Substituted derivatives of benzene or their salts, pharmaceutical composition based on thereof

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivative of benzene or its salt of the formula (I): wherein X1 means -C(=O)-NR5-, -NR5-C(=O)-; X2 means -NR6-C(=O)-, -NR6-CH2-; R1 means halogen atom, lower alkyl or lower alkoxy-group; R2 and R3 mean hydrogen or halogen atom; R4 means hydrogen atom, -SO3H- or sugar residue; ring A represents benzene or pyridine ring; ring B represents piperidine ring, and a pharmaceutical composition based on thereof. Proposed compounds possess anti-coagulating effect based on inhibition of blood coagulation activated factor X that are useful as anti-coagulants or prophylactic agents against diseases caused by thrombosis and embolism.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

5 cl, 9 tbl, 38 ex

 

The scope of the invention

This invention relates to new substituted derivative of benzene or its salts, which are used as a pharmaceutical agent, particularly as an inhibitor of activated factor X in the coagulation of blood, and also to the pharmaceutical agent with the same effect.

Prerequisites to the creation of inventions

Due to changing life style of Europe and America, and increased populations of older people in recent years, the number of patients with thromboembolic disease, including myocardial infarction, cerebral thrombosis and peripheral arterial thrombosis, is growing from year to year and the social significance of their treatment increases more and more. Along with fibrinolytic therapy and antiplatelet therapy, anticoagula therapy is a part of medical therapy in the prevention and treatment of thrombosis (Sogo Rinsho, 41; 2141-2145, 1989). In particular, the security that must withstand prolonged introduction, and the exact and correct expression antikoaguliruyuschey activity are essential in the prevention of thrombosis. Warfarin potassium is often used in the world as the only oral anticoagulant, but this medicine is extremely difficult to apply clinically, because it is difficult to control anticoagulatory the ability of the typical person who values the mechanism of its action (J.Clinical Pharmacology, 32, 196-209, 1992, and N. Eng. J. Med., 324(26), 1865-1875, 1991), therefore, great attention is focused on the development of a more useful and easily applicable anticoagulants.

Thrombin controls the conversion of fibrinogen into fibrin, which is the final stage of coagulation, and is also deeply involved in the activation and aggregation of platelets ("T-PA and Pro-UK, published S.Matsuo published Gakusai, Kikaku pp. 5-40 "Blood Coagulation", 1986), and its inhibitor is the main object of studies of anticoagulants as a goal the development of pharmaceuticals. However, thrombin inhibitors, which could be introduced orally, up to now did not come out on the market due to their low bioavailability in oral introduction and problems associated with their security (Biomed. Biochim. Acta, 44, 1201-1210, 1985).

Activated factor X in the coagulation of blood is a key enzyme that is localized at the point of connection of the main cascade and alternative reactions of coagulation and is localized above in the course of the cascade towards thrombin, therefore there is the probability that the inhibition of this factor is more effective than inhibition of thrombin, and that this inhibitor can inhibit the coagulation system in a specific way (THROMBOSIS RESEARCH (19), 339-349, 1980).

As compounds with inhibitory effect on activated factor X in the coagulation of blood, known derivatives of midinotate-alkylbenzene or their salts (Japanese Patent Laid-Open No. 208946/1993; Thrombosis Haemostasis, 71(3), 314-319, 1994, and Thrombosis Haemostasis, 72(3), 393-396, 1994).

In WO 96/16940 mentioned that aydinonat-derivative, represented by the following formula or its salt is a compound having inhibitory effect on activated factor X in the coagulation of blood:

(symbols in the formula you can see in the specified publication).

In WO 99/00121, WO 99/00126, WO 99/00127, WO 99/00128, WO 00/39111, WO 00/39117 and WO 00/39118 connection phenylenediamine represented by the following formula, etc. are referred to as inhibitor of factor XA:

(formula symbols, see these publications).

Further, in WO 99/32477 as anticoagulant mentioned a wide range of compounds represented by the following formula:

(symbols in the formula you can see in the specified publication).

In antikoaguliruyuschey therapy inhibitor of activated factor X in the coagulation of blood is supposed to inhibit the coagulation system effectively and specifically in comparison with thrombin inhibitor. Accordingly, there is an urgent need for a selective inhibitor of activated factor X in the coagulation of blood, which has a chemical structure different from the above known compounds, and which are suitable for oral administration and has excellent the initial action.

Description of the invention

In the result of various studies found that the substituted derivative of benzene, represented by the following formula (I)or its salt, having the characteristic features of chemical structure, which consists in the fact that the ring of benzene or heterokonta (ring A) is linked with the benzene ring through an amide bond (X1), and the like, the indicated benzene ring optionally linked to the piperidine ring or a benzene ring (ring) via amide linkages (X2), and the like, the Central benzene ring is always-OR4(-OH, -O-SO3H or-O - sugar residue) and R1always has a Deputy other than a hydrogen atom (halogen atom, lower alkyl which may be substituted by a halogen atom, or a lower alkoxygroup, which may be substituted by halogen atom), has excellent inhibitory effect on activated factor X in the coagulation of blood and, in particular, has excellent activity in oral introduction, through which it was created the invention.

Thus, the present invention relates to substituted derivative of benzene, represented by the following formula (I), or salts thereof and to pharmaceutical compositions containing it as active ingredient, especially inhibitor of activated factor X in the coagulation of blood:

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The symbols in the formula have the following meanings:

X1: -C(=O)-NR5-, -NR5-C(=O)-, -CH2-NR5- or-NR5-CH2-;

X2: -C(=O)-NR6-, -NR6-C(=O)-, -CH2-NR6- or-NR6-CH2-;

R1: halogen atom, lower alkyl which may be substituted by a halogen atom, or a lower alkoxygroup, which may be substituted by a halogen atom;

R2and R3: the same or different and each means a hydrogen atom, a halogen atom, CN, -NH-SO2-(lower alkyl), -NH-CO-(lower alkyl), -CO-(lower alkyl), -CO-(lower alkoxygroup), -CO-NH2, lower alkyl which may be substituted by a halogen atom, or a lower alkoxygroup, which may be substituted by a halogen atom or-S-(lower alkyl);

R4: a hydrogen atom, -SO3H or the residue of sugar;

ring: benzene ring or a five - or six-membered heterokonta containing from 1 to 4 heteroatoms, which are selected from the group consisting of N, S and O;

ring: ring of piperidine, where the nitrogen atom is substituted by an R7when R4means a hydrogen atom or-SO3N-or where R4means the residue of sugar, it is a piperidine ring, where the nitrogen atom

substituted R7or a benzene ring substituted

R5and R6: one is the same or different and each means a hydrogen atom or lower alkyl;

R7and R8each means a hydrogen atom, a lower alkyl, -SO2-(lower alkyl) or a five - or six-membered heterokonta containing from 1 to 4 heteroatoms, which are selected from the group consisting of N, S and O,

provided that, when X2means-NR6-C(=O)- and R4means a hydrogen atom, ring a represents a five - or six-membered heterokonta containing from 1 to 4 heteroatoms, which are selected from the group consisting of N, S and O.

The compound (I) according to this invention has a structure different from that disclosed in Japanese Patent Laid-Open No. 208946/1993 and in WO 96/16940 in the sense that the ring a represents a benzene ring or heteroclite without amidinothiourea, and the portion of the molecule X2means-C(=0)-NR6-, -NR6-C(=O)-, -CH2-NR6- or-NR6-CH2-not having a simple essential communication etc.

Further, the compound (I) according to this invention has a structure that differs from WO 99/00121, WO 99/00126, WO 99/00127, WO 99/00128, WO 00/39111, WO 00/39117 and WO 00/39118 in the sense that R4always has a hydrogen atom, -SO3H or the residue of sugar, ring B is piperidine ring in which the nitrogen atom is substituted by an R7or a benzene ring substituted by a group

etc.

In addition, compound (I) according to this invention has a structure different from the compounds specifically described in WO 99/2477, in that the ring does not have a triazole ring, R4always has a hydrogen atom, -SO3H or the residue of sugar, etc.

Further, the compound (I) according to this invention will be explained in detail.

The term "lower" in the definition of formula in the description means a linear or branched carbon chain having 1-6 carbon atoms, unless otherwise specified. Therefore, examples of "lower alkyl" are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Of them, preferred are those who have 1-3 carbon atoms, and especially preferred methyl and ethyl. "The lowest alkoxygroup" means-O-(lower alkyl)and, more specifically, its examples include methoxy, ethoxy, propoxy, isopropoxy, although they are not restrictive. Methoxy, ethoxy preferred.

Examples of the "halogen atom" include fluorine atom, chlorine atom, bromine atom and iodine atom. Particularly preferred chlorine atom and a bromine atom.

"Lower alkyl that may be replacing the Yong halogen atom or a lower alkoxygroup, which may be substituted by a halogen atom" means the above-mentioned "lower alkyl" or "lower alkoxygroup", where from 1 to 6 carbon atoms substituted "by halogen atoms, and their examples are trifluoromethyl, deformity, vermeil, chloromethyl, 2-chloroethyl, 2-bromacil, triptoreline, deformedarse, formatosi, chloromethoxy etc., although they are not restrictive. Vermeil, formatosi especially preferred.

"The balance of sugar" means sugar residue of the monosaccharide. For example, the remaining sugar is what remains after removing one hydroxyl group, especially when position 1 of the sugar, such as glucose, mannose, galactose, arabinose, xylose, ribose, N-acetylglucosamine, glucuronic acid, mannurone acid and so on, although they are not restrictive, but also included the remains of sugar where the specified hydroxyl group substituted by a lower alkoxygroup, or the like. Preferred sugar residue from glucuronic acid.

As for the "five - or six-membered heterokonta containing from 1 to 4 heteroatoms which may be selected from the group consisting of N, S and O, and its examples are pyridine, pyrimidine, pyrazin, pyridazine, triazine, pyrrole, furan, thiophene, thiazole, imidazole, imidazoline, oxazole, isothiazol, pyrazole, isoxazol, triazole and tetrazole, although they are not granitelike. Specified heterokonta not limited to unsaturated ring, but includes a saturated ring, such as pyrrolidine, imidazolidine, pyrazolidine, piperidine, piperazine and morpholine. Can also be included heterokonta condensed with a benzene ring, such as quinoline, isoquinoline, cinoxacin and benzimidazole. Especially preferably a pyridine ring. When specified heteroclita is furan or thiophene and R1means 2-chloro or 2-methyl, X1is located at the position other than 5, furan or thiophene.

X1means-C(=O)-NR5-, -NR5-C(=O)-, -CH2-NR5- or-NR5-CH2- and preferable-C(=O)-NR5- or-NR5-C (=O)-, X2means-C(=O)-NR6-, -NR6-C(=O)-, -CH2-NR6- or-NR6-CH2- and preferable-NR6-C(=O) -, or-NR6-CH2-.

R5and R6are the same or different and each means a hydrogen atom or lower alkyl, and more preferred is a hydrogen atom. When both R7and R8mean lowest alkali, especially preferably when they are isopropyl, though, when they are heterokontae, they preferably pyridine ring.

Preferably, the ring And was a benzene ring or a pyridine ring.

When R4means a hydrogen atom or-SO3H, ring B oznachaet the piperidine ring, where the nitrogen atom is substituted by an R7for example

When R4means the remainder of the sugar, the ring means a piperidine ring, where the nitrogen atom is substituted by an R7or a benzene ring; substituted

(a benzene ring substituted by the group 1,4-diazepan-1-yl, where the nitrogen atom is substituted by an R8), for example,

Especially preferred compounds among the compounds of this invention are:

4'-bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-β-D-galactopyranosyl-1-isopropylpiperazine-4-carboxanilide,

2'-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)-4'-bromo-6'-[(5-chloro-2-pyridyl)carbarnoyl]-1-isopropylpiperazine-4-carboxanilide,

4'-bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-β-D-glucopyranosyloxy-1-isopropylpiperazine-4-carboxanilide,

5-chloro-3-[(5-chloro-2-pyridyl)carbarnoyl]-2-[(1-isopropylpiperazine-4-carbonyl)amino]phenyl-β-D-glucopyranoside uronic acid,

5-bromo-3-[(5-chloro-2-pyridyl)carbarnoyl]-2-[(1-isopropylpiperazine-4-carbonyl)amino]phenyl-β-D-glucopyranoside uronic acid,

4'-chloro-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide,

4'-bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide,

2'-[(5-bromo-2-pyridyl)carbarnoyl]-4'-chloro-6'-hydroxy-1-

isopropylpiperazine-4-carboxanilide,

5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[(1-isopropyl-4-

piperidyl)methyl]amino}benzamide,

N-(5-bromo-2-pyridyl)-5-chloro-3-hydroxy-2-{[(1-isopropyl-4-

piperidyl)methyl]amino}benzamide,

3-[(4-methoxybenzoyl)amino]-2-{[(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenyl-β-D-glucopyranosid,

3-[(4-methoxybenzoyl)amino]-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenyl-β-D-glucopyranoside uronic acid, etc.

The connection according to this invention includes various stereoisomers such as geometrical isomers, tautomers and optical isomers or as mixtures thereof, either in their isolated forms.

The connection according to this invention can be in the form of additive salts with an acid. Additionally, it can form a salt with a base depending on the type of substituent. Specific examples of such salts are additive salts with a mineral acid, such as chloromethane acid, Hydrobromic acid, iodomethane acid, sulfuric acid, nitric acid and phosphoric acid, or organic acid, such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonate Isleta and econsultancy acid, or with the amino acid character, such as aspartic acid and glutamic acid, and salts with inorganic base, such as sodium, potassium, magnesium, calcium and aluminum, with an organic base such as methylamine, ethylamine, and ethanolamine, amino acid basic character, such as lysine and ornithine, and ammonium salt.

Additionally, the scope of the present invention included hydrates, pharmaceutically acceptable various solvate and polymorphs of the compounds according to this invention. In addition, it goes without saying that the invention is not limited to the compounds listed in the following examples, but includes all substituted derivatives of benzene represented by the formula (I)and their pharmaceutically acceptable salts.

Moreover, the connection according to this invention includes all so-called prodrugs, i.e. compounds that can be converted into a compound represented by the formula (I)or its salt by metabolism in vivo. Examples of the group forming prodrug compounds of this invention are those referred to in Prog. Med. 5: 2157-2161 (1985), and those mentioned in "Ïyakuhin no Kaihatsu" (Development of Pharmaceuticals), published by Hirokawa Shoten, 1990, Vol.7, "Molecular Design", pages 163-198. In particular, as prodrugs of the compounds of this invention can be Taco is a prodrug, when the prodrug having a hydroxyl group, undergoes metabolism in vivo with the formation of glycoside represented by the formula (I), and such prodrug is also in the scope of this invention.

In addition, this invention includes, of course, glycoside represented by the formula (I), which is formed as a result of metabolism in vivo.

Ways to get

Typical methods for obtaining compounds of this invention will be explained further below.

In the case of compounds according to this invention (I), where R4means a hydrogen atom, it can be obtained in the following way:

In the formulas, ring A, X1X2, R1, R2and R3have the above values; Q and W are such that, when Q indicates NH2or-NH-(lower alkyl), W denotes a leaving group,- COOH, -Cho or-CH2-whereas when Q denotes a leaving group,- COOH, -Cho or-CH2-, W signifies NH2or-NH-(lower alkyl); R1means a hydrogen atom, a lower alkyl or a protective group for an amine; R2means a hydrogen atom or a protective group for a phenol; and examples of leaving groups are hydrogen atom, -O-SO2-alkyl and-O-SO2-aryl.

Stage And

For the synthesis of compounds (Ia) use the interaction of the compound (II) with compound (IV), where proishodyaschie condensation of carboxylic acids with amine, aldehyde with an amine or a compound having a leaving-CH2group, with an amine.

In the case of the interaction of carboxylic acids with amine, this reaction is preferably corresponds to the usual acylation reaction in the presence of a condensing agent for the formation of amide linkages.

Examples of the condensing agent which is preferred for use are N,N-dicyclohexylcarbodiimide (DCC), 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide, carbonyldiimidazole, diphenylphosphoryl (DPPA) and diethylphosphate-cyanide.

It is also possible that the carboxylic acid is transformed into an active derivative of the corresponding carboxylic acid and then condensed with the amine.

Examples of active carboxylic acid derivative are active ester obtained by the interaction of the compounds phenolic type, such as p-NITROPHENOL or N-hydroxyamine, such as 1-hydroxysuccinimide and 1-hydroxybenzotriazole, monoalkyl ester of carboxylic acid, a mixed acid anhydride obtained by the interaction with an organic acid and a mixed acid anhydride type phosphoric acid, obtained by the interaction with diphenylphosphinylchloride and N-methylmorpholine; acid azide obtained by the interaction of ester with hydrazine and alkylation; acid halides such as orangered acid and bromohydrin acid, and the anhydride of the acid of the symmetric type. Usually the above reaction is carried out in a solvent with cooling or at room temperature, although in some cases it can be carried out in anhydrous conditions depending on the type of reaction acylation.

Examples of applicable solvents are inert solvents which do not participate in the reaction, such as dimethylformamide, dioxane, tetrahydrofuran, simple ether, dichloroethane, dichloromethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, acetonitrile, dimethyl sulfoxide, ethanol, methanol and water and a mixture of these solvents, preferred suitable selection depending on the applied method.

In addition, depending on the applied method, there are some cases where the reaction proceeds smoothly in the presence of base or by using such a base as a solvent, where the basis is N-methylmorpholine, triethylamine, trimethylamine, pyridine, sodium hydride, tert-piperonyl potassium, utility, sodium amide, potassium carbonate, sodium carbonate, sodium bicarbonate, cesium carbonate or the like.

In addition to the above, can be used in any reaction, forming an amide bond.

In the case of interaction between aldehyde and amine, the reaction can be carried out as is but according to the reaction of reductive amination in the presence of a reducing agent.

As a suitable reducing agent can be used sodium borohydride, cyanoborohydride sodium, triacetoxyborohydride sodium, complex, borane-trimethylamine and the like. Additionally, catalytic hydrogenation may be conducted at atmospheric pressure or under reduced pressure in the presence of a catalyst such as palladium-carbon and platinum oxide. The reaction is carried out under cooling or under heating in alcohol or in a solvent which does not participate in the reaction. In addition, depending on the applied method, there are some cases where the reaction smoothly proceeds in the presence of acid, such as acetic acid, toluensulfonate acid and sulfuric acid, or using this acid as a solvent.

In the case of interaction of compounds containing a leaving CH2group, and an amine, the reaction can be carried out under customary reaction of N-alkylation.

The reaction is carried out under cooling or under heating in a solvent which does not participate in the reaction. In addition, depending on the applied method, there are some cases where the reaction smoothly proceeds in the presence of a base, as described above, or the use of such a base as a solvent.

Stage

For the synthesis of compounds (Ia) use the form of the interaction of the compound (III) and compound (V), where is the reaction of carboxylic acid with an amine, aldehyde with an amine or a compound having a leaving-CH2group, with an amine. This reaction is carried out in the same manner as in stage A.

When R1in compound (Ia) according to this invention is a protective group for the amine and the protective group is not otscheplaut during stages a and b, the separation using the method appropriate for the removal of the protective group R1for example, the removal of acid, such as triperoxonane, or removal and restoration accession catalytic hydrogen, spend when it is possible to obtain the compound (I) according to this invention, where R1means a hydrogen atom. Further, when R2compound (Ia) according to this invention is a protective group for the phenol and the protective group is not otscheplaut during stages a and b, the separation using the method appropriate for the removal of the protective group R2such as the removal and restoration accession catalytic hydrogen, the separation of pentamethylbenzene and triperoxonane acid or cleavage by hydrolysis using a base such as sodium hydroxide, spend when it is possible to obtain the compound (I) according to this invention, where R4means a hydrogen atom.

With regard to protective g is uppy for Amina, cited as an example for R1no particular limitation as long as it is the group that is usually used to protect the amine, and its examples are the lowest alkoxycarbonyl, Uralelectromed, acyl, lower alkyl, aralkyl and sulfonyl or the like.

As for the protective group for a phenol, cited as an example for R2no particular limitation as long as it is the group that is usually used for the protection of phenol, and its examples include optionally substituted lower alkyl, aralkyl, three(lower alkyl)silyl, lower alkylsulphonyl, lower allyloxycarbonyl and sulfonyl. "Aralkyl" means a group where the hydrogen atom of the specified alkyl substituted by aryl, and its specific examples are benzyl and phenylethyl. Specific examples of the "acyl" are formyl, acetyl, propionyl, butyryl.

Next method, which is shown in the following reaction schemes presented as examples of particularly effective way:

In the formulas, ring A, R1, R2, R1, R2, R3, R5and R6have the above values.

This reaction, where the amide bond is produced by interaction of the compound (VI) with amine (IVa) or compound (VII) with an amine (Va), to obtain compound (Ib) or compound (Ic),and it is conducted in the above solvent, which does not participate in the reaction, at room temperature or when heated. In addition, depending on the applied method, there are some cases, when the reaction proceeds smoothly in the presence of base or by using such a base as a solvent, where the basis is N-methylmorpholine, triethylamine, trimethylamine, pyridine, sodium hydride, tert-piperonyl potassium, utility, sodium amide or the like.

When used as a compound (I) according to this invention, where R4means a hydrogen atom, and turn it into a sulfonic acid, using complex trimethylamine-sulfur trioxide or the like, it is possible to obtain the compound (I) according to this invention, where R4means-SO3H.

The compound (I) according to this invention, where R4means the residue of sugar, can be obtained in the following way using the compounds, where R4means a hydrogen atom, or compounds that can be synthesized by a known method described in the patent publications cited in the section "Background to the invention".

In the formulas, ring A, ring B, R1, R2, R3X1and X2have the values indicated above; Y represents a leaving group, and R9means the residue of sugar, which may be the protected.

Stage

This reaction, where containing the donor sugar and phenol combination of compounds (Id) and compound (VIII) result in interaction, preferably in the presence of the activator, to synthesize the compound (Ie), with the remainder of the sugar, which may have a protective group. This reaction can follow the General process for the production of glycosides. Examples of the method are those described in Yuki Gosei Depending Kyokai Shi. vol. 50, No. 5 (1992), pp. 378-390, and in "Jikken Called Koza", vol. 26, 'Yuki Gosei' VIII, page 267-354, published in 1992, Maruzen.

Examples of the donor sugar are sugar derivatives having a leaving group in position 1 of the sugar. Examples of leaving groups are halogen, thioalkyl, tigertail, acyloxy, trichloroacetimidate, diaryl phosphate, imidate of dialogopen, tetramethylphosphonium and dialkyl-pofit.

The examples of the condensing agent are silver carbonate, triftorbyenzola silver, silver perchlorate, silver oxide, sodium hydroxide, potassium carbonate, sodium methoxide, sodium hydride, databaseconnect, trimethylsilyl-triplet, boron TRIFLUORIDE, metalcraft, tetraploid silicon, tin chloride, p-toluensulfonate acid and its salt, anhydride triftormetilfullerenov acid, copper bromide, bromide, mercury and N-bromosuccinimide.

It is also possible to use the sugar donor having, for example, hydroxyl groups is in position 1, then use this activator as triphenylphosphine, diethyl-azodicarboxylate etc.

Usually the above reaction is carried out in a solvent under conditions of from cooling to heating. Depending on the type of reaction get glycoside there are some cases where the reaction should be carried out in anhydrous conditions.

As for the solvent, there may be used inert solvent which does not participate in the reaction, such as dimethylformamide, dioxane, tetrahydrofuran, simple ether, dichloroethane, dichloromethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, toluene, acetonitrile, dimethyl sulfoxide, methanol, ethanol, etc. and a mixture of such solvents, and preferably are eligible to choose them depending on the applied method.

In addition to these reactions, there may be used any reaction unless it is a reaction that forms a glycosidic bond.

When in the compound (Ie) according to this invention R9means the residue of sugar, which may have a protective group, and when the specified protective group is not otscheplaut on stage, it is also possible to obtain a connection according to this invention, where R9means the residue of sugar, not having a protective group, by removal using the method that is appropriate for otwal is of the specified protective group, such as cleavage by hydrolysis using a base such as sodium carbonate, or the removal of the restoration, such as the introduction of catalytic reduction.

There are no specific restrictions for protective group, as this group is the one that is usually used to protect the hydroxyl group, carboxyl group and the like, and specific examples include optionally substituted lower alkyl, aralkyl, three(lower alkyl)silyl and acyl. "Aralkyl" means a group where the hydrogen atom of the specified lower alkyl substituted by aryl, and its specific examples are benzyl and the like, Specific examples of acyl are acetyl, propionyl, Isopropenyl and benzoyl.

Incidentally, the source compounds for the compounds of this invention can be obtained as represented in the example by the way.

In the formula the ring R3X2, R1, R2, Q and W have the same meanings as already mentioned, U represents-COOH, -COOP3, -NH2, NH-(lower alkyl), -NH-P4, -NH(P4)-(lower alkyl), -NO2, -CHO, - CH2OH, -(lower alkyl) or stretching of CH2group, and R3and R4means a protective group for carboxyl and Amin, respectively.

For the synthesis of compounds (IIa) are the interaction of the compound (I) with compound (V), when this occurs, the condensation reaction of carboxylic acid with an amine, aldehyde with an amine or a compound having a leaving CH2group, with an amine. This reaction is carried out in the same manner as in the above stage A. When U means-NO2in the compound (IIa), the compound, where U represents-NH2can be obtained by reduction reactions; when U represents-COOH or-COOP3connection, where U represents-Cho, can be obtained by reduction reactions; when U represents-CH2HE or -(lower alkyl), connection, where U represents-Cho, or-COOH, can be obtained by the oxidation reaction, and when U mean COOP3, -NH-P4or-N(P4)-(lower alkyl), connection, where U represents-COOH, -NH2or-NH-(lower alkyl)can be obtained by a method suitable for the removal of each of the protective groups, such as, for example, cleavage by hydrolysis using a base such as sodium hydroxide, or acids, such as chloromethane acid, removal of the restoration, such as the introduction of catalytic hydrogen, or the removal of acid, such as triperoxonane acid.

In the formulas, ring A, R1, R2, R3X1, R2, Q, W, and U have the above values.

For the synthesis of the connection is in (IIIa) are the interaction of the compound (IX) with compound (IV), when this occurs, the condensation reaction of carboxylic acid with an amine, aldehyde with an amine or a compound having a leaving CH2group, with an amine. This reaction is carried out in the same manner as in the above stage A. When U means-NO2in the compound (IIIa), the connection, where U represents-NH2can be obtained by reduction reactions; when U represents-COOH or-COOP3connection, where U represents-Cho, can be obtained by reduction reactions; when U represents-CH2HE or -(lower alkyl), connection, where U represents-Cho, or-COOH, can be obtained by the oxidation reaction, and when U mean COOP3, -NH-P4or-N(P4)-(lower alkyl), connection, where U represents-COOH, -NH2or-NH-(lower alkyl)can be obtained by a method suitable for the removal of each of the protective groups, such as, for example, cleavage by hydrolysis using a base such as sodium hydroxide, or acids, such as chloromethane acid, removal of the restoration, such as the introduction of catalytic hydrogen, or the removal of acid, such as triperoxonane acid.

The method, which is shown in the following schemes of reactions is particularly effective for the synthesis of compounds represented by formulas (II) and (III).

In the formulas, ring A, R1, R2, R3, R5, R6, R1and R2have the above values.

This reaction, where the amide bond is produced by interaction of the compound (X) with the amine (Va) or compound (XI) with an amine (IVa), resulting in a receive connection (IIb) or the compound (IIIa), and the reaction is carried out in the above inert solvent at room temperature or when heated. Depending on the applied method may be the case when the reaction proceeds smoothly when the reaction is carried out in the presence of a base, such as N-methylmorpholine, triethylamine, trimethylamine, pyridine, sodium hydride, tert-piperonyl potassium, utility or sodium amide, or the use of such a base as a solvent.

Incidentally, the phase of introduction of the sugar residue is not limited to the above stages. Thus, obtaining a connection through an optional combination of stages, which can usually be adapted (modified) specialists, such as the stage at which containing donor sugar and phenol combination of compound (VIII) with compound (II), (III), (VI), (VII), (IX), (X) or (XI) result in interaction, preferably in the presence of activator, resulting in a synthesized compound having a sugar residue which may be protected, and then it is condensed with (IV), (IVa), (V) or (Va) according to the method described above.

In addition, the compound represented by formula (I)can be obtained by an optional combination of known stages, which can be tailored by experts, such as alkylation, acylation, oxidation, recovery and hydrolysis.

The connection according to this invention, which is obtained may be isolated as such and purified by the known methods such as extraction, precipitation, separation, chromatography, fractional crystallization, recrystallization, etc. Also, the connection according to this invention can be converted into a desired salt by a conventional salt-forming reaction. In addition, the connection according to this invention can exist in the form of optical isomers, when it has asymmetric carbon atoms. These optical isomers can be separated in the usual way by fractional crystallization, when the isomer is subjected to recrystallization from a suitable salt, or by column chromatography or the like.

Industrial application

The connection according to this invention shows a strong anticoagulate action by inhibiting activated factor X in the coagulation of blood in a specific way. Therefore, the connection is applicable as an inhibitor of blood coagulation is whether medications for use in the prevention and treatment of diseases, caused by thrombus or embolus.

Examples of such diseases include disorders of the brain, such as cerebral infarction, cerebral thrombosis, cerebral embolism, transient ischemic stroke (TIA), subarachnoid hemorrhage (vasospasm), and the like, ischemic heart disease, such as acute and chronic myocardial infarction, unstable angina, thrombosis of the coronary artery and the like, pulmonary vascular disorders such as pulmonary thrombosis, pulmonary embolism and the like, and various vascular disorders, such as obstruction of peripheral artery disease, deep vein thrombosis, syndrome of diffuse intravascular coagulation, the formation of a blood clot after surgery with artificial blood vessels or after artificial valve replacement, re-occlusion and re-stricture after bypass surgery coronary artery, re-occlusion and re-stricture after surgery, RTSA (percutaneous intraluminal coronary angioplasty) or PTCR (percutaneous intraluminal coronary recanalization) or a blood clot during extrakorporale circulation.

In addition, it is assumed the possibility of using compounds according to this invention as a medicine for the prevention and treatment of infection, the virus is influenza on the basis of the ability to inhibit the growth of influenza virus, under the inhibitory effect of the compounds according to this invention in the activated factor X in the coagulation of blood (Japanese Patent Laid-Open No. 227971/1994).

The ability of compounds of this invention inhibit activated factor X in the coagulation of blood and to prolong the coagulation time in oral introduction by the following tests.

1) Test in vitro for the measurement of coagulation time of activated factor X in the coagulation of blood

To 90 μl of human blood plasma, add 10 μl of drug or saline solution and 50 μl of factor XA person (Enzyme Research Labs), carry out incubation at 30°C for 3 minutes, add 100 ál of 20 mm CaCl2pre-heated to 37°and the time until coagulation was measured by coagulometer (X Amelung). With regard to the human blood plasma, 45 ml of blood taken from a vein in the elbow bend in six healthy volunteers with a syringe containing 5 ml of 3.8% sodium citrate, and centrifuged at 4°C for 15 minutes at 3000 rpm./min and separated blood plasma is drained and frozen, then thawed before use. As for factor XA person, choose the concentration at which coagulation time, when add saline solution (control), is from about 30 to 40 seconds. The value of the ARTICLE2(the concentration at which time to which gulali doubled) is determined by plotting the dependence of the concentrations of drugs and their relative value (ratio) time of coagulation in relation to the control, then through linear regression. The results are shown in the following table 1.

Table 1
ConnectionThe test for measuring the time of the activated coagulation factor X coagulation of human blood (ST2)(μm)
Example 10,295
Example 30,062
Example 80,137
Example 100,617
Example 180,153

2) Test in vitro for the measurement of coagulation time of bovine thrombin

To 50 μl of human blood plasma add 50 μl of drug or saline solution, spend incubation at 37°C for 3 minutes, add 50 μl of thrombin (500 units thrombin (derived from the bull; Mochida Pharmaceutucal)), preheated to 37°and the time until coagulation was measured by coagulometer (X Amelung). With regard to the human blood plasma, 45 ml of blood taken from a vein in the elbow bend in six healthy volunteers with a syringe, which introduced 5 ml of 3.8% sodium citrate, and centrifuged at 4°C for 15 minutes at 3000 rpm./min and separated blood plasma is drained and frozen, select the concentration at which coagulation time, when add physiological process is (control), is about 20 seconds. The value of the ARTICLE2(the concentration at which coagulation time increases two times) is determined by plotting the dependence of the concentrations of drugs and their relative value (ratio) time of coagulation in relation to the control, and then subjecting it to linear regression.

As a result, all values ARTICLE2for the compounds of examples 10 and 18 were lower than 100 microns.

3) test for measuring the inhibition of the enzyme by the method of synthetic substrate

In a 96-well microplate add 80 ál of reaction buffer (pH 8,4), 15 μl of a solution of the compound and 30 μl of 2 mm synthetic substrate S-2222 (Chromogenix), then add 25 ál of 0.025 units/ml of activated factor X in the coagulation of human blood (factor XA; Enzyme Research Labs), the reaction is performed at 37°C for 10 minutes, changes in optical density at 405 nm was measured by Bio-Rad model 3550) and calculate the IC50.

The measurement results of the above tests 1), 2) and (3) confirm that the connection according to this invention inhibits activated factor X in the coagulation of blood in a specific way and finds strong anticoagulate effect on the blood. This is confirmed by the fact that the compounds shown in examples 1, 3, 8, 10 and 18, in the present invention prolong the coagulation time at a low concentration, detecting prevoshoditelstva against blood coagulation.

4) Test for ex vivo measurement of coagulation time of the cynomolgus monkeys (oral introduction)

The drug (5 mg/ml or 0.5 mg/ml), which was dissolved (suspended) in 0.5% methylcellulose, forcibly, by feeding through a tube, is administered in a dose of 2 ml/kg (10 mg/kg or 1 mg/kg) to male cynomolgus monkeys (body weight about 4 kg), starving for 12 hours or longer, blood samples of 2 ml take them out from the femoral vein using 1/10 volume of 3.8% sodium citrate before medication and after 1, 2, 4, 6 and 8 hours and the blood plasma is separated by centrifugation at 3000 rpm./min for 10 minutes. Using the obtained blood plasma, measured with alternative (extrinsic) coagulation (PT) and the live coagulation (ART) in accordance with the following methods (a) and (b). The experiment is carried out without anesthesia. In this case, values are presented as the ratio of the time of coagulation in the group with the introduction of drugs to the time of coagulation in the control group (no drug administration), and the value at the time of blood collection, showing the strongest influence on the extension of time of coagulation.

a) alternative coagulation (PT)

Ortho Brain Thromboplastin (54 ml/vial; liofilizovannye drug; Ortho-Clinical Diagnostics) was dissolved in 2.5 ml of water Milli-Q and pre-heated at 37°C. previously Separated blood plasma (50 μl) is heated at 37°With whom for 1 minute, add 50 ál of the above solution of thromboplastin and measure the coagulation time. The result is shown in the following table 2.

Table 2
ConnectionDoseThe test for measuring the time of coagulation in cynomolgus monkeys (RT)
Example 110 mg/kgof 7.69
Example 310 mg/kgthe ceiling of 5.60
Example 181 mg/kg1,94
Example 191 mg/kgof 2.26
Control

connection
10 mg/kg2,00

(Control)

(Example 44 from WO 00/39118)

The result of this test found that the compounds according to this invention have excellent effects prolong coagulation time, even during oral introduction. When compared with example 44 (control) from WO 00/39118 confirmed that the compounds of examples 1 and 3 according to this invention have a longer-lasting effect of the prolongation of coagulation time of when the same dose and find excellent anticoagulate action. In addition, the compounds shown in examples 18 and 19 detect such an effect of prolongation of coagulation time of when the Oze, part one-tenth compared with the control, and as confirmed, find excellent anticoagulate action.

b) direct coagulation (ART)

To 50 μl of the indicated plasma add 50 ál Hemoliance Thrombosil I (Dia-Iatron), the mixture is heated at 37°C for 3 minutes, add 50 ál of 20 mm solution of CaCl2pre-heated to 37°and measure the coagulation time. For measurement of coagulation time of use CSA made Amelung.

The dose changes anticoagulative actions over time are also examined by changing the input dose or time of blood collection.

Pharmaceutical composition, which contains as active ingredient one or more compounds of this invention represented by formula (I)or their pharmaceutically acceptable salts, are prepared in the form of tablets, diluted powders, fine granules, granules, capsules, pills, solutions, solutions for injections, suppositories, ointments, plasters and the like, using traditionally used pharmaceutical carriers, fillers and other additives, and is administered either orally or parenterally (for example, by injection through the skin, through the mucous and the like).

Clinical dose of the compounds according to this invention for people if possible to determine, given the symptoms, body weight, the age, sex and the like of the patient that requires treatment, and it is usually equal to from 0.1 to 500 mg via oral introduction, or from 0.01 to 100 mg parenteral adult per day, where the daily dose is administered once or divided into several doses per day. As the dose varies depending on various conditions, in some cases it may be sufficient a smaller dose than the ranges specified above.

Solid formulation for use by oral administration according to this invention is used in the form of tablets, diluted powders, granules and the like. In such solid drug is one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid or magnesium aluminate. Usually, the composition may contain additives other than the inert diluent, such as a lubricant (e.g. magnesium stearate), dezintegriruetsja substance (e.g., calcium salt glycolate, cellulose), stabilizing agent (e.g., lactose) and solubilizers agent or solubilizing excipient (for example, glutamic acid or aspartic acid). If necessary, tablets or pills may be coated with a film soluble in the stomach likesecret substances, such as sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose or the like.

A liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like and contains a generally used inert diluent, such as pure water or ethanol. In addition to the inert diluent, this composition may also contain auxiliary agents, such as solubilizers agent or solubilizing auxiliary substance, wetting agent, suspendisse agent and the like, as well as sweeteners, flavoring agents, aromatic agents and antiseptics.

Formulations for injection for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the diluent for use in aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of the diluent for use in non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oil (e.g. olive oil), alcohol (e.g. ethyl alcohol), Polysorbate 80 (trade name) and the like.

Such a composition may contain additional agents, such as an isotonic agent, an antiseptic agent, HC is Einaudi agent emulsifying agent, dispersing agent, a stabilizing agent (e.g., lactose) and solubilizers agent or solubilizing excipient. These compositions are sterilized by filtration through inhibiting bacteria filter, adulteration of germicide or irradiation. Alternatively, they can be used so that, initially, turn into sterile solid compositions and dissolving them in sterile water or a sterile solvent for injection before use.

When the connection according to this invention has a low solubility,it may be subject to solubilisers processing. Solubilizers processing can be carried out by known methods that can be applied to pharmaceuticals, such as how, where add surfactants (polyethoxysiloxane hydrogenated castor oil, esters of polyoxyethylene-anhydromannitol and higher fatty acids, polyoxyethylene-polyoxypropylene-glycols, esters of sucrose and fatty acids, and the like), and the method, where the medication is prepared in the form of a solid dispersion together with solubilization agent such as a polymer, for example, water-soluble high polymer, such as hydroxypropyl-methylcellulose (receiver array), polyvinylpyrrolidone (PVP) and polyethylene glycol (PEG) or soluble in the intestine is OLIMAR, such as carboxymethyl-ethylcellulose (MIXTURE), phthalate hydroxypropyl-methylcellulose (NRSR) and a copolymer of methyl methacrylate-methacrylic acid (trade name Eudragit L and S, produced by Rohm & Haas). In addition, if necessary, can be used in a way where the drug is converted into a soluble salt, or a way where get connection enable using cyclodextrin or the like. Solubilizing means can be appropriately replaced depending on each drug of interest [Saikin no Seizai Gijutsu to Sono Oyo (Recent Pharmaceutical Technology and Application), I. Utsumi, et al., Iyaku Journal, 157-159 (1983) and Yakugaku Monograph, No.1, Bioavailability, K. Nagai, et al., published by Soft Science, 78-82 (1988)]. Along with the above methods, preferably can be used in a way where the solubility of drugs will enhance the formation of its solid dispersion with solubilization agent (Japanese Patent Laid-Open No. 49314/1981 and FR 2460667).

The best option of carrying out the invention

The following description specifically explains a method of obtaining compounds of this invention with reference to examples of the preparation of compounds according to this invention. Due to the fact that the new compounds included in the source compounds for the compounds according to this invention, methods of obtaining them are described as examples of the comparison.

Example comparison 1

Lithium is-aluminum hydride (500 mg) suspended in 40 ml of tetrahydrofuran, add a solution of 3.55 g of ethyl-1-isopropylpiperazine-4-carboxylate in 10 ml of tetrahydrofuran at -50°C and the mixture is stirred for 2.5 hours at a temperature of from a temperature under cooling with ice to room temperature. To this add 0.5 ml water, 0.5 ml of 2 N. aqueous sodium hydroxide solution, 1.5 ml of water and anhydrous magnesium sulfate under ice cooling, the precipitate is removed by filtration and the solvent is evaporated in vacuum to get 2,96 g (1-isopropyl-4-piperidyl)methanol.

Example 2 comparison

Oxalicacid (3.15 ml) dissolved in 30 ml of dichloromethane, added with a solution of 320 ml of dimethyl sulfoxide in 6 ml of dichloromethane at -70°C, the mixture is stirred for 15 minutes, add a solution of 2.93 g (1-isopropyl-4-piperidyl)methanol in 15 ml of dichloromethane at -70°C and the mixture is stirred for 1 hour. Then add 12.5 ml of triethylamine at -70°C, the mixture is heated to room temperature, then add water and a saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, the solvent is evaporated in vacuo and to the residue is added ethyl acetate. After removing insoluble substances by filtration, the solvent is evaporated in vacuum to get to 1.15 g (1-isopropylpiperazine-4-carbaldehyde. This connection uses the La the next reaction without purification.

Example 3 comparison

3-Hydroxy-2-nitrobenzoic acid (10.5 g) was dissolved in 60 ml of N,N-dimethylformamide, then add 15 ml of benzylbromide and 19.0 g of potassium carbonate at 0°C and the mixture is stirred at room temperature overnight. The reaction solution is filtered through celite and the filtrate was concentrated in vacuo.To the resulting residue, water is added, the mixture extracted with simple ether and the extract washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated in vacuum to obtain 20.7 g benzyl-3-benzyloxy-2-nitrobenzoate.

Example 4 comparison

To 20.7 g benzyl-3-benzyloxy-2-nitrobenzoate was added 100 ml of ethanol and 120 ml of 1 N. aqueous sodium hydroxide solution and the mixture is stirred at room temperature overnight, at 60°C for 3 hours and at 80°C for 5 hours. The ethanol is then evaporated in vacuo, the resulting aqueous solution was washed with simple ether and add chloroethanol acid. The precipitate is collected by filtration and dried in vacuum,to get to 15.8 g of 3-benzyloxy-2-nitrobenzoic acid.

An example of comparison of 5

To 5,47 g of 3-benzyloxy-2-nitrobenzoic acid, add 20 ml of thionyl chloride and a few drops of N,N-dimethylformamide and the mixture is stirred at 80°C for 30 minutes. The reaction solution was concentrated in HAC the mind ,to the obtained residue, add 35 ml of pyridine and to 2.55 g of 2-amino-5-chloropyridine at 0°C and the mixture is stirred at room temperature overnight. The reaction solution was concentrated in vacuo,to the obtained residue is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, the solvent is evaporated in vacuum and conduct azeotropic operation with toluene to obtain 7,44 g of 3-benzyloxy-N-(5-chloro-2-pyridyl)-2-nitrobenzamide.

Example 6 comparison

To 7,44 g of 3-benzyloxy-N-(5-chloro-2-pyridyl)-2-nitrobenzamide add 40 ml triperoxonane acid and 3.72 g of pentamethylbenzene and the mixture was stirred at 40°C during the night. The reaction solution was concentrated in vacuo,to the residue is added saturated aqueous sodium hydrogen carbonate solution to such an extent that the balance does not become alkaline, and the mixture is extracted with chloroform. The organic layer is extracted with 1 N. aqueous sodium hydroxide solution, the aqueous layer was acidified by adding chloroethanol acid and the mixture extracted with chloroform. The extract is dried over anhydrous magnesium sulfate, the solvent is evaporated in vacuo and to the residue is added 200 ml of a suspension of Raney Nickel in ethanol. It is stirred for 6 hours in an atmosphere of hydrogen, we use the N,N-dimethylformamide and insoluble substance is filtered off. The solvent is evaporated in vacuo and to the residue water is added. The precipitate is collected by filtration and dried in vacuum,to get 4,58 g 2-amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide.

Example 7 comparison

2-Amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (a 3.06 g) and of 1.80 g of N-chlorosuccinimide dissolved in 60 ml of N,N-dimethylformamide, the solution was stirred at 50°C for 8 hours and at room temperature for 4 hours and the insoluble matter is filtered off. The solvent is evaporated in vacuo, to the residue was added 1 N. aqueous sodium hydroxide solution and the mixture extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, the solvent is evaporated in vacuo and the resulting residue is purified column chromatography on silica gel. To crudely purified product add ethanol and the precipitate is collected by filtration and dried in vacuum,to get the 767 mg of 2-amino-5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide. Uterine fluid concentrate, then add a mixture of ethyl acetate and simple isopropyl ether and the precipitate collected by filtration and dried in vacuum,to get more 942 mg of the above compound.

Example 8 comparison

2-Amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (5,27 g) dissolved in 60 ml of N,N-dimethylformamide and RA the solution stirred at -15° C. N-Bromosuccinimide (of 3.56 g) add, divide into four portions, at intervals of 5 minutes between the portions and the mixture was stirred at -15°C for 1.5 hours. Then add more of 0.36 g of N-bromosuccinimide, the mixture was stirred at -15°C for 2 hours, then add 120 ml of water and 120 ml of ethyl acetate and the mixture is stirred at room temperature for 10 minutes. The obtained precipitate was separated by filtration through celite and the organic layer of the filtrate is collected, while the aqueous layer was additionally extracted with ethyl acetate. Powder activated carbon (2.6 g) is added to the obtained organic layer and the mixture is stirred for 15 minutes and filtered through celite. The filtrate is washed with water and dried over anhydrous sodium sulfate, the solvent is evaporated in vacuum and the residue is dried to obtain 5,70 g 2-amino-5-bromo-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide.

Example 9 comparison

3-Hydroxy-2-nitrobenzoic acid (2.00 g) was dissolved in 110 ml of N,N-dimethylformamide, then add 1,53 g of 4-Chloroaniline and 3.15 g of the hydrochloride of 1-ethyl-3-[3-(N,N-dimethylamino)propyl]carbodiimide and of 2.21 g of 1-hydroxybenzotriazole and the mixture is stirred at room temperature for 4 days. The reaction solution was concentrated in vacuo,a saturated solution of salt added to the concentrate and the mixture is extracted with chloroform. The organic layer is dried n the d magnesium sulfate and concentrated in vacuo. The resulting residue is purified column chromatography on silica gel using a mixture of chloroform:methanol (100:1) as eluent, to obtain 2,97 g of 4'-chloro-3-hydroxy-2-nitrobenzamide.

Example 10 comparison

To 7,09 g of 3-benzyloxy-2-nitrobenzoic acids are added 30 ml of thionyl chloride and a few drops of N,N-dimethylformamide and the mixture is stirred at 80°C for 30 minutes. The reaction solution was concentrated in vacuo,then 40 ml of pyridine and 4,91 g 2-amino-5-bromopyridine added to the obtained residue at 0°C and the mixture is stirred at room temperature overnight. The reaction solution was concentrated in vacuo,then to the resulting residue is added saturated aqueous solution of sodium bicarbonate and methanol and the mixture is extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, the solvent is evaporated in vacuum and the residue is subjected to azeotropic treatment with toluene to obtain br11.01 g of 3-benzyloxy-N-(5-bromo-2-pyridyl)-2-nitrobenzamide.

Example 11 comparison

To 10.7 g of 3-benzyloxy-N-(5-bromo-2-pyridyl)-2-nitrobenzamide add 50 ml triperoxonane acid and 4,88 g pentamethylbenzene and the mixture is stirred at room temperature for 4 days. The reaction solution was concentrated in vacuo, to the residue is added saturated aqueous solution of sodium bicarbonate to tako the extent what balance does not become alkaline, and the mixture is extracted with chloroform. The organic layer is extracted with 1 N. aqueous sodium hydroxide solution and the aqueous layer add concentrated chloroethanol acid. The precipitate is collected by filtration and dried in vacuum to obtain 7,86 g of N-(5-bromo-2-pyridyl)-3-hydroxy-2-nitrobenzamide.

Example 12 comparison

N-(5-Bromo-2-pyridyl)-3-hydroxy-2-nitrobenzamide (7,71 g) is suspended in 50 ml of ethanol and 22 ml of distilled water, then add 12.7 g of recovered iron and 2.45 g of ammonium chloride and the mixture is heated to boiling with the return of phlegmy within 6 hours. Then it is cooled to room temperature, insoluble matter is filtered off and washed with chloroform. The filtrate was concentrated in vacuo, add saturated aqueous solution of sodium bicarbonate, the mixture is extracted with chloroform and the extract was washed with a saturated solution of salt. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated in vacuum to get at 0.42 g of 2-amino-N-(5-bromo-2-pyridyl)-3-hydroxybenzamide. Then N,N-dimethylformamide is added to the insoluble matter obtained by filtering the reaction solution, the mixture is filtered and the filtrate concentrated inthe vacuum.To the resulting residue, water is added and the precipitate collected, filtrowanie the m and dried in vacuum, to get more of 3.28 g of the above compound. Although it contains impurities, it is not purified and used for the next reaction as is.

Example 13 comparison

2-Amino-N-(5-bromo-2-pyridyl)-3-hydroxybenzamide (1,99 g) and 990 mg of N-chlorosuccinimide dissolved in 30 ml of N,N-dimethylformamide, the solution was stirred at 50°With over 2 hours and the insoluble matter is filtered off. The solvent is evaporated in vacuo, to the residue water is added and the precipitate collected by filtration. It is dried in vacuo, purified column chromatography on silica gel, to the obtained crudely purified product water is added and the precipitate collected by filtration and dried in vacuum to obtain 1.12 g of 2-amino-N-(5-bromo-2-pyridyl)-5-chloro-3-hydroxybenzamide.

Example 1

2-Amino-5-bromo-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (5,14 g) and 2.83 g of 1-isopropylpiperazine-4-carboxylic acid are dissolved in 75 ml of N,N-dimethylformamide, then add to 4.33 g of the hydrochloride of 1-ethyl-3-dimethylaminopropylamine and 3.04 g of 1-hydroxybenzotriazole and the mixture is stirred at room temperature for 46 hours. The reaction solution was added to 750 ml of 1% aqueous sodium bicarbonate solution and there is added 200 ml of ethyl acetate. The ethyl acetate is evaporated in vacuo and the resulting solid is collected by filtration and washed with water. Polucen the e solid is suspended in 100 ml of methanol and 10 ml of water and the suspension is stirred over night. The precipitate is collected by filtration and dried in vacuum to get to 4.41 g of 4'-bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide.

4'-Bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide (480 mg) is suspended in 15 ml of chloroform, 15 ml of methanol and 10 ml of 1,4-dioxane, then add 434 mg of 1,8-diazabicyclo[5,4,0]-7-undecene and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added 1.19 g of 1-bromo-1-deoxy-2,3,4,6-Tetra-O-acetyl-α-D-galactopyranoside and the mixture is stirred at room temperature for 3 hours. To the reaction solution add 868 mg of 1,8-diazabicyclo[5,4,0]-7-undecene, the mixture is stirred at room temperature for 3 hours and add it to 1.19 g of 1-bromo-1-deoxy-2,3,4,6-Tetra-O-acetyl-α-D-galactopyranoside. The mixture is then stirred at room temperature for 12 hours, concentrate it under vacuum.To the resulting residue are added 50 ml of water and the mixture is washed with 50 ml of chloroform and extracted with n-pentanol. The solvent is evaporated in vacuo and the resulting residue is purified by ODS column chromatography using a mixture of 0.1% aqueous solution triperoxonane acid:acetonitrile (71:29) as the eluent, to obtain 300 mg of triptoreline 4-bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-β-D-ha is octopyranoside-1-isopropylpiperazine-4-carboxanilide.

The compounds of examples 2, 4 and 8 receive the same manner as in example 1.

Example 3

4'-Bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide (500 mg) suspended in 10 ml of chloroform, 10 ml of methanol and 5 ml of 1,4-dioxane and then added to 0.45 ml of 1,8-diazabicyclo[5,4,0]-7-undecene and the mixture is stirred at room temperature for 1.5 hours. To the reaction solution was added to 1.11 g of 2-acetamido-2,3,6-tri-O-acetyl-2-deoxy-α-D-glyukopiranozil-bromide and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added to 0.90 ml of 1,8-diazabicyclo[5,4,0]-7-undecene, the mixture is stirred at room temperature for 30 minutes and to it was added a 1.11 g of 2-acetamido-2,3,6-tri-O-acetyl-2-deoxy-α-D-glyukopiranozil-bromide. The mixture is then stirred at 60°for 2 hours and concentrated in vacuo. To the resulting residue are added 50 ml of water and the mixture is washed with 50 ml of chloroform and extracted with n-pentanol. The solvent is evaporated in vacuo and the resulting residue is purified by ODS column chromatography using a mixture of 0.1% aqueous solution triperoxonane acid:acetonitrile (71:29) as the eluent, to obtain 364 mg trifenatate 2'-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)-4'-bromo-6'-[(5-chloro-2-pyridyl)carbarnoyl]-1-isopropylpiperazine-4-carboxanilide.

Use the 5

3-Hydroxy-N1-(4-methoxybenzoyl)-N2-[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]-1,2-phenylenediamine (300 mg), 377 mg of methyl 1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranosid uronate and 225 mg of bromide benzyl-tri-n-butylamine suspended in 6 ml of chloroform, add 1.9 ml 1 N. aqueous sodium hydroxide solution and the mixture was stirred at 60°With over 2 hours. To the reaction solution was added 754 mg of methyl 1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranosid uronate and the mixture was stirred at 60°C for 3 hours. The reaction solution is extracted with chloroform and the extract washed with saturated aqueous solution of salt. The resulting organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo.The resulting residue is purified by column chromatography on silica gel, using as eluent a mixture of chloroform:methanol:saturated aqueous ammonia (100:10:1)to obtain 210 mg crudely purified methyl (3-[(4-methoxybenzoyl)amino]-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenyl-2,3,4-tri-O-acetyl-β-D-glucopyranosid) uronate. Crudely purified product (220 mg)obtained in this way is dissolved in 5.5 ml of methanol and 2.7 ml of distilled water, added 85 mg of sodium carbonate and the mixture is stirred at room temperature for 2.5 hours and then at 60°With over 2 hours. This concentrate is the vacuum and the resulting residue is purified by ODS column chromatography, using as eluent a mixture of 0.1% aqueous solution triperoxonane acid:tetrahydrofuran (70:30)to obtain 150 mg crudely purified trifenatate 3-[(4-methoxybenzoyl)amino]-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenyl-β-D-glucopyranoside uronic acid. Crudely purified product (310 mg)obtained in this way, clear through GHUR (Develosil ODS-UG-5), using as eluent a mixture of 0.1% aqueous solution triperoxonane acid:tetrahydrofuran (75:25)to obtain 115 mg of triptoreline 3-[(4-methoxybenzoyl)amino]-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenyl-β-D-glucopyranoside uronic acid.

Example 6

4'-Chloro-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide (150 mg) is suspended in 1.6 ml of chloroform and 1.6 ml of methanol, then add 152 mg of 1,8-diazabicyclo[5,4,0]-7-undecene and the mixture is stirred at room temperature for 35 minutes. To the reaction solution was added 397 mg of methyl 1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranosid uronate and the mixture is stirred at room temperature for 15 minutes and concentrated in vacuo.The resulting residue is purified column chromatography on silica gel, using as eluent a mixture of chloroform:methanol:saturated aqueous ammonia (100:20:2)to obtain 240 mg crudely purified product of methyl-{5-chloro-3-[(5-chloro-pyridyl)carbarnoyl]-2-[(1-isopropylpiperazine-4-carbonyl)amino]phenyl-β -D-glucopyranosid} uronate. Crudely purified product (230 mg) was dissolved in 4.6 ml of methanol and 2.3 ml of distilled water, then add 114 mg of sodium carbonate and the mixture is stirred at room temperature for 1 hour. It neutralizes triperoxonane acid and concentrated in vacuo.The resulting residue is purified by column chromatography OSD, using as eluent a mixture of 0.1% aqueous solution triperoxonane acid:acetonitrile (71:29), to obtain 86 mg of triptoreline 5-chloro-3-[(5-chloro-2-pyridyl)carbarnoyl]-2-[(1-isopropylpiperazine-4-carbonyl)amino]phenyl-β-D-glucopyranoside uronic acid.

Example 7

4'-Bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide (1,00 g) is suspended in 20 ml of chloroform and 20 ml of methanol, then add of 0.91 ml of 1,8-diazabicyclo[5,4,0]-7-undecene and the mixture is stirred at room temperature for 2 hours. To the reaction solution was added to 2.41 g of methyl 1-bromo-1-deoxy-2,3,4-tri-O-acetyl-α-D-glucopyranosid uronate and the mixture is stirred at room temperature for 16 hours. To the reaction solution was added 1.07 g of sodium carbonate and 20 ml of water and the mixture is stirred at room temperature for 23 hours and concentrated in vacuo. To the resulting residue are added 50 ml of 5% aqueous sodium bicarbonate solution and the mixture is washed what cloroformo and extracted with n-pentanol. The solvent is evaporated in vacuo and the resulting residue is purified by ODS column chromatography, using as eluent a mixture of 0.1% aqueous solution triperoxonane acid:acetonitrile (71:29), to obtain 502 mg trifenatate 5-bromo-3-[(5-chloro-2-pyridyl)carbarnoyl]-2-[1-isopropylpiperazine-4-carbonyl]amino]phenyl β-D-glucopyranoside uronic acid.

Example 9

2-Amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (100 mg) and 80 mg of 1-isopropylpiperazine-4-carbaldehyde suspended in 5 ml of toluene, then added 10 mg hydrate p-toluensulfonate acid and the mixture is heated to boiling with the return of phlegmy for 2 hours with azeotropic removal of water operation. Then the solvent is evaporated under vacuum, added to the obtained residue, 7 ml of acetic acid and 88 mg of the complex of borane-trimethylamine and the mixture was stirred at 70°for 15 hours. The solvent is evaporated in vacuum,to the residue is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, the solvent is evaporated in vacuumand the resulting residue is purified column chromatography on silica gel. After adding 1 N. chloroethanol acid and water to the obtained N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[(1-isopropyl-4-piperidyl)methyl]amino}benzamide mix the tub of freezing, to obtain 102 mg of the hydrochloride of N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[(1-isopropyl-4-piperidyl)methyl]amino}benzamide.

The compounds of examples 10, 11, 12 and 13 receive the same manner as in example 9.

Example 14

4'-Chloro-3-hydroxy-2-nitrobenzamide (1,43 g) is suspended in 50 ml of methanol, then add 5 ml of distilled water, 2,80 g of recovered iron and 530 mg of ammonium chloride and the mixture is stirred at 60°With over 2 hours. The reaction mixture was filtered through celite and concentrated in vacuo.To the obtained residue, add a saturated solution of salt and the mixture is extracted with chloroform. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The obtained residue and 320 mg of 1-isopropylpyridine-4-carbaldehyde suspended in 14 ml of toluene, then added 37 mg hydrate p-toluensulfonate acid and the mixture is heated to boiling with the return of phlegmy within 24 hours with azeotropic removal of water operation. Then concentrated in vacuo, to the obtained residue, add 14 ml of acetic acid and 350 mg of a complex of borane-trimethylamine and the mixture was stirred at 70°for 17 hours. Then concentrated in vacuo, added to the obtained residue, 5% aqueous sodium bicarbonate solution and the mixture extracted with chloroform. The organic layer is dried over magnesium sulfate and concentrated in vacuo.Received the initial residue is purified column chromatography on silica gel, using as eluent a mixture of chloroform:methanol:saturated aqueous ammonia (100:10:1)to obtain 380 mg crudely purified 4'-chloro-3-hydroxy-2-{[(1-isopropyl-4-piperidyl)methyl]amino}benzanilide. Crudely purified product (380 mg) clean ODS column chromatography, using as eluent a mixture of 0.001 N. chloromethane acid:methanol (10:3), and then dried by freezing to obtain 162 mg of the hydrochloride of 4'-chloro-3-hydroxy-2-{[(1-isopropyl-4-piperidyl)methyl]amino}benzanilide.

The compounds of examples 15 and 16 receive the same manner as in example 14.

Example 17

To 612 mg 1-isopropylpiperazine-4-carboxylic acid add 5 ml of thionyl chloride and a few drops of N,N-dimethylformamide and the mixture is stirred at 60°for 1 hour. The solvent is evaporated in vacuum,to the obtained residue, add 465 mg of 2-amino-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide and 20 ml of pyridine at 0°C and the temperature of the mixture was raised to room temperature and the mixture is stirred at room temperature overnight. The solvent is evaporated in vacuo, add saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, the solvent is evaporated in vacuo and the resulting residue is purified column chromatography on silica gel. The resulting crude product is spenderat in ethanol, add 1 N. chloroethanol acid, the mixture is stirred and the precipitate is collected by filtration and dried in vacuum,to obtain 226 mg of the hydrochloride of 2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide. As this compound contains ethanol, transferred into an aqueous solution and dried by freezing and measured NMR.

The compound of example 20 receive the same manner as in example 17.

Example 18

To 450 mg of 1-isopropylpiperazine-4-carboxylic acids are added to 2.6 ml of thionyl chloride and 3 drops of N,N-dimethylformamide and the mixture is stirred at 60°for 30 minutes and concentrated inthe vacuum. To the obtained residue is added toluene and the mixture was concentrated in vacuo.After carrying out the specified operation double-add 520 mg of 2-amino-5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide and 6 ml of pyridine and the mixture is stirred at room temperature for 15 hours. Then it was concentrated in vacuo, add 5% aqueous sodium bicarbonate solution and the mixture extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, the solvent is evaporated in vacuo and the resulting residue is purified column chromatography on silica gel, using as eluent a mixture of chloroform:methanol:saturated aqueous ammonia (100:20:2)to obtain 490 mg crudely purified 4'-chloro-2'-[(5-chloro-2-PI is ideal)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide. Crudely purified product (310 mg) clean ODS column chromatography, using as eluent a mixture of 0.001 N. chloromethane acid:methanol (1:1)and dried by freezing to get 301 mg of the hydrochloride of 4'-chloro-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide.

Example 19

2-Amino-5-bromo-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (2,39 g) and of 1.32 g of 1-isopropylpiperazine-4-carboxylic acid are dissolved in 35 ml of N,N-dimethylformamide, then add 2,02 g of the hydrochloride of 1-ethyl-3-dimethylaminopropylamine, 1.42 g of 1-hydroxybenzotriazole and a 1.46 ml of triethylamine and the mixture is stirred at room temperature for 22 hours. To the reaction solution was added 105 ml of water and 105 ml of ethyl acetate, the mixture is stirred at room temperature for 3 hours and the resulting precipitate was separated by filtration, washed with ethyl acetate and water and dried in vacuum. The obtained solid is suspended in 60 ml of ethanol, add 5 ml of 1 N. chloroethanol acid and the mixture is stirred at room temperature for 30 hours. The precipitate is filtered, washed with ethanol and dried in vacuum to obtain 1.35 g of the hydrochloride of 4'-bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide.

The compound of example 24 receive the same manner as in example 19.

Example 21

To 374 mg 1-from propylpiperidine-4-carboxylic acid, add 3 ml of thionyl chloride and a few drops of N,N-dimethylformamide and the mixture is stirred at 80° With over 30 minutes. The solvent is evaporated in vacuo, to the residue add 509 mg of 2-amino-N-(5-bromo-2-pyridyl)-5-chloro-3-hydroxybenzamide and 20 ml of pyridine at 0°C and the temperature of the mixture was raised to room temperature and the mixture is stirred at room temperature overnight. Then the solvent is evaporated in vacuo, add saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate, the solvent is evaporated in vacuo and the resulting residue is purified column chromatography on silica gel. Add 1 N. chloroethanol acid and water to the obtained N-(5-bromo-2-pyridyl)-5-chloro-3-hydroxy-2-[(1-isopropylpiperazine-4-carbonyl)amino]benzamide and dried by freezing to obtain 602 mg of the hydrochloride of 2'-[(5-bromo-2-pyridyl)carbarnoyl]-4'-chloro-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide.

The compound of example 22 receive the same manner as in example 21.

Example 23

4'-Bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide (495 mg) was dissolved in 15 ml of N,N-dimethylformamide, added 1.39 g of complex trimethylsiloxy sulfur and the mixture was stirred at 50°for 124 hours. Additionally add complex trimethylsiloxy sulfur (0,70 g), the mixture was stirred at 50°C for 21 hours, add 0 ml of water and the mixture is stirred at room temperature for 20 minutes. The obtained precipitate was separated by filtration and washed with water. The obtained solid is suspended in methanol, stirred at room temperature for 12 hours, filtered off, washed with methanol and dried in vacuum.The obtained solid substance was dissolved in 40 ml of methanol and 2 ml of 1 N. aqueous sodium hydroxide solution, the resulting filtrate is separated by filtration and the solvent is evaporated in vacuum.The resulting residue is again dissolved in a mixed solvent of water and methanol, the solution is neutralized with 0.1 N. chloroethanol acid and the resulting precipitate was separated by filtration, washed with water and dried in vacuum. The obtained crudely purified product is dissolved in dilute aqueous sodium hydroxide solution and purified column chromatographie ODS, using as eluent a mixture of acetonitrile:water (5:95 ˜ 40:60). Acetonitrile, in the fraction containing the target product is evaporated in vacuum and the precipitate is filtered off, washed with water and dried in vacuum to obtain 202 mg of 5-bromo-3-[(5-chloro-2-pyridyl)carbarnoyl]-2-[(1-isopropylpiperazine-4-carbonyl)amino]phenyl-hydrosulfate.

Example 25

2-Amino-5-bromo-N-(5-chloro-2-pyridyl)-3-hydroxybenzamide (0,37 g) and 0.50 g of 1-isopropylpiperazine-4-carboxylic acid are dissolved in 10 ml of N,N-dimethylformamide, then added 0.31 g of the hydrochloride of 1-these is-3-dimethylaminopropylamine, 0,22 g of 1-hydroxybenzotriazole and 0.45 ml of triethylamine and the mixture is stirred at room temperature for 18 hours and at 60°C for 4 hours. The reaction solution was concentrated in vacuo,to the resulting residue are added 50 ml of chloroform and 50 ml of 5% aqueous sodium bicarbonate solution and the mixture extracted with chloroform. The solvent is evaporated in vacuo and the resulting residue is washed with methanol and dried in vacuum,to get to 0.37 g of 4'-bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-methanesulfonamido-4-carboxanilide.

Structural formulas and physical and chemical properties of the compounds of the above examples and comparison examples are shown in tables 3-4. Symbols in the tables have the following meanings: NMR spectrum, nuclear magnetic resonance (internal standard: TMS); FAB-MS: mass spectrometry.

The compounds shown in tables 5-9, easily were obtained in the same manner as the manner specified in the examples and examples of the preparation above, or with some modifications which are obvious to a person skilled in this field.

In the structural formulas in tables 3 and 4 and table 9 "Y" means isopropyl, O-" means methoxy, "-" means methyl and "SO2-means SO2is methyl. The symbol "__" in the structural formula in table 5-8 indicates the position of the communication. Some compounds description is installed in tables 3 and 4, can be a mixture of conformational isomers.

Table 3
Example comparison No.Structural formula (g)Data about properties
1NMR (CDCl3):

δ: 1,04 (6N, d, J=6.0 Hz), of 1.18 and 1.33 (2H, m), 1.41 to and 1.56 (1H, m)of 1.75 (2H, d, J=13,7 Hz), 2,11 (2H, dt, Jd=9,3 Hz, Jt=to 11.6 Hz), 2,63-2,77 (1H, m), 2,85-to 2.94 (2H, m), 3,49 (2H, d, J=5.7 Hz).
2NMR (CDCl3):

δ: 1,04 (6N, d, J=6.6 Hz), 1,61 is 1.75 (2H, m), 1,87 is 1.96 (2H, m), 2,16-2,31 (3H, m), 2,67-2,87 (3H, m), for 9.64 (1H, d, J=1.3 Hz).
3NMR (DMSO-d6):

δ: 5,33 (4H, s), 7,31 was 7.45 (10H, m), 7,6l (1H, DD, J=1.4 Hz, 7.5 Hz), to 7.68 (1H, t, J=7.9 Hz), 7,74 (1H, DD, J=1.5 Hz and 8.2 Hz)
4NMR (DMSO-d6):

δ: 5,32 (2H, s), 7,31-7,44 (5H, m), 7,56 (1H, DD, J=1.4 Hz, 7.5 Hz), to 7.68 (1H, t, J=7.9 Hz), 7,74 (1H, DD, J=1.5 Hz and 8.2 Hz)
5NMR (CDCl3):

δ: 5,23 (2H, s), 7,22-7,26 (2H, m), 7,31-7,39 (5H, m), 7,46 (1H, t, J=8,3 Hz), 7,69 (1H, DD, J=2.7 Hz, 9.1 Hz), 8,03 (1H, d, J=2,9 Hz), compared to 8.26 (1H, d, J=8,8 Hz), 9,01 (1H, users)
6 NMR (DMSO-d6):

δ: to 5.93 (2H, s), 6,44 (1H, t, J=7.9 Hz), PC 6.82 (1H, d, J=7,7 Hz), 7,27 (1H, d, J=7,3 Hz), to 7.93 (1H, DD, J=2,6 Hz, 9.0 Hz), 8,14 (1H, d, J=8,8 Hz), to 8.41 (1H, d, J=2.4 Hz), 9,60 (1H, s), 10,46 (1H, s)
7NMR (DMSO-d6):

δ: 6,04 (2H, users), to 6.80 (1H, d, J=2.4 Hz), was 7.36 (1H, d, J=2.0 Hz), to 7.93 (1H, DD, J=2,5 Hz and 8.8 Hz), 8,11 (1H, d, J=9.3 Hz), 8,42 (1H, d, J=2.5 Hz), 10,16 (1H, users), 10,67 (1H, s)
8NMR (DMSO-d6):

δ: the 6.06 (2H, users), of 6.90 (1H, d, J=2.0 Hz), 7,47 (1H, d, J=1.9 Hz), to 7.93 (1H, DD, J=2,4 Hz and 8.8 Hz), 8,10 (1H, d, J=8,8 Hz), 8,42 (1H, d, J=2.4 Hz), 10,14 (1H, users), is 10.68 (1H, users)
9NMR (CDCl3):

δ: was 7.08 (1H, d, J=7,1 Hz), 7,26 (1H, d, J=7.5 Hz), 7,34 (2H, d, J=8,8 Hz), 7,55 (2H, d, J=8,8 Hz), EUR 7.57 to 7.62 (1H, m), 7,79 (1H, users), 10,48 (1H, users)
10NMR (CDCl3):

δ: 5,24 (2H, s), 7,22-7,27 (2H, m), 7,30-7,41 (5H, m), 7,47 (1H, t, J=8.1 Hz), 7,83 (1H, DD, J=2,4 Hz, 8,8 Hz), 8,14-8,17 (1H, m), by 8.22 (1H, d, J=8,8gts), of 8.90 (1H, users)
11NMR (DMSO-d6):

δ: of 7.25 (2H, d, J=7.9 Hz), to 7.50 (1H, t, J=8.0 Hz), 8,00-of 8.09 (2H, m), 8,5l (1H, DD, J=0.7 Hz, 2.4 Hz), 11,24 (1H, s), 11,37 (1H, s)
12NMR(DMSO-d 6):

δ: 5,94 (2H, users), 6,44 (1H, t, J=8.1 Hz), 6,85 (1H, DD, J=1.0 Hz, 7.8 Hz), 7,27, (1H, DD, J=1.0 Hz, 8,3 Hz), 8,03 (1H, DD, J=2,4 Hz and 8.8 Hz), of 8.09 (1H, d, J=8,8 Hz), 8,48 (1H, d, J=2.4 Hz), 10,38-10,52 (1H, user.)
13NMR (DMSO-d6):

δ: 6,04 (2H, users), to 6.80 (1H, d, J=2.2 Hz), was 7.36 (1H, d, J=2.2 Hz), with 8.05 (2H, users), 8,49 (1H, d, J=1.5 Hz), 10,16 (1H, users), 10,66 (1H, s)

Table 4
Example No.Structural formula (g)Data about properties
1NMR (DMSO-d6):

δ: 1,01 was 1.06(1,5H, d, J=5,9 Hz), 1,23 (4,5H, d, J=6.4 Hz), 1,65-of 1.81 (2H, m), 1,82 with 2.14 (2H, m), 2,64-2,70 (1H, m), 2,87 are 2.98 (2H, m), 3,37-4,03 (13H, m), is 4.85 (1H, d, J=7,3 Hz), 7,42 (1H, s), 7,50 (1H, s), of 7.90-of 7.95 (1H, m), 8,09-8,13 (1H, m), 8,39-to 8.41 (1H, m), 8,84 (0,75H, users), 8,95 (0,25H, users), 9,46 (0,25H, (C), 9,50 (0,75H, C), 10,78 (0,75H, C), 10,92 (0,25H, C)

FAB-MS (m/z): 659 (M+H)+
2NMR (DMSO-d6):

δ: 1,02 (1,5H, d, J=5,9 Hz), 1,23 (4,5H, d, J=6.4 Hz), 1,72-of 2.15 (4H, m), 2,63-of 2.72 (1H, m), 2,84 are 2.98 (2H, m), 3,14-3,55 (8H, m), 3.72 points is 3.76 (1H, m), 4,60-5,25 (5H, m), 7,46 (1H, d, J=2.1 Hz), 7,5l (1H, d, J=1.6 Hz), to 7.99 (1H, DD, J=1.3 Hz, 9,2 Hz), 8,06-8,10 (1H, m), 8.34 per-at 8.36 (1H, m), 8,75 (0,75H, users), 8,91 (0,25H, users), 9,24 (0,75H, C), 9,27 (0,25H,
C), accounted for 10.39 (0,75H,, 10,53 (0,25H, C)

FAB-MS (m/z): 659 (M+H)+
3NMR (DMSO-d6):

δ: 1,02-1,05 (1,2H, m), 1,22 (4,8H, d, J=6.9 Hz), 1,62-2,16 (7H, m), 2,68-and 2.79 (1H, m), 2,82-to 3.02 (3H, m), 3,13 is 3.23 (2H, m), 3,38-4,13 (9H, m), equal to 4.97-4,99 (1H, m), 7,37-7,39 (1H, m), 7,43 was 7.45 (1H, m,), of 7.90-7,94 (1H, m), to 7.99 (1H, d, J=8,3 Hz), 8,08-of 8.15 (1H, m), scored 8.38 (0,8H, d, J=2,9 Hz), to 8.41 (0,2H, d, J=2,9 Hz), 8,71-8,82 (2H, m), 10,65 (0,8H, s), 10,87 (0,2H, C)

FAB-MS (m/z): 699 (M+H)+
4NMR (DMSO-d6+CD3OD):

δ: 2,16-of 2.24 (2H, m), of 2.86 (3H, s), 3,15-of 3.27 (4H, m), 3.33 and-of 3.60 (7H, m), 3,69 is 3.76 (2H, m), 3,83 (3H, s), 3,90-of 3.96 (1H, m), of 4.95 (1H, d, J=7,4 Hz), 6.89 in (2H, d, J=8,8 Hz),? 7.04 baby mortality (2H, d, J=8,8 Hz), 7,11 (1H, d, J=8,3 Hz), 7,29-7,33 (1H, m), 7,52 (1H, d, J=8,3 Hz), 7,86 (2H, d, J=8,8 Hz), to 7.93 (2H, d, J=8,8 Hz)

FAB-MS (m/z): 637 (M+H)+
5NMR (DMSO-d6):

δ: 2,13-2,22 (2H, m), 2,85 (3H, d, J=2,9 Hz), 3,12-of 3.27 (3H, m), 3.33 and-of 3.73 (7H, m), 3,82 (3H, s), 3,88-of 3.97 (1H, m)4,00 (1H, d, J=9.3 Hz), 5,12 (1H, d, J=6.3 Hz), from 5.29 (3H, users), to 6.88 (2H, d, J=8,8 Hz), 7.03 is-7,06 (3H, m), 7,29-7,33 (1H, m), of 7.48 (1H, d, J=7.8 Hz), the 7.85 (2H, d, J=9,2 Hz), 7,89 (2H, d, J=8,8 Hz), 9,48 (1H, s), 9,54 (1H, users), 9,88 (1H, s), 12,83 (1H, users)

FAB-MS (m/z): 65l (M+H)+
6NMR (DMSO-d6):

δ: 1,02-1,05 (1,2H, m), 1,23 (4,8H, d, J=6.9 Hz), 1,66 and 2.13 (4H, m), 2,62-of 3.46 (9H, m), as 4.02-of 4.05 (1H, m), 5,12 (1H, d, J=6.8 Hz), of 5.40 (3H, users), 7,31-7,33 (1H, m), 7,38-7,40 (1H, m, to $ 7.91-of 7.95 (1H, m), 8,08-8,13 (1H, m), 8,40 (0,75H, d, J=2.5 Hz), to 8.41 (0,25H, d, J=2.5 Hz), 8,76-of 8.92 (1H, m), 9,46 (0,2H, C), 9,49 (0,8H, s), 10,79 (0,8H, C), of 10.93 (0,2H, C), 12,88 (1H, users)

FAB-MS (m/z): 627 (M+H)+
7NMR (DMSO-d6):

δ: 1,02 was 1.04 (1,2H, m), 1,22 (4,8H, d, J=6.4 Hz), 1,63 and 2.13 (4H, m), 2,63-2,70 (1H, m), 2,86-3,14 (2H, m), 3,36-of 3.46 (6H, m), 4,01-of 4.05 (1H, m), 5,12 (1H, d, J=6.9 Hz), 5,18 is 5.54 (3H, usher.), 7,43 was 7.45 (1H, m), 7,47-7,5l (1H, m), 7,92-of 7.95 (1H, m), 8,08-to 8.14 (1H, m), scored 8.38-8,42 (1H, m), 8,80-9,00 (1H, usher.), 9,44 (0,2H, C), 9,48 (0,8H, s), 10,79 (0,8H, C), of 10.93 (0,2H, C), is 12.85 (1H, users)

FAB-MS (m/z): 672 (M+H)+
8NMR (DMSO-d6):

δ: 1,02-1,05 (1,8H, m), 1,23 (4,2H, d, J=6.4 Hz), 1,66 with 2.14 (4H, m), 2,62-to 2.74 (1H, m), 2,83-and 3.16 (4H, m), 3,28-3,33 (5H, m), 3,37-3,47 (3H, m), 3,61-and 3.72 (2H, m), equal to 4.97-4,99 (1H, m), and 5.30-of 6.20 (3H, user.), 7,42-7,44 (1H, m), 7,47-7,49 (1H, m), 7,92-of 7.95 (1H, m), 8.07-a 8,13 (1H, m), scored 8.38-8,42 (1H, m), 8,89 (0,3H, users), 9,07 (0,7H, users), 9,43 (0,3H, s), for 9.47 (0,7H, s), 10,76 (0,7H, s), 10,91 (0,3H, s)

FAB-MS (m/z): 673 (M+H)+
9NMR (DMSO-d6):

δ: of 1.27 (6H, d, J=6.3 Hz), 1,60-1,75 (2H, m), 1,95-2,07 (3H, m), 2,89 (2H, q, J=11,1 Hz), 3,18 (2H, users), 3,37 (2H, d,

J=a 12.7 Hz), 3,85-of 3.95 (1H, m), 7,15-7,30 (2H, m), 7,32 (1H, d, J=7,3 Hz), 8,00 (1H, DD, J=2,5 Hz and 8.8 Hz), 8,19 (1H, d, J=8,8 Hz), to 8.45 (1H, d, J=2.5 Hz), 10,23-the 10.40 (1H, usher.), 10,82 made 11.32 (1H, usher.), 11,53 (1H, users)

FAB-MS (m/z): 403 (M+H)+
10 NMR (DMSO-d6):

δ: of 1.23 (6H, d, J=6.9 Hz), 1,45 is 1.58 (2H, m), 1,75-1,9l (3H, m), and 2.83 (2H, q, J=11,1 Hz)of 3.00 (2H, d, J=6.4 Hz), 3.27 to is 3.40 (3H, m), was 7.08 (1H, d, J=1.9 Hz), 7,20 (1H, d, J=2.4 Hz), of 7.97 (1H, DD, J=2.7 Hz, 8,8 Hz), 8,18 (1H, d, J=9.3 Hz), 8,43 (1H, d, J=2.4 Hz), 9,94 (1H, users), or 10.60-10,95 (1H, usher.), 11,51 (1H, s)

FAB-MS (m/z): 437 (M+H)+
11NMR (DMSO-d6):

δ: of 1.25 (6H, d, J=6.4 Hz), 1,50-to 1.67 (2H, m), 1,75-2,02 (3H, m), of 2.86 (2H, q, J=11,1 Hz), 3,06 (2H, users), 3,30 is-3.45 (3H, m),? 7.04 baby mortality (1H, users), 7,14 (1H, users), 7,29 (1H, d,J=7.8 Hz), 8,08 (1H, DD, J=2.5 Hz, and 9.3 Hz), 8,16 (1H, d, J=8,8 Hz)and 8.50 (1H, d, J=2.4 Hz), to 10.09 (1H, users), 10,20-10,90 (1H, usher.), 11,60 (1H, users)

FAB-MS (m/z): 449 (M+H)+
12NMR (DMSO-d6):

δ: of 1.23 (6H, d, J=6.9 Hz), 1,44 is 1.58 (2H, m), 1,75-2,00 (3H, m), and 2.83 (2H, q, J=11.2 Hz), 3,01 (2H, d, J=6.3 Hz), 3.27 to 3,43 (3H, m), 7,07 (1H, users), 7,20 (1H, d, J=2.4 Hz), 8,08 (1H, DD, J=2,4 Hz and 8.8 Hz), 8,13 (1H, d, J=8,8 Hz)and 8.50 (1H, d, J=1.9 Hz), 9,82 (1H, users), 10,77 (1H, users), 11,50 (1H, s)

FAB-MS (m/z): 483 (M+H)+
13NMR (DMSO-d6):

δ: of 1.26 (6H, d, J=6.8 Hz), 1,57 by 1.68 (2H, m), 1,83-of 1.95 (3H, m), is 2.30 (3H, s), 2.77-to 2,89 (2H, m), 3,05 (2H, d, J=6.3 Hz), 3,28-

3,40 (3H, m)6,91 (1H, t, J=7.8 Hz), 7,07 (1H, DD, J=1.4 Hz, 7,8gts), 7,31 (1H, DD, J=1.4 Hz, 7.8 Hz), 7,74 (1H, DD, J=2.0 Hz, 8,3 Hz), 8,03 (1H, d, J=8,3 Hz), 8,21 (1H, d, J=2.0 Hz), 10,08 (1H, users)

FAB-MS (m/z): 383 (M+H)+
14NMR (DMSO-d6):

δ: 1,22-of 1.26 (6H, m), 1,49-1,6l (2H, m), 1,74-of 1.92 (3H, m), 2,78-2,87 (2H, m), 3,10 (2H, d, J=6,GC), of 3.25 to 3.35 (3H, m), 6.75 in-6,79 (1H, m), 6,95-6,97 (1H, m), 7,07-to 7.09 (1H, m), 7,35-7,39 (2H, m), 7,72 to 7.75 (2H, m), 9,65 (1H, users), 10,33 (1H, s)

FAB-MS (m/z): 402 (M+H)+
15NMR (DMSO-d6):

δ: of 1.23 (6H, d, J=6.4 Hz), 1,47-of 1.62 (2H, m), 1,80-of 1.94 (3H, m), 2,3l (3H, s)2,84 (2H, q, J=11.2 Hz), 3,14 (2H, d, J=4.9 Hz), 3.27 to of 3.42 (3H, m), 6,93 (1H, d, J=7,3 Hz), 7,00-to 7.18 (3H, m), 7.23 percent (1H, t, J=7.8 Hz), to 7.50 (1H, d, J=8,3 Hz), 7,56 (1H, s), 9,72-9,90 (1H, usher.), 10,33-10,48 (1H, user.)

FAB-MS (m/z): 382 (M+H)+
16NMR (DMSO-d6):

δ: 1,18-of 1.26 (6H, m), 1,42-to 1.63 (2H, m), 1,68-2,04 (3H, m), 2.77-to of 2.93 (2H, m), 3.00 and-3,70 (5H, m in), 3.75 (3H, m), 6,84-of 7.24 (5H, m), a 7.62 (2H, d, J=8,8 Hz), 9,67 (1H, users), 10,33 (1H, users)

FAB-MS (m/z): 398 (M+H)+
17NMR (DMSO-d6):

δ: 1,06 (l,5H, d, J=6.4 Hz), 1,24 (4,5H, d, J=6.3 Hz), 1,75 is 2.10 (4H, m), 2.63 in is-3.45 (6H, m), 7,01-to 7.09 (2H, m), 7,12-7,20 (1H, m), of 7.90-of 7.96 (1H, m), 8,13 (0,25H, d, J=8,3 Hz), 8,15 (0,75H, d, J=8,8 Hz), of 8.37 (0,75H, d, J=3.0 Hz), 8,39 (0,25H, d, J=2.5 Hz), 9,20-of 9.30 (0,75H, usher.), 9,41 (0,75H, C), 9,46 (0,25H, (C), 9,74-9,80

(0,25H, usher.), 9,84 (0,75H, C)9,85 (0,25H, (C), accounted for 10.39 (0,75H, C), 10,59 (0,25H, C)

FAB-MS (m/z): 417 (M+H)+
18NMR (DMSO-d6):

´ : 1,05 (1,8H, d, J=6.8 Hz), 1,25 (4,2H, d, J=6.3 Hz), 1,81-to 2.18 (4H, m), 2,63-3,26 (4H, m), 3,34-3,44 (2H, m), 7,05-7,06 (1H, m), 7,15-7,17 (1H, m), to $ 7.91-of 7.96 (1H, m), 8,09-8,13 (1H, m), of 8.37-to 8.41 (1H, m), for 9.47 (0,7H, s), 9,56 (0,3H, s), 10,45-is 10.68 (1,7H, m), 10,41 (0,3H, users), 10,61 (0,7H, s), 10,81 (0,3H, s)

FAB-MS (m/z): 451 (M+H)+
19NMR (DMSO-d6):

δ: 1,04 (1,8H, d, J=6.8 Hz), 1,24 (4,2H, d, J=6.3 Hz), 1,74-2,12 (4H, m), 2,60 is-3.45 (6H, m), 7,15-7,19 (1H, m), 7.23 percent-7,27 (1H, m), 7,89-of 7.97 (1H, m), 8.07-a to 8.14 (1H, m), 8,35-8,4l (1H, m), 9,39-of 9.55 (1,7H, m), 9,98-10,10 (0,3H, usher.), 10,44-10,50 (1H, m), to 10.62 (0,7H, s), 10,81 (0,3H, s)

FAB-MS (m/z): 497 (M+H)+
20NMR (DMSO-d6):

δ: 1,06 (1,5H, d, J=6.4 Hz), 1,24 (4,5H, d, J=6.3 Hz), 1,75-of 2.08 (4H, m), 2,65-of 3.42 (6H, m), 7,01-was 7.08 (2H, m), 7,12-7,19 (1H, m), 8,01-8,13 (2H, m), 8,44 (0,75H, d, J=2.5 Hz), 8,46 (0,25H, d, J=2.4 Hz), 9,25 (0,75H, users), 9,41 (0,75H, C), 9,46 (0,25H, (C), 9,77 (0,25H, users), 9,84 (0,75H, C), 9,86 (0,25H, (C), accounted for 10.39 (0,75H, (C), of 10.58 (0,25H, C)

FAB-MS (m/z): 461 (M+H)+
21NMR (DMSO-d6):

δ: 1,03 (1,2H, d, J=6.8 Hz), 1,23 (4,8H, d, J=6.3 Hz), 1,68 is 2.10 (4H, m), 2,60-3,30 (6H, m), 7,05-to 7.09 (2H, m), 8,01-8,10 (2H, m), 8,44-8,48 (1H, m), 8,98 (0,8H, users), of 9.30-9,52 (1,2H, m), 10,38 (0,8H, C), the 10.40 (0,2H, C), to 10.62 (0,8H, C),

10,81 (0,2H, C)

FAB-MS (m/z): 497 (M+H)+
22NMR (DMSO-d6):

δ: 1,04 (1,5H, d, J=6.3 Hz), 1.26 in (4,5H, d, J=6.9 Hz), 1,83-2,22 (4H, m),2,33 (0,8H, C)2,35 (2,2H, C), 2,64 is 3.23 (4H, m), 3,32 is 3.40 (2H, m), 7,11-7,13 (1H, m), 7,22-of 7.25 (1H, m), a 7.85 to $ 7.91 (1H, m), 7,95-8,08 (1H, m), 8,25-8,29 (1H, m), 9,65 (0,75H, C), 9,70 (0,25H, (C), 10,12 (0,75H, users), of 10.58 (0,25H, users), 10,79 (1H, users), 11,36 (0,25H, (C), 11,49 (0,75H, C)

FAB-MS (m/z): 431 (M+H)+
23NMR (DMSO-d6):

δ: 1,08 (1,2H, d, J=6.8 Hz), 1,22 (4,8H, d, J=6.8 Hz), 1,65-of 2.21 (4H, m), 2,55-3,50 (6H, m), 7,45 is 7.50 (1H, m), 7,62-of 7.70 (1H, m), 7,89-of 7.95 (1H, m), 8,05-to 8.14 (1H, m), at 8.36-8,42 (1H, m), 8,63-8,79 (1H, usher.), 9,51 (0,8H, s), 9,67 (0,2H, C), 10,78 (0,8H, s), 10,92 (0,2H, C)

FAB-MS (m/z): 575 (M-H)-
24NMR (DMSO-d6):

δ: 1,46-of 1.57 (2H, m), 1,82-1,90 (2H, m), 2,81-2,90 (1H, m), 3,20 of 3.28 (2H, m), 4,08-to 4.14 (2H, m), 7,13-7,16 (3H, m), 7,27 (1H, d, J=1.5 Hz), 7,88 (1H, DD, J=1.5 Hz, 8,8 Hz), of 8.09 (1H, d, J=Hz), 8,21 (2H,, d, J=7,3 Hz), with 8.33 (1H, d, J=Hz), 9,42 (1H, s), 10,50 (1H, s), 10,56 (1H, s), 13,49 (1H, s)

FAB-MS (m/z): 532 (M+H)+
25NMR (DMSO-d6):

δ: 1,44-of 1.55 (2H, m), 1,75-of 1.81 (2H, m), 2,48-of 2.54 (1H, m), 2,66-to 2.74 (2H, m), 2,82 (3H, s), 3,45-3,51 (2H, m), 7,16-7,19 (2H, m), to 7.93 (1H, DD, J=3.0 Hz, 8,8 Hz)to 8.12 (1H, d, J=8,8 Hz), scored 8.38 (1H, d, J=2,4 Hz), to 9.32 (1H, users), 10,28 (1H, users), 10,57 (1H, s)

FAB-MS (m/z): 451 (M+H)+

img src="https://img.russianpatents.com/829/8291537-s.jpg" height="190" width="164" >

1. A derivative of benzene of the formula (I)or its salt

where:

X1: -C(=O)-NR5-, -NR5-C(=O)-;

X2: -NR6-C(=O)-, -NR6-CH2-;

R1: halogen atom, lower alkyl or lower alkoxygroup;

R2and R3the same or different and each means a hydrogen atom or a halogen atom;

R4: a hydrogen atom, -SO3H or the residue of sugar;

ring: ring of benzene or pyridine;

ring: ring of piperidine, where the nitrogen atom is substituted by an R7when R4means a hydrogen atom; or when R4means the remainder of the sugar, the ring means a piperidine ring in which the nitrogen atom is substituted by an R7or a benzene ring substituted by a group of diazepan formula:

R5and R6means a hydrogen atom,

R7and R8each signify lower alkyl, -SO2-(lower alkyl) or pyridine,

provided that, when X2means-NR6-C(=O)- and R4means a hydrogen atom, ring a represents a pyridine

2. The compound according to claim 1 is whether its salt, where R4means a hydrogen atom, -SO3H or the residue of glucuronic acid.

3. The compound according to claim 1 or its salt, where R4means a hydrogen atom.

4. The compound according to claim 1, selected from the following compounds:

4'-bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-β-D-galactopyranosyl-1-isopropylpiperazine-4-carboxanilide,

2'-(2-acetamido-2-deoxy-β-D-glucopyranosyloxy)-4'-bromo-6'-[(5-chloro-2-pyridyl)carbarnoyl]-1-isopropylpiperazine-4-carboxanilide,

4'-bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-β-D-glucopyranosyloxy-1-isopropylpiperazine-4-carboxanilide,

5-chloro-3-[(5-chloro-2-pyridyl)carbarnoyl]-2-[(1-isopropylpiperazine-4-carbonyl)amino]phenyl-β-D-glucopyranosid-uronic acid,

5-bromo-3-[(5-chloro-2-pyridyl)carbarnoyl]-2-[(1-isopropylpiperazine-4-carbonyl)amino]phenyl-β-D-glucopyranosid-uronic acid,

4'-chloro-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropyl-piperidine-4-carboxanilide,

4'-bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropyl-piperidine-4-carboxanilide,

2'-[(5-bromo-2-pyridyl)carbarnoyl]-4'-chloro-6'-hydroxy-1-isopropyl-piperidine-4-carboxanilide,

5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[(1-isopropyl-4-piperidyl)methyl]amino}benzamide,

N-(5-bromo-2-pyridyl)-5-chloro-3-hydroxy-2-{[(1-isopropyl-4-piperidyl)methyl]amino}benzamide,

3-[4-methoxybenzoyl)amino]-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenyl-β -D-glucopyranosid and

3-[(4-methoxybenzoyl)amino]-2-{[4-(4-methyl-1,4-diazepan-1-yl)benzoyl]amino}phenyl-β-D-glucopyranosid-uronic acid, or its salt.

5. The pharmaceutical composition inhibiting activated factor X in the coagulation of blood, comprising the compound according to claim 1 or its salt as an active ingredient, together with pharmaceutically acceptable carrier or excipient.

Priority claims:

item 1:

the priority of 22.12.2000 on the date of filing JP 20000390321, in terms of signs: R4- the remainder of the sugar;

ring: ring of benzene;

ring: benzene ring substituted by a group of diazepan;

the priority of 21.11.2001 on the date of filing of application PCT/JP 01/10176, in terms of signs: R4: -SO3H-;

R7and R8: -SO2- (lower alkyl) or pyridine;

the priority of 22.11.2000 date of filing JP 20000356146, part of the other signs.

item 2:

the priority of 22.12.2000 on the date of filing JP 20000390321, in terms of signs: R4means the residue of glucuronic acid;

the priority of 21.11.2001 on the date of filing of application PCT/JP 01/10176, in terms of signs: R4: -SO3N;

the priority of 22.11.2000 date of filing JP 20000356146, in terms of signs: R4means a hydrogen atom.

item 3:

the priority of 22.11.2000 on the date of filing the Declaration, the Ki JP 20000356146.

item 4:

the priority of 22.11.2000 date of filing JP 20000356146, part of connections:

4'-chloro-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide,

4'-bromo-2'-[(5-chloro-2-pyridyl)carbarnoyl]-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide,

2'-[(5-bromo-2-pyridyl)carbarnoyl]-4'-chloro-6'-hydroxy-1-isopropylpiperazine-4-carboxanilide,

5-chloro-N-(5-chloro-2-pyridyl)-3-hydroxy-2-{[(1-isopropyl-4-piperidyl)methyl]amino}benzamide,

N-(5-bromo-2-pyridyl)-5-chloro-3-hydroxy-2-{[(1-isopropyl-4-piperidyl)methyl]amino}benzamide;

the priority of 22.12.2000 on the date of filing JP 20000390321, part of the other connections.

paragraph 5:

the priority of 22.12.2000 on the date of filing JP 20000390321, in part, compositions comprising compound I where:

R4- the remainder of the sugar;

ring: ring of benzene;

ring: benzene ring substituted by a group of diazepan;

the priority of 21.11.2001 on the date of filing of application PCT/JP 01/10176, in part, compositions comprising compound I where:

R4: -SO3H-;

R7and R8: -SO2-(lower alkyl) or pyridine;

the priority of 22.11.2000 date of filing JP 20000356146, part of the other compounds I.



 

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15 cl, 1 tbl, 99 ex

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19 cl, 3 tbl, 12 ex

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FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to new derivatives of quinazoline of the formula (I):

wherein m = 0, 1, 2 or 3; each group R1 that can be similar or different is taken among halogen atom, trifluoromethyl, hydroxy-, amino-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy-, (C2-C6)-alkynyloxy-, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino- and (C2-C6)-alkanoylamino-group, or among the group of the formula: Q1-X1- wherein X1 represents oxygen atom (O); Q1 represents aryl-(C1-C6)-alkyl, heteroaryl, heteroaryl-(C1-C6)-alkyl, heterocyclyl or heterocyclyl-(C1-C6)-alkyl and wherein neighboring carbon atoms in any (C2-C6)-alkylene chain in substitute at R1 are separated optionally by insertion to the chain the group taken among oxygen atom (O) and N(R5) wherein R5 represents hydrogen atom or (C1-C6)-alkyl, or when the inserted group represents N(R5); R5 can represent also (C2-C6)-alkanoyl and wherein any group -CH2 or -CH3 in substitute R1 carries one or more substitutes in each indicated group -CH2 or -CH3 and wherein these substitutes are taken among halogen atom or (C1-C6)-alkyl, or substitute taken among hydroxy-, amino-group, (C1-C6)-alkoxy-, (C1-C6)-alkylthio-group, (C1-C6)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-, (C2-C6)-alkanoyloxy, (C2-C6)-alkanoylamino- and N-(C1-C6)-alktyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X3-Q3wherein X3 represents oxygen atom (O) and Q3 represents heteroaryl, and wherein any aryl, heteroaryl or heterocyclyl group in substitute at R1 carries optionally 1, 2 or 3 substitutes that can be similar or different and taken among halogen atom, trifluoromethyl, cyano-, hydroxy-, amino-group, carbamoyl, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, (C1-C6)-alkoxy-, (C2-C6)-alkenyloxy, (C2-C6)-alkynyloxy,(C1-C6)-alkylthio-group, (C1-C)-alkylsulfinyl, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylamino-, di-[(C1-C6)-alkyl]amino-group, (C1-C6)-alkoxycarbonyl, N-(C1-C6)-alkylcarbamoyl, N,N-di-[(C1-C6)-alkyl]carbamoyl, (C2-C6)-alkanoyl, (C2-C6)-alkanoyloxy-, (C2-C)-alkanoylamino- and N-(C1-C6)-alkyl-(C2-C6)-alkanoylamino-group, or among the group of the formula: -X4-R8 wherein X4 represents a simple bond and R8 represents hydroxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, cyano-(C1-C6)-alkyl, amino-(C1-C6)-alkyl, (C1-C6)-alkylamino-(C1-C6)-alkyl or di-[(C1-C6)-alkyl]amino-(C1-C6)-alkyl, or among the group of the formula: -X5-Q4 wherein X5 represents a simple bond or -CO, and Q4 represents heterocyclyl or heterocyclyl-(C1-C6)-alkyl that carries optionally 1 or 2 substitutes that can be similar or different and taken among halogen atom, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl and (C1-C6)-alkoxy-group and wherein any heterocyclyl group in substitute at R1 carries optionally 1 or 2 oxo-substitutes, and wherein any aryl group in the group R1 represents phenyl; any heteroaryl group in the group R1 is taken among pyrrolyl, imidazolyl, triazolyl and pyridyl, and any heterocyclyl group in the group R1 is taken among oxyranyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, 1,1-dioxotetrahydro-1,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl and homopiperazinyl; R2 represents hydrogen atom; n = 0, 1, 2 or 3; R3 represents halogen atom, trifluoromethyl, cyano-, hydroxy-group, (C1-C6)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or (C1-C6)-alkoxy-group, or its pharmaceutically acceptable salt. Also, invention relates to methods for preparing compounds of the formula (1) and to pharmaceutical composition based on thereof for using as an anti-tumor agent. Invention provides preparing new derivatives of quinazoline possessing an anti-tumor activity.

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

17 cl, 7 tbl, 7 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-aminomethylquinolone-2 of the general formula (1)

(2)

or (3) wherein R1 means hydrogen atom (H) or Alk; R2 is taken among Alk; -OAlk, -SCH3, -Hal, -CF3, 3,4-OCH2CH2O-, 3,4-OCH2O-, 4-OCF3, 2-Ph, -OPh, -NHCOR, 2-OCH3, 5-Ph, 4-Obzk, 3-NO2, 2-CH3, 5-iPr, di-OAlk, di-Hal; or R2 represents halogen atom and alkyl group, or halogen atom and alkoxy-group taken simultaneously and independently of one another; or R2 represents the group -CONR4R5 wherein each R4 and R5 means independently of one another the group Alk, or they form the group -(CH2)n- wherein n = 2-6. R means -CH3; R3 means hydrogen atom (H); X is taken among hydrogen atom (H), 6-(C1-C3)-Alk, 6-iPr, 6-iBu; 7-(C1-C2)-Alk, 8-(C1-C2)-Alk, 6-(C1-C2)-OAlk, 6-OCF3, 7-(C1-C2)-Alk, 7-SCH3, 6,7-OCH2O-, 6,7-OCH2CH2O-, 5,6,7-OCH3, 6-F; X and Y are similar or different and taken among 7,8-CH3, 6,8-CH3, 5,8-CH3, 5,7-CH3, 6,7-CH3, 6,7-OCH3, 6-CH3, 7-Cl. Also, invention relates to a method for preparing indicated compounds and to pharmaceutical composition inhibiting activity of NO-synthetase based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims preparing medicinal agents for treatment diseases associated with hyperactivity of phagocytizing cells, for example, rheumatic arthritis, asthma and others.

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

19 cl, 1 tbl, 95 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I) and pharmaceutical composition based on thereof possessing properties of ligand binding with adenosine receptors selectively. Invention provides preparing new compounds possessing useful biological properties.

EFFECT: valuable properties of compounds.

6 cl, 375 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 4-aminopiptidine of the general formula (I): wherein R1 means (C1-C6)-alkyl, -(CH2)m-Y-Z11 or -(CH2)m-Z12 wherein Z11 means (C1-C6)-alkyl; Z12 means bis-phenyl, (C3-C7)-cycloalkyl, (C3-C7)-heterocycloalkyl with 1 or 2 heteroatoms taken among nitrogen (N) or oxygen (O) atoms, possibly substituted phenyl, naphthyl, possibly substituted (C5-C9)-heteroaryl wherein heteroatoms are taken among N; or Z12 means ; Y means O; or R1 means ; R2 means -C(Y)-NHX1, -C(O)X2 or -SO2X3; R3 means hydrogen atom (H), (C1-C4)-alkyl, (C2-C4)-alkenyl, possibly substituted heteroarylalkyl or -C(Y)-NHX1, -(CH2)n-C(O)X2 or -SO2X3 wherein X1-X3 have different values. Also, invention describes methods for preparing indicated substances by synthesis in liquid and solid phase. These compounds possessing good affinity to definite subtypes of somatostatin receptors can be used in treatment of pathological states or diseases caused by one or some somatostatin receptors.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

14 cl, 4 tbl, 778 ex

FIELD: organic chemistry of natural compounds, medicine, oncology.

SUBSTANCE: invention relates to new compounds - C7-ester-substituted taxanes of the general structural formula:

wherein R2 represents benzoyloxy-group; R7 represents R7aCOO-; R10 represents hydroxy-group; X3 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among oxygen (O), nitrogen (N) and sulfur (S) atoms; X5 represents -COX10 wherein X10 represents (C1-C8)-alkyl, (C2-C8)-alkenyl, phenyl or 5- or 6-membered heteroaryl group comprising heteroatom taken among O, N and S; or it (X5) represents -COOX10 wherein X10 represents (C1-C8)-alkyl or (C2-C8)-alkenyl; R7a represents (C1-C20)-alkyl or (C2-C20)-alkenyl; Ac represents acetyl group. These compounds possess an anti-tumor activity. Also, invention relates to a method for inhibition of tumor growth in mammals and to a pharmaceutical composition based on synthesized compounds. Invention provides preparing new derivatives of taxanes possessing the enhanced anti-tumor activity and reduced toxicity as compared with taxol and taxoter.

EFFECT: improved and valuable medicinal properties of compounds.

39 cl, 4 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of isoquinoline carboxamide of the formula (I):

and to their pharmaceutically acceptable salts wherein R1 means hydrogen atom, hydroxy-group or -NHR2 wherein R2 means alkyl, arylalkyl, heterocyclylalkyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, cycloalkyl, alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl that comprises one or some heteroatoms taken among nitrogen, oxygen and sulfur atoms, arylalkylcarbonyl, heterocyclylalkylcarbonyl that comprises one or some heteroatoms taken among nitrogen and oxygen atoms, alkyloxycarbonyl, arylalkyloxycarbonyl, heterocyclylalkyloxycarbonyl that comprises one or some heteroatoms taken among nitrogen atom, heterocyclyl that comprises one or some heteroatoms taken among nitrogen and sulfur atoms, alkylsulfonyl, arylsulfonyl or the group of the formula:

R3 and R4 mean alkyl independently of one another; R5 means alkyl; or R4 and R5 in common with carbon and sulfur atoms to which they are bound form a heterocycle; R6 means alkyl; R13 means hydrogen atom or the group of the formula:

R15 means aryl under condition that if R3, R4 and R5 form methyl, R6 forms tert.-butyl then R13 means hydrogen atom, and if R15 means phenyl then R2 doesn't mean benzyloxycarbonyl and 2-quinoline carbonyl (other values of radicals are given in cl. 1 of the invention claim). Also, invention relates to a medicinal agent based on these compounds used in treatment of HIV-mediated diseases. Invention provides preparing new compounds and a medicinal agent based on thereof in aims for treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and medicinal agent.

14 cl, 11 tbl, 173 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I):

wherein R1 represents the following groups:

wherein * means the addition point; R4 means fluorine, chlorine, bromine atom, -CF3, -N=C, -CH3, -OCF3 or -CH2OH; R5 means chlorine, bromine atom or -OCH3; R6 means -CH3 or chlorine atom; R7 means -CH3 or chlorine atom; R8 means -CH3, fluorine, chlorine atom or -CF3; R2 represents pyridyl or group:

or ; R3 represents hydrogen or fluorine atom, and their tautomers, E-isomers or Z-isomers, racemates, enantiomers and salts also that are inhibitors of activity of tyrosine kinase KDR and FLT. Also, invention describes medicinal agents comprising the claimed compounds and designated for treatment of diseases associated with inhibition of activity of kinase KDR and FLT.

EFFECT: valuable biochemical and medicinal properties of compounds.

6 cl, 1 tbl, 30 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: claim describes substituted anthranylamides of the general formula (I): wherein A means group =NR7; W means oxygen atom; D, E, F, G, X, Z, R1, R2, R7 and R9 have values given in the description and their isomers and salts also. Also, claim describes intermediate compounds used in preparing indicated anthranylamides. Also, invention relates to medicinal agents, their compositions and their using. Proposed compounds can be used in treatment of diseases associated with persistent angiogenesis that can be cause of different diseases, such as psoriasis, arthritis, for example, rheumatic arthritis, hemangioma, angiofibroma, ophthalmic diseases, for example, diabetic retinopathy, neovascular glaucoma, kidney diseases, for example, glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombosis microangiopathy, rejection of transplants and glomerulopathy, fibrosis diseases, for example, hepatic cirrhosis, diseases associated with proliferation of mesangial cells and arteriosclerosis that can result to progression of these diseases. Invention provides the development of the corresponding medicinal agent designated for treatment of abovementioned diseases. The development of the preparation allows expanding assortment of agents used in treatment of such diseases.

EFFECT: valuable medicinal properties of compounds.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing aminoxyl ethers, for example, N-hydrocarbyloxy-derivatives of steric hindranced amines that can be used as light- and/or thermostabilizing organic materials and/or a regulator in the polymerization reaction. Invention describes a method for preparing aminoxyl ethers by interaction of the corresponding N-oxyl derivative with hydrocarbon organic solvent in the presence of organic peroxide and a catalyst representing copper or copper compound, preferably, inorganic compound Cu (I) or Cu (II) as a solution in suitable solvent chosen in the catalytically effective amount. Method provides preparing the end product with the high yield by simplified technological schedule and without using high temperatures.

EFFECT: improved method of synthesis.

15 cl, 2 tbl, 27 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention relates to a new method for preparing derivative of pyridine of the formula [d]: wherein values of R1, R3 and R4 are given below. Method involves interaction of a new derivative of pyridone of the formula [a]: wherein R3 represent halogen atom, cyano-group or nitro-group; R4 represents hydrogen atom or halogen atom with derivative of α-diazoester of the formula [f]: -N2CHCOR1 [f] wherein R1 represents (C1-C6)-alkoxy-group, and this interaction is carried out in the presence of acid. Proposed method is suitable and profit method for preparing derivatives of pyridine of the formula [d] possessing with specific system of substitutes and eliciting the herbicide activity.

EFFECT: improved preparing method.

8 cl, 2 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 3-hydroxypiperidine of the general formula (I): wherein R means (a): -C(O)(CH2)nC(O)OH; (b): wherein R1 means -N(R2)(R3); each R2 and R3 means hydrogen atom, lower alkyl or cyclic tertiary amine; (c): -P(O)(OH)2 or (d): -C(O)(CH2)n and -NHC(O)(CH2)nN(R2)(R3) wherein n means a whole number 1-4. Indicated compounds can be used as prodrugs in preparing medicinal agents used in treatment of diseases associated with blocking agents for receptors of subtype NMDA.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 1 tbl, 20 ex

FIELD: organic chemistry, medicinal virology, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrazole of the formula (I-A):

wherein R1 means (C1-C12)-alkyl that can be optionally substituted with 1-3 substitutes taken among fluorine, chlorine and bromine atoms, (C3-C8)-cycloalkyl, phenyl, pyridyl or (C1-C4)-alkyl substituted with phenyl; R2' means optionally substituted phenyl wherein phenyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano- and nitro-group; R3 means (C1-C12)-alkyl or (C1-C4)-alkoxy-(C1-C4)-alkyl; A' means (C1-C4)-alkyl optionally substituted with phenyl or optionally substituted with 4-pyridyl wherein phenyl or 4-pyridyl can be substituted with 1-2 substitutes taken among (C1-C4)-alkyl, (C1-C4)-alkoxyl, hydroxyl, fluorine, chlorine and bromine atoms, cyano-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH2-U-heterocyclyl wherein U represents O, S or NR'' wherein R'' means hydrogen atom or (C1-C4)-alkyl and wherein heterocyclyl means pyridyl or pyrimidinyl that is optionally substituted with 1-2 substitutes taken among (C1-C4)-alkyl, fluorine, chlorine and bromine atoms, cyano-, nitro-group and NRR' wherein R and R' mean independently of one another hydrogen atom or (C1-C4)-alkyl; or A' means group of the formula CH(OH)-phenyl; or A' means the group CH=CHW wherein W means phenyl; X means S or O, and their pharmaceutically acceptable salts. These compounds are inhibitors of human immunodeficiency virus (HIV) reverse transcriptase and, therefore, can be used in treatment of HIV-mediated diseases. Also, invention relates to a pharmaceutical composition used in treatment of HIV-mediated diseases.

EFFECT: valuable medicinal properties of compounds and composition.

11 cl, 5 tbl, 32 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

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