Derivatives thiadiazolyl of pyridazine, inhibiting angiogenesis, the method of production thereof, pharmaceutical composition and method of reception

 

(57) Abstract:

Describes derivatives thiadiazolyl of pyridazine General formula (I) and their N-oxide forms, the pharmaceutically acceptable acid additive salt and stereochemical isomeric form, where R1represents hydrogen, C1-6alkyl, di (C1-6alkyl) amino, hydroxymethyl or benzoyloxymethyl; R2and R3represent hydrogen, R4means hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl, nitro, amino, C1-6allyloxycarbonyl or Het1; R5means hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl or nitro; R6means hydrogen or halogen; or, if R4and R5are located adjacent to each other, they may together form a bivalent radical of formula-CH=CH-CH=CH-; a represents a bivalent radical of the structural formula; where X in the formula (a-2) represents a direct bond, -O-, -S-, C=O, -NR8or Het2; X in formulas (a-3) and (a-6) is-O-; X in formula (a-4) is-NR8-; R7represents hydrogen; C1-6alkyl or Ar2is methyl; R8represents hydrogen, C1-6alkyl or Ar2is methyl; Alk1is1-6Alka is Ilichevsky a heterocycle, selected from oxazolyl, oxazolyl or oxadiazolyl, substituted on the carbon atom WITH1-4by alkyl; Het2is dioxolane, as well as methods for their preparation, pharmaceutical composition containing them, and method of reception. New compounds are inhibitors ontogenese and can be used to treat antagonistiekih diseases such as neovascular glaucoma, diabetic retinopathy, psoriasis and rheumatoid arthritis. 6 C. and 5 C.p. f-crystals, 6 PL.

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-O-Alk'-X- (a-4)

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-S-Alk1-X- (a-6)

The invention relates to new derivatives of 3-(3-substituted-1,2,4-thiadiazole-5-yl)pyridazine acting as inhibitors of angiogenesis, and to receive them; in addition, it refers to the containing compositions and to their use as pharmaceuticals.

Angiogenesis, i.e. the formation of new blood vessels by endothelial cells, plays a huge role 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 involved in rasputia, 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 deal with such angiogenesis-dependent 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 the European patent 0398427, published on 22 November 1990, described antirhinoviral pyridinoline and in the European patent 0435381, published July 3, 1991, describes pyridazinone with antipaternalism activity. In the European patent 0429344, published may 29, 1991, discloses derivatives aminopyridazine as a cholinergic agonist 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 R1represents hydrogen, C1-6alkyl, di(C1-6alkyl)amino, hydroxymethyl or benzoyloxymethyl;

R2and R3represent hydrogen,

R4means hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl, nitro, amino, C1-6allyloxycarbonyl or Het1;

R5means hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl or nitro;

R6means hydrogen or halogen; or, if R4and R5are located adjacent to each other, they may together form a bivalent radical of formula-CH=CH-CH=CH-;

A represents a bivalent radical of formula:

-O-Alk1-X- (a-4),

-N(R7)-Alk1-X- (a-2) or

-N(R7)-Alk1-X-Alk2- (a-3)

-S-Alk1-X- (a-6),

where X in the formula (a-2) represents a direct bond, -O-, -S-, C= O, -NR8or Het2Gorod, WITH1-6alkyl or AG2is methyl;

R8represents hydrogen, C1-6alkyl or AG2is methyl;

Alk1is1-6alcander;

Alk2is1-4-alcander;

AG2represents phenyl;

Het1represents a monocyclic heterocycle selected from oxazolyl, oxazolyl, oxadiazolyl, substituted on the carbon atom WITH1-4by alkyl;

Het2is dioxolane.

As used in the preceding and the following definitions, halogen is a generic name for fluorine, chlorine, bromine and iodine; C1-4alkyl defines a linear or branched saturated hydrocarbon chain 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 and so on;2-4alcander defines bivalent linear or branched saturated hydrocarbon chain radicals containing from 2 to 4 carbon atoms such as, for example, 1,2-ethandiyl, 1,3-PI means, C1-6alcander includes C1-4alcander and higher homologues containing from 5 to 6 carbon atoms, such as, for example, 1,5-pentanediyl, 1,6-hexanediol, etc., the Term "C= O" refers to a carbonyl group.

Regardless, there is a bivalent radical(a-2) or (a-3) in the compounds of the present invention, the nitrogen-NR7the fragment preferably is associated with pyridazinyl fragment of the above compounds. Similarly, regardless of whether the bivalent radical(a-4), (a-5) or (a-6), oxygen atom or sulfur, preferably associated with pyridazinyl fragment. Examples of the bivalent radical a are, for example:

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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 acids include, for example, inorganic acid, the NSS and the like acids; or organic acids, such as, for example, acetic, propionic, hydroxyestra, lactic, pyruvic, 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 can form the above-mentioned connection. The above Enya. 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, particularly those N-oxides, in which one of pyridinoline of Izotov is N-oxidized.

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, independently of each other:

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

b) R2and R3represent hydrogen;

c) R4means hydrogen, halogen, C1-6the means hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl or nitro;

e) the bivalent radical a is (a-2) or (a-3), where7represents hydrogen or C1-6alkyl, or a is (a-6) where X represents O; Alk1in said radicals (a-2), (a-3) or (a-6) preferably represents a C2-4alcander.

A special group of compounds are those compounds of formula (I) in which R1represents hydrogen, C1-4alkyl or di(C1-4alkyl)amino; R2and R3represent hydrogen; R4means hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl, nitro, amino, C1-6allyloxycarbonyl or Het1; R5means hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl or nitro; the bivalent radical a is (a-2), (a-3), (a-4) or (a-6) where AK1preferably represents C2-4alcander.

A preferred group of compounds are those compounds of formula (I), in which the bivalent radical a is a (a-2), (a-4) or (a-6), in which Alk1represents a C2-4alcander.

A more preferred group of compounds are those prefer the blowing connection:

6-(3-methyl-1,2,4-thiadiazole-5-yl)-N-[4-[3-(trifluoromethyl)phenoxy] butyl-3-pyridazinone,

N-methyl-6-(3-methyl-1,2,4-telazol-5-yl)-N-[4-[3-(trifluoromethyl)phenoxy] butyl]-3-pyridazinones and

6-(3-methyl-1,2,4-thiadiazole-5-yl)-N-[4-[3-(trifluoromethyl) phenylthio] butyl-3-pyridazinones and their pharmaceutically acceptable acid additive salts, stereoisomeric forms or N-oxides.

Compounds of the present invention can be generally obtained by the interaction of pyridazine 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 group, 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-dimethyl-formamide, acetonitrile, isobutyl ketone, etc., preferably in the presence of base, h is Leno 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 the bivalent radical A' is the radical of formula (a-2), (a-4) or (a-6) where X represents a direct bond, these compounds are described by formula (I-a) can be obtained by condensation of a phenol of the formula (V) and the intermediate compounds of formula (IV), for example, using the reaction Mitsunobu (Mitsunobu) (Synthesis, 1, 1981). The above reaction is carried out in a reaction-inert solvent, such as THF and in the presence of triphenylphosphine and diisopropylcarbodiimide (DYADS).

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In addition, the compounds of formula (I-a) can be obtained from the following well-known in this field by the reactions of O-alkylation by reacting the intermediate compounds of formula (IV), where W represents a removable group, as defined above, with a phenol of the formula (V), where a' is the same as defined above.

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This reaction of O-alkylation can be conveniently carried out by mixing the reactants, optionally in a reaction-inert solvent. Optional you can add a suitable base, such as, for example, sodium carbonate, sodium bicarbonate, sodium hydroxide, etc. to bind the acid which is formed during the course reaka, for example, salt of alkali or alkaline earth metal, the reaction of (V) with a suitable base as defined above, with the subsequent use of the above salt form in the reaction with intermediate compound of formula (VI). Mixing and increased to a certain extent, the temperature can increase the reaction rate; in particular, the reaction can be carried out at the boiling temperature of the reaction mixture under reflux. Additionally, it may be advantageous to carry out the above alkylation reaction in an inert atmosphere, such as, for example, does not contain oxygen, argon or nitrogen gas.

The compounds of formula (I) can be also obtained by the conversion of compounds of formula (I) into each other according to well-known in this field reactions of transformation groups. For example, the compounds of formula (I), in which the bivalent radical a is a radical of formula (a-2) to (a-6) where X represents Het2and the specified Het2represents dioxane, can be converted into the corresponding compounds of formula (I), where the X represents C=0, by hydrolysis in acidic conditions.

The compounds of formula (I) can also be converted into sootvetstvuyu 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 are, for example, water, lower alkanols, for example ethanol, etc., hydrocarbons such as toluene, ketones, such as 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, in General, known in the art.

Intermediate will connect a group to delete, defined above, with an intermediate compound of formula (VIII) optionally in the form of its acid salt additive.

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Intermediate compounds of formula (III), where the bivalent radical a is a radical of formula (a-2), these intermediate compounds represented by intermediate compounds (III-a) or where the specified radical And a represents the formula (a-3), such specified intermediate compounds is represented as an intermediate compound (III-b), can be obtained by the interaction of their respective halogenerators, i.e., the intermediate compound (IX) or (X) with an intermediate compound of formula (IX).

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This interaction can be performed by stirring the intermediate of formula (IX) or (X) with an intermediate compound of formula (XI) in a reaction-inert solvent, such as THF, in the presence of calcium oxide. If desired, the temperature may be increased in the range between room temperature and the boiling temperature of the reaction mixture and, if necessary, the reaction can be carried out in an autoclave at high pressure.

Intermediate compounds of formula (IX) or (X) can also interact with the intermediate compounds, what, for example, benzyl group. If desirable, well-known in this field reactions of transformation of functional groups can be performed before the specified protective group is removed using known in the field of methods, such as, for example, hydrogenation with palladium on carbon in presence of hydrogen gas.

Intermediate compounds of formula (IV), in which A' represents a bivalent radical of formula (a-2), (a-4) or (a-6) where X is Oh, can be obtained by the reaction of intermediate compounds of formula (II) with an intermediate compound of formula (XII) in a reaction-inert solvent such as N, N-dimethylformamide, and optionally in the presence of a suitable base, such as, for example, sodium carbonate.

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The compounds of formula (I) and some intermediate compounds may have in its structure one or more stereogenic centers with R or S configuration. For example, the compounds of formula (T), in which the bivalent radical A, represents a radical of the formula (a-2) to (a-6) where Alk1is2-6alcander can have stereogenic centers as, for example, compounds 88 and 89.

The compounds of formula (I) obtained by opiskelen from each other by means well known in the field of separation techniques. Racemic compounds of the formula (I) can be converted into the appropriate form diastereomeric salts by interaction with a suitable chiral acid. These form the diastereomeric salts are subsequently separated, 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 trebuetsya. In these methods, it is advantageous to use enantiomerically pure source materials.

The compounds of formula (I) have useful pharmacological properties, the inhibition of angiogenesis in vivo and in vitro, as demonstrated in pharmacological example C. 1.

From the point of view of their pharmacological activity, 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 ptx2">

From the point of view of usefulness of the considered compounds for the treatment or prevention of angiogenesis-dependent diseases, in the present invention a method of treating warm-blooded animals suffering from such diseases, the above method involves the systematic introduction of therapeutically effective amounts of compounds of formula (I), N-oxide or pharmaceutically acceptable acid additive salt.

Taking into account their useful pharmacological properties, the compounds being considered can be integrated into various pharmaceutical forms for the purposes of their appointment. 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 mixed into a homogeneous mixture with a pharmaceutically acceptable carrier, such carrier may have many different 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, when receiving kDa, 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, binders, dezintegriruetsja agents, etc. in the case of powders, granules, capsules and tablets. Due to the ease of the introduction of tablets and capsules represent the most advantageous oral unit dosage forms, which are commonly used 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 is considerable harmful effects 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 solubility in water compared with the shape of the base is usually more suitable for preparation of aqueous solutions.

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 Scripture and in the claims refers to physically discrete units suitable as well 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 with notches and coated tablets), capsules, granules, packets of powders, pellets, solutions or suspensions for injection, measured teaspoon locamation compositions can be in the form of solid dosage forms, for example, 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, klasterizovannykh corn starch, polyvinylpyrrolidone or hypromellose); fillers (e.g. lactose, microcrystalline cellulose and calcium phosphate); lubricating agents (e.g. 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, hypromellose or hydrogenated edible fats); emulgirujushchie esters or ethyl alcohol); and preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid).

Pharmaceutically acceptable sweeteners include preferably at least one intense sweetener, such as saccharin, saccharin sodium or calcium, aspartame, Acesulfame potassium, sodium cyclamate, alitum, dihydrochalcone 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, the 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).

Pharm what 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 may be needed stronger flavors, such as Caramel Chocolate flavoring. Mint cool perfume, Fantasy perfume, and the like 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 umerennogo 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 doses, with added preservative. The compositions can take such forms as suspensions, solutions or emulsions 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 drops.

Specialists in this field easily modelagency, the effective amount will be from about 0.001 mg/kg to 10 mg/kg body weight and in particular from 0.01 mg/kg to 1 mg/kg of body weight. It may be convenient to provide the required dose in the form of two, three, four or more podos at suitable intervals during the day. The above padosi can be prepared as unit dosage forms, for example, containing from 0.01 to 500 mg, and in particular from 0.1 to 200 mg of 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

3-Chloro-6-methylpyridazine (0.3 mol) and thionyl chloride (400 g) was stirred and heated at boiling under reflux overnight. The solvent was evaporated. The residue was dissolved in DHM (500 ml). The mixture was cooled to 0oC. was Added the hydrochloride of 1-aminoethylamino (1:1) (33 g). Then at 0oWith was added dropwise sodium hydroxide (50%, 80 ml). The mixture was left to warm to room temperature, then was stirred for 1 hour,Yali, was dried, filtered and the solvent was evaporated. The residue was boiled in ethanol (800 ml), silica gel (20 g) and activated carbon Norit (3 g). The mixture was filtered through dekalim and the filtrate was evaporated. The residue was purified using silica gel on a glass filter (eluent: DHM). Pure fractions were collected and the solvent was evaporated. The residue was led from ethanol. The precipitate was filtered and dried, obtaining of 18.3 g (29%) 3-chloro-6-(3-methyl-1,2,4-thiadiazolyl-5-yl)pyridazine (intermediate compound 1).

Similarly received 3-chloro-6-(1,2,4-thiadiazolyl-5-yl)pyridazine (intermediate compound 2) and 5-(6-chloro-3-pyridazinyl)-N,N-dimethyl-1,2,4-thiadiazole-3-amine (intermediate compound 3).

Example A. 2

A mixture of 4-(4-bromobutoxy)-1,2-dichlorobenzene (0.03 mol), methylamine (20 g) and calcium oxide (7 g) in THF (100 ml) was stirred at 125oWith during the night in the autoclave. The mixture was filtered through dekalim and the filtrate was evaporated. The residue was mixed with DIPE and the mixture was filtered through dekalim. The filtrate was transferred into the salt of hydrochloric acid (1:1) under the action of a mixture of HCl/2-propanol. The precipitate was filtered and dried, obtaining 6 g (70,3%) of 4-(3,4-dichlorophenoxy)-N-methyl-1-butanamine (intermediate compound 4, etc., 132oC).

oC and left overnight. Was added water and was extracted with a mixture of DHM. The organic layer was dried, filtered and evaporated. The residue was purified on a glass filter over silica gel (eluent: CH2CL2/CH3HE is from 98/2 to 90/10). Pure fractions were collected and evaporated. The oily residue was dissolved in DIPE and translated in salt hydrochloric acid (1:2) in 2-propanol. The precipitate was filtered and dried to give 10 g (30%) of the dihydrochloride of N-[3-(trifluoromethyl)phenyl] - 1.6 hexanediamine (intermediate compound 5).

Similarly got the dihydrochloride of N-phenyl-1,4 butanediamine (intermediate compound 6).

Example A. 4

a) a Mixture of 1-(4-bromobutoxy)-3-(trifluoromethyl)benzene (0.11 mol) and benzylamine (0.6 mol) in dimethylacetamide (250 ml) was stirred at 80oC for 6 hours, then poured into water and was extracted with toluene. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was transferred into the salt of hydrochloric acid (1:1) in DIPE. The precipitate was filtered and dried, obtaining 23.3 g (59%) of the hydrochloride of N-[4-[3-trifluoromethyl)phenoxy]butyl] benzoylmethylene (intermediate compound 7).

b) a Mixture of intermediate compound 7 (0.03 mol) and paraformaldehyde of thiophene (4%, 2 ml) and potassium acetate (4 g). After absorption of gaseous hydrogen (1 equivalent), the catalyst was filtered and the filtrate was evaporated. The residue was stirred in water and the mixture was extracted with DHM. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was dissolved in DIPE and translated in salt hydrochloric acid (1:1) mixture of HCl/2-propanol. The precipitate was filtered and dried, obtaining by 8.22 g (73%) of the hydrochloride of N-methyl-N-[4-[3-trifluoromethyl)phenoxy]butyl] benzoylmethylene (intermediate compound 8).

c) a Mixture of intermediate compound 8 (0.019 mol) in methanol (150 ml) was first made using palladium on carbon (10%, 2 g) as a catalyst. After absorption of gaseous hydrogen (1 equivalent), the catalyst was filtered and the filtrate was evaporated. The residue was converted into the free base by the action of NaOH solution. The aqueous solution was extracted with toluene. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was transferred into the salt of hydrochloric acid (1:1) in DIPE. The precipitate was filtered and dried, obtaining 1,21 g (22,5%) of N-methyl-4-[3-trifluoromethyl)phenoxy]-1-butanamine (intermediate compound 9).

Example 5 A.

A mixture of intermediate connection is UP>C for 4 hours. The solvent was evaporated. The residue was absorbed DHM. The mixture was stirred, filtered through dicalite and the filtrate was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH from 100/0 to 97/3). Pure fractions were collected and the solvent was evaporated, receiving of 22.2 g (100%) 4-[methyl[6-(3-methyl-1,2,4-thiadiazole-5-yl)-3-pyridazinyl] amino] -1-butanol (intermediate compound 10).

C. obtain the final compounds

Example C. 1

A mixture of intermediate compound 1 (0.02 mol) of intermediate compound 9 (0,0212 mol) and sodium carbonate (0.03 mol) in DMF (60 ml) was stirred and heated at 60oWith during the night. The mixture was evaporated, the residue was dissolved in a mixture of toluene and water and the layers were separated. The aqueous layer was extracted with toluene. 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). Pure fractions were collected and the solvent was evaporated. The residue was led from 2-propanol. The precipitate was filtered and dried, obtaining 2,77 g (33%) of N-methyl-6-(3-methyl-1,2,4-thiadiazole-5-yl)-N-[4-[3-(trifluoromethyl)phenoxy] butyl] -3-pyridazinone (compound 52).

Example Century. 2

Diisopropylethylamine), 4-triptoreline (0.01 mol) and triphenylphosphine (0, 036 mol) in THF (60 ml) under cooling with ice. The mixture was stirred at room temperature for 30 minutes. The solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: DHM). Pure fractions were collected and the solvent was evaporated. The residue was dissolved in DIPE and translated in salt hydrochloric acid (1:1). The precipitate was filtered and dried. This fraction was boiled in DIPE, was filtered and dried, obtaining 1,31 g (36%) of monohydrochloride N-methyl-6-(3-methyl-1,2,4-thiadiazole-5-yl)-N-[4-[4-(trifluoromethyl)phenoxy] butyl]-3-pyridazinone (compound 55).

Example B. 3

A mixture of compound 95 (0,0065 mol) in aqueous sulfuric acid solution (1%, 200 ml) was stirred and heated at boiling under reflux overnight. The reaction mixture was cooled and the precipitate was filtered, washed with water and dried, obtaining 3 g(100%) 5-[[6-(3-methyl-1,2,4-thiadiazole-5-yl)-3-pyridazinyl] amino] -1-[3-(trifluoromethyl)phenyl]-1-pentanone (compound 69).

Example 4 b

a) a Mixture of 3-chloro-6-cyanopyridine (0.03 mol) in triethylamine (12 ml) and DMF (50 ml) was stirred on an ice bath. Hydrogen sulfide was barbotirovany through the mixture for 20 minutes. The mixture was stirred over night. Gas is ivali water, was dissolved in DMF and the solvent was evaporated, receiving 3 g (48%) of 6-mercapto-3-pyridinecarboxamide (intermediate compound 11).

b) a Mixture of intermediate 11 (of 0.017 mol) in DMF (80 ml) was stirred at room temperature. Portions was added sodium hydride (50%, 0.02 mol). The mixture was stirred for 30 minutes. Was added dropwise a mixture of 1-(4-chloroethoxy)-3-(trifluoromethyl)benzene (0.02 mol) in DMF (20 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was stirred in DIPE (100 ml), was filtered and dried, obtaining 3.1 g(47%) 6-[[4-[3-(trifluoromethyl)phenoxy] butyl] thio]-3-pyridinecarboxamide (intermediate compound 12).

c) a Mixture of intermediate compound 12 (0,009 mol) and N,N-dimethylacetamide of dimethylacetal (0.015 mol) in toluene (100 ml) was stirred and heated at the boil under reflux for 3 hours, the solvent was evaporated, obtaining 4.1 g (100%) N-[1-(dimethylamino)ethylidene]-6-[[4-[3-(trifluoromethyl)phenoxy] butyl] thio] -3-pyridinecarboxamide (intermediate compound 13).

d) was Stirred mixture of intermediate compound 13 (0,009 mol) and pyridine (0.02 mol) in ethanol (80 ml). Was added to a mixture of hydroxylamine-O-sulfonic acid (0.01 mol) in metalwor washed with dilute NaOH solution and water, was dried, filtered and the solvent was evaporated. The residue was purified column chromatography on silica gel (eluent: DHM). Pure fractions were collected and the solvent was evaporated. The residue was led from 2-propanol. The precipitate was filtered and dried, obtaining 1 g (26%) of 3-(3-methyl-1,2,4-thiadiazole-5-yl)-6-[[4-[3-(trifluoromethyl)phenoxy] butyl]thio]pyridazine (compound 94).

Example Century. 5

A mixture of compound 101 (0,0094 mol) in HCl (80 ml) was stirred and heated at the boil under reflux for 25 minutes. The mixture was cooled on ice, was podslushivaet concentrated solution of NH4HE was extracted DHM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2CL2/CH3IT). Pure fractions were collected and the solvent was evaporated. The residue was dissolved in 2-propanol and translated in salt hydrochloric acid under the action of a mixture of HCl/2-propanol. The mixture was left to crystallize. The precipitate was filtered and dried, obtaining 1.1 g (2%) of the compound (102).

In tables f 1 to f 5 lists the compounds that were obtained according to one of the above examples and table F. 6 shows how experime analysis for carbon, hydrogen and nitrogen to 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 J. Fortunato M. "Laboratory Investigations", vol.73(#5), p. 734, 1995. The compound was tested at several concentrations to determine the inhibitory capacity (IC50). Multiple connections, as shown in table C. 1, characterized by the value of the IC50lower than 100 nm.

1. Derivatives of 3-(3-substituted-1,2,4-thiadiazole-5-yl)pyridazine General formula (I)

< / BR>
and their N-oxide forms, the pharmaceutically acceptable acid additive salt and stereo proximity or benzoyloxymethyl;

R2and R3represent hydrogen,

R4means hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl, nitro, amino, C1-6allyloxycarbonyl or Het1;

R5means hydrogen, halogen, C1-6alkyl, C1-6alkoxy, trifluoromethyl or nitro;

R6means hydrogen or halogen; or, if R4and R5are located adjacent to each other, they may together form a bivalent radical of formula-CH=CH-CH=CH-;

A represents the bivalent radical of the formula

-O-Alk1-X- (a-4)

-N(R7)-Alk1-X- (a-2) or

-N(R7)-Alk1-X-Alk2(a-3)

-S-Alk1-X- (a-6)

where X in the formula (a-2) represents a direct bond, -O-, -S-, C= O, -NR8or Het2X in the formula (a-3) and (a-6) is-O-; X in formula (a-4) is-NR8-;

R7represents hydrogen, C1-6alkyl or AG2is methyl;

R8represents hydrogen, C1-6alkyl or AG2is methyl;

Alk1is1-6alcander;

Alk2is1-4-alcander;

AG2represents phenyl;

Het1represents a monocyclic heterocycle selected from oxazolyl, oxazolyl or tx2">

2. Connection on p. 1, in which R1represents hydrogen, C1-6alkyl or di(C1-6alkyl)amino; R4selected from hydrogen, halogen, C1-4of alkyl, C1-4alkyloxy, trifloromethyl, nitro, C1-6allyloxycarbonyl or Het1.

3. Connection on p. 1, in which the bivalent radical a is (a-2), (a-4) or (a-6), in which Alk1is2-4alcander.

4. Connection on p. 3 in which Alk1is butandiol.

5. Connection on p. 1, representing

6-(3-methyl-1,2,4-thiadiazole-5-yl)-N-[4-[3-(trifluoromethyl)phenoxy] butyl]-3-pyridazinone,

N-methyl-6-(3-methyl-1,2,4-thiadiazole-5-yl)-N-[4-[3-(trifluoromethyl)phenoxy] butyl]-3-pyridazinone or

6-(3-methyl-1,2,4-thiadiazole-5-yl)-N-[4-[3-(trifluoromethyl)phenylthio] -butyl] -3-pyridazinone,

their stereoisomeric forms or pharmaceutically acceptable acid additive salt.

6. Inhibiting angiogenesis pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient a therapeutically effective amount of a compound according to any one of paragraphs.1-5.

7. A method of obtaining a pharmaceutical composition according to p. 6, in which uniformly mix farmee angiogenesis.

9. The method of obtaining compounds of General formula I on p. 1, where1-R6and As are specified in paragraph 1 values, which consists in the fact that the compound of General formula II

< / BR>
where R1-R3have the above values;

W is a suitable removable group,

subjected to interaction with the compound of General formula III

< / BR>
where R4-R6and a have the above values,

in a reaction-inert solvent and optionally in the presence of a suitable base and, if necessary, the compound obtained is transformed into another compound of formula (I), the 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 Vice versa, an acid additive salt of the compounds of formula (I) is transformed into the form of a free base by means of alkali and, if desired, receive their stereochemical isomeric form.

10. The method of obtaining compounds of General formula (1-a) under item 1

< / BR>
where R1-R6are specified in paragraph 1 values;

And' means a radical of the formula (a-2), (a-4) or (a-6) where X is always a direct link,

namely, that link is Nole General formula (V)

< / BR>
where R4-R6have the above values,

in a reaction-inert solvent and in the presence of diisopropylcarbodiimide and, if necessary, the compound obtained is transformed into another compound of formula (I), the 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 Vice versa, an acid additive salt of the compounds of formula (I) is transformed into the form of a free base by means of alkali and, if desired, receive their stereochemical isomeric form.

11. The method of obtaining compounds of General formula (1-a) under item 1

< / BR>
where R1-R6are specified in paragraph 1 values;

the radical A' is a radical of formula (a-2), (a-4) or (a-6),

X represents a direct bond,

including the condensation of compounds of General formula (VI)

< / BR>
where R1-R3and A' have the above meanings;

W is a suitable removable group,

with a phenol of General formula (V)

< / BR>
where R4-R6have the above values,

in reactino-inert solvent and optionally in the presence of a suitable base, and obratno, an acid additive salt of the compounds of formula (I) is transformed into the form of a free base by means of alkali and, if desired, receive their stereochemical isomeric form.

 

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