD (device, which is controlled by the computer) camera and automatic, specially designed program that analyzes the image, as described in Nissanov, J., Tuman, R. W., Gruver, L. M. and Fortunate J. M. in "Laboratory Investigations", vol. 73 (#5), p. 734, 1995. Link is 1, 2 and 6 show the values of the IC50< 10 nm.

1. Derivatives of 5-substituted 1,2,4-thiadiazolyl formula (I)

(I)

their N-oxide forms, the pharmaceutically acceptable acid additive salt and stereochemical isomeric forms,

where X IS N;

R1- C1-6alkyl;

R2is hydrogen;

R3, R4and R5each independently selected from hydrogen, trifloromethyl;

is Ar2, Ar2CH2-or Het2where Ar2- phenyl, Het2is a monocyclic heterocycle selected from thiadiazolyl, pyridinyl, pyrimidinyl or pyrazinyl.

2. Connection on p. 1, in which X Is N; R1is methyl; R2is hydrogen; R3and R4is hydrogen and R5- trifluoromethyl.

3. Connection on p. 1, in which the compound is 1-[4-(3-methyl-1,2,4-thiadiazole-5-yl)phenyl] -4-[3-(trifluoromethyl)phenyl] piperazine or 1-[5-(3-methyl-1,2,4-thiadiazole-5-yl-2-pyridinyl] -4-[3-(trifluoromethyl)phenyl] piperazine, their stereoisomeric forms and pharmaceutically acceptable acid additive salt.

4. Composition, inhibiting angiogenesis, characterized in that it comprises a pharmaceutically acceptable carrier and as active ingredient terapeuticas the positions on p. 4 by homogeneous mixing pharmaceutically acceptable carrier and a compound according to PP.1-3.

6. The compound according to any one of paragraphs.1-3, inhibiting angiogenesis.

7. A method of obtaining a connection on p. 1, in which the intermediate compound of formula (II) interacts with an intermediate compound of formula (III) in a reaction-inert solvent and optionally in the presence of a suitable base

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where X, R1- R5and defined in paragraph 1;

W represents a suitable removable group;

or, if necessary, the compounds of formula (I) transform into each other, following well-known in the art reactions of transformation, or, if desired, the compound of formula (I) converted into pharmaceutically acceptable acid additive salt, or an acid additive salt of the compounds of formula (I) is transformed into the form of a free base using alkali; and, if desirable, get their stereochemical isomeric form.

8. A method of obtaining a connection on p. 1, in which the intermediate compound of formula (IV) is treated with hydroxylamine-O-sulfonic acid in a reaction-inert solvent in the presence of a suitable base, thereby obtaining the compounds of formula (1-a), defined as compounds of formula (I) in which R1- methyl:

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where the radicals X, R2

9. The compound of formula (IV)

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and the acid additive salt, N-oxide form, or its stereochemical isomeric form,

in which X, R2-R5and bivalent radical defined in paragraph 1.

10. The method of obtaining the compounds of formula (IV) under item 9, which consists in the fact that the compound of formula (IX) is treated with N,N-dimethylacetamide by dimethylacetal in a reaction-inert solvent, obtaining the compound of formula (IV)

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followed if necessary by conversion of compounds of formula (IV) into each other following well-known in the art reactions of transformation, or, if desired, the compound of formula (IV) is converted into pharmaceutically acceptable acid additive salt, or an acid additive salt of the compounds of formula (IV) is transformed into the form of a free base by means of alkali and, if desired, receive

 

Same patents:

The invention relates to organic chemistry, namely to new derivatives of benzoperylene

The invention relates to the derivatives of pyrrolidine formula I

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where R1- H, C1-C6alkyl; phenyl, possibly substituted; biphenyl, possibly substituted; 1H, 5H - pyrido [3,2,1-ij] chinolin; phenyl WITH1-C6alkyl, optionally substituted; biphenyl WITH1-C6alkyl, optionally substituted; biphenylcarboxylic; terphenyl; naphthyl, optionally substituted; Z denotes-S-, -O-, -och2-, -N(R16), where R16- H, C1-C6alkyl, C3-C8cycloalkyl1-C6alkyl, panels1-C6alkyl, a chemical bond; X1means-CO-, -(CH2)r-CO-N(R17), where R17means H, C1-C6alkyl (where r = 0 or 1), -CH2NHSO2-, -(CH2)s-N (R18)-CO- (where R18- N, s=1-3), - CH2NHCОСН2O-, -CH2N (R19Of PINES = CH- (where R19- H, -CH2OCH2-, -CH2-N (R20)-CH2- (where R20- H, C1-C6alkyl, C1-C6alkylsulphonyl, phenylcarbinol)1-C5alkylen,2-C4albaniles, a chemical bond; X2- phenylene, optionally substituted hydroxy, theoffender, purandar, piperidinyl,< / BR>
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R2and R3each - H; and R4- phenyl, possibly substituted with halogen; R5- phenyl, possibly substituted; a cycle of G is phenyl,3-C7cycloalkyl, pyridyl, thienyl; loop J is phenyl; L is phenyl; p=0-2;----- means the presence or absence of chemical bonding;displays a CIS - or TRANS-configuration D relative to E; provided that X1means-CH2NHCО-, X2means 1,4-phenylene and X3means a chemical bond or a C1-C5alkylen, when the carbon atom bound CD and adjacent carbon atom in the cycle are connected by a simple relation and V1does not mean a chemical bond, when X1means-CH2O-; and pharmaceutically acceptable salt or hydrate of the compound

The invention relates to a method for the preparations of thiazolidinediones of the formula III, where a denotes CH=CH or S, W is O; X Is S, O or NR2where the remainder R2is hydrogen or C1-C6by alkyl; Y is CH or N; R is naphthyl, thienyl or phenyl, which optionally one - or twofold substituted C1-C3the alkyl, CF3C1-C3alkoxygroup, F, Cl or bromine; R1is hydrogen, C1-C6alkyl and n = 1-3, by restoring the compounds of formula IV metal aluminum in proton solvent

The invention relates to new derivatives of 2-(1,2,4-triazole-1-yl)-1,3,4-thiadiazole of the formula I, in which R1means a hydrogen atom, a C1-4alkyl group or phenyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen atom, hydroxy-group, nitro group, WITH1-4alkoxygroup, (C1-4alkyl) amino and di(C1-4alkyl)amino group; or a group of formula (a) Z means a hydrogen atom or a C1-4alkoxygroup, R0means a group of the formula Alk-NR4R5where Alk is alkalinous group having a straight or branched C1-6chain, one of R2and R3is amino and the other is an amino group or a 5-6-membered saturated heterocyclic group containing one or two atom(s) of nitrogen and/or oxygen and attached via its nitrogen atom, and the specified heterocyclic group may be substituted WITH1-4alkyl group, phenyl group or kalogeropoulou group, or the last of the R2and R3is a group of the formula - SR

The invention relates to new bicyclic to carboxamide formula (i) in which (1) X represents N and (a) Z is =CR1-CR2and Y is N, Z is =CR1and Y represents O, S or NR4or (C) Z is = CR1-N= and Y represents CR2or (2), X represents NR4Z represents CR1= and Y is N, Q is O, R1and R2are СОR6, C(= NOR6R13, alkyl-C(=NOR6R13, NR8R9, CF3or R6, R3is1-6alkoxygroup, R4represents H or alkyl, R5is heteroaryl, optionally substituted with halogen, alkyl, CONR11R12, CF3or CN, aryl, substituted with halogen; R6represents H, alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, arylalkyl, heteroaromatic or heteroseksualci, R7represents alkyl, hydroxy, OR10, NR8R9CN, CO2H, CO2R10, CONR11R12, R8and R9represent H or alkyl, or NR8R9represents a heterocyclic ring, optionally substituted by R14, R10represents an alkyl, heterocycle, R11and R12represent H or alkyl, and the salts

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

The invention relates to new compounds of the formula (I), where R1is (C3-C7)cycloalkyl group or a 3-7-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, oxygen, or sulfur, which may be optionally substituted by oxopropoxy; R2- aryl group, which optionally can be substituted by 1-3 halogen atoms; And a is methylene or carbonyl group; a simple bond; D is oxygen atom or sulfur; G is - (C1-C4)alkylenes group; L is a group of the formula-C(R4)(R5)-, where R4and R5defined in the claims, Z is two hydrogen atoms or an oxygen atom, n = 0 or 1, or its pharmaceutically acceptable salts, esters, Quaternary amines or hydrates

The invention relates to new heterocyclic compounds of the formula (I), where R1represents a group of formula (II), R is 2,4-dioxothiazolidine-5-ylmethylene group and others, And represents C1-6alkylenes group, A represents an oxygen atom, R4represents a substituted phenyl or pyridyl which may have a Deputy, R6represents a hydrogen atom or a C1-6alkyl group, D represents an oxygen atom or sulfur, E is a CH group or a nitrogen atom, or their pharmacologically acceptable salts

The invention relates to new 1,4-benzothiazepine-1,1-dioxides of the formula (I), where R1is non-branched C1-6alkyl group, R2is non-branched C1-6alkyl group, R3is hydrogen, R4represents phenyl, R5R6and R8selected from hydrogen, R7represents a group of formula (Ia) and (IB), where the hydroxy-group may be substituted by acetyl, R16represents-COOH, -CH2-OH, -CH2-O-acetyl-Sooma, R9and R10the same or different and each represents hydrogen or C1-6alkyl group, X represents-O-, or its salt, solvate and physiologically acceptable derivative

The invention relates to novel potassium salts derived biphenylmethane - mono - or dicale 2-[[5-ethyl-3-[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1,3,4-thiadiazoline-2-ilidene] aminocarbonyl] -1-cyclopentanecarboxylate having anti-hypertensive activity

The invention relates to a derivative of a simple ester, application and intermediate compounds used for their production

The invention relates to new preparations of thiazolidinediones of the formula I, where A denotes a carbocyclic ring with 5 or 6 carbon atoms or a heterocyclic aromatic 5-or 6-membered ring containing an S atom or N; B is-CH=CH-; W represents O; X represents O; Y represents N; R represents pyridyl, thienyl or phenyl, in case you need one - or disubstituted C1-C3-alkyl, CF3, Cl or bromine; R1represents C1-C6-alkyl;n represents 2, and their tautomers, enantiomers, diastereomers or physiologically acceptable salts and medicinal product on the basis of their

The invention relates to heterocyclic compounds having excellent pharmacological properties, and to intermediate compounds used for the synthesis of these compounds

The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates
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