Pyrrolopyridazine derivatives

FIELD: organic chemistry, medicine, gastroenterology, pharmacy.

SUBSTANCE: invention relates to a pyrrolopyridazine derivative of the following formula: wherein R1 represents (C3-C7)-cycloalkyl-(C1-C6)-alkyl group that can be substituted optionally with (C1-C6)-alkyl group; R2 represents (C1-C6)-alkyl group; R3 represents hydroxymethyl group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbonyloxymethyl group, (C1-C6)-alkoxycarbonyloxymethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxycarbonyl group; R4 represents (C6-C10)-aryl group that can be substituted optionally with substitutes taken among the group consisting of (C1-C6)-alkyl groups, halogen-(C1-C6)-alkyl groups, (C1-C6)-alkoxy-groups, halogen-(C1-C6)-alkoxy-groups and halogen atoms; A represents imino-group, oxygen or sulfur atom, or its pharmaceutically acceptable salt. Pyrrolopyridazine derivatives elicit inhibitory activity with respect to gastric juice secretion and protective activity with respect to stomach mucosa and can be useful as a curative agent for prophylaxis or treatment of ulcer disease. Except for, invention relates to a pharmaceutical composition based on compounds of the invention and to a method for prophylaxis and treatment of ulcer disease.

EFFECT: valuable medicinal properties of compound.

25 cl, 1 tbl, 11 ex

 

The technical field to which the invention relates.

This invention relates to pyrrolopyridine derivatives or their pharmaceutically acceptable salts; to pharmaceutical compositions containing as active ingredient pyrrolopyridine derivative or its pharmaceutically acceptable salt (preferably, the compositions are suitable as a means of prevention or treatment of peptic ulcer); for use pyrrolopyridine derivative or its pharmaceutically acceptable salt in obtaining pharmaceutical compositions (preferably, the composition for prevention or treatment of peptic ulcer disease); or to a method of prevention or treatment of a disease (preferably, peptic ulcer), involving the introduction of a pharmaceutically effective amount pyrrolopyridine derivative or its pharmaceutically acceptable salt to a warm-blooded animal (preferably, person).

Background of invention

It is believed that an imbalance between aggressive factors and protective factors in relation to the mucous membrane of the stomach causes peptic ulcers. The secretion of gastric juice is an aggressive factor and suppressing the secretion of gastric juice is useful for the prevention or treatment of disease. Anticholinergic agents, receptor antagonists of the Geest is in H 2such as cimetidine and such, and proton pump inhibitors such as omeprazole and the like, are used clinically as inhibitors of gastric secretion. Although these tools are excellent remedies in case of peptic ulcer disease, the disease may recur after discontinuation of treatment. Recently it was reported that Helicobacter pylori is related to the recurrence of ulcers. In fact, have been several attempts to use an inhibitor of gastric secretion in combination with an antibacterial agent for the treatment of disease.

Accordingly, it can be expected that the connection detecting a strong inhibitory activity against the secretion of gastric juice, excellent protective activity against gastric mucosa and strong antibacterial activity against Helicobacter pylori, is an excellent therapeutic agent (preferably, a prophylactic and therapeutic agent against peptic ulcer disease).

Known to some pyrrolopyridine derivatives having inhibitory activity against the secretion of gastric juice and protective activity against gastric mucosa (see, for example, WO 91/17164, WO 92/06979, WO 93/08190 etc). Also is known about the activity of some pyrrolopyridine derivatives against Helicobacter pylori (the m, for example, the publication of the patent application of Japan Hei 7-247285, etc).

Description of the invention

The inventors continued studies of pharmacological activity pyrrolopyridine derivatives in order to develop a therapeutic agent (preferably, anti-ulcer disease)that detect a strong inhibitory activity against the secretion of gastric juice, which protects the mucous membranes of the stomach and has excellent antibacterial activity against Helicobacter pylori in a long time. The result found that some pyrrolopyridine derivatives with certain substituents in position 3 find a strong inhibitory activity against the secretion of gastric juice and protective activity against gastric mucosa and find excellent antibacterial activity against Helicobacter pylori.

Pyrrolopyridine derivatives of the present invention have the following formula:

where

R1is (C2-C6)-alkenylphenol group, halogen-(C2-C6)-alkenylphenol group, (C3-C7)-cycloalkyl group, which optionally may be substituted (C1-C6)-alkyl, or (C3-C7-cycloalkyl-(C1-C6)-alkyl which ing group, which optionally may be substituted (C1-C6)-alkyl;

R2is (C1-C6)-alkyl group;

R3is hydroxymethylene group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbamoyl group, which optionally may be substituted by substituents selected from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy and halogen, (C1-C6)-alkoxycarbonylmethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxyalkyl group, which optionally may be substituted by substituents selected from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy and halogen;

R4is (C6-C10)-aryl group, which optionally may be substituted by substituents selected from the group consisting of (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkoxy and halogen;

And is aminogroup, an oxygen atom or a sulfur atom.

In the above formula (I) (C1-C6)-alkyl group in the definition of R2or (C1-C6)-al the ilen group, included in the definition of R1, R3or R4represents, for example, methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow or hexoloy group, preferably - (C1-C4)-alkyl group, preferably a methyl or ethyl group, and most preferably a methyl group.

(C2-C6)-Alchemilla group or (C2-C6)-Alchemilla group, halogen-(C2-C6)-alkenylphenol group in the definition of R1represents, for example, vinyl, 1-propenyloxy, 2-propenyloxy, Isopropenyl, 1-butenyloxy, 2-butenyloxy, 1-methyl-1-propenyloxy, 1-methyl-2-propenyloxy, 2-methyl-1-propenyloxy, 2-methyl-2-propenyloxy, 2-pentanediol or 2-hexenyl group, preferably - (C2-C4)-alkenylphenol group, preferably - (C3-C4)-alkenylphenol group, more preferably 2-propenyloxy or 2-butenyloxy group, and most preferably 2-butenyloxy group.

A typical example of the halogen-(C2-C6)-alkenylphenol group in the definition of R1is, for example, 2,2-defermined, 3-fluoro-2-propenyl, 3-chloro-2-propenyl, 3-bromo-2-propenyl, 3-iodine-2-propenyl, 3,3-debtor-2-propenyl, 2,3-dichloro-2-propenyl, 3,3-dichloro-2-propenyl, 2,3-dibromo-2-propenyl, 3,3-dibromo-2-propenyl, 4,4,4-rifter-2-butenyl, 5-fluoro-2-pentenyl or 6-fluoro-2-examilia group, preferably 3-chloro-2-protanilla, 3,3-debtor-2-protanilla, 3,3-dichloro-2-protanilla or 4,4,4-Cryptor-2-bucinellina, and preferably 3-chloro-2-protanilla, 3,3-debtor-2-protanilla or 3,3-dichloro-2-protanilla group.

(C3-C7)-Cycloalkyl part (C3-C7)-cycloalkyl group, which optionally may be substituted (C1-C6)-alkyl group, or (C3-C7-cycloalkyl-(C1-C6)-alkyl groups, which optionally may be substituted (C1-C6)-alkyl group in the definition of R1represents, for example, cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo or cycloheptyl group, preferably -(C3-C6)-cycloalkyl group, preferably cyclopropyl, cyclopentyl or tsiklogeksilnogo group, and most preferably cyclopropyl group.

A typical example (C3-C7)-cycloalkyl group, which optionally may be substituted (C1-C6)-alkyl group in the definition of R1is, for example, cyclopropyl, 2-methylcyclopropyl, 2-ethylcyclopropane, 2-propyltrichlorosilane, 2-hexyltrichlorosilane, cyclobutyl, 2-methylcyclobutene, cyclopentene, 2-methyl is clintalina, 2-ethylcyclopentane, tsiklogeksilnogo, 2-methylcyclohexanone or cycloheptyl group, preferably cyclopropyl, 2-methylcyclopropyl, 2-ethylcyclopropane, cyclobutyl, Cyclopentanone, 2-methylcyclopentanone, tsiklogeksilnogo or 2-methylcyclohexyl group, preferably cyclopropyl, 2-methylcyclopropyl, Cyclopentanone, 2-methylcyclopentanone, tsiklogeksilnogo or 2-methylcyclohexyl group, and most preferably cyclopropyl or 2-methylcyclopropyl group.

A typical example (C3-C7-cycloalkyl-(C1-C6)-alkyl groups, which optionally may be substituted (C1-C6)-alkyl group in the definition of R1is, for example, the group cyclopropylmethyl, 2-cyclopropylethyl, 2-methylcyclopropyl, 2-(2-methylcyclopropyl)ethyl, 3-(2-methylcyclopropyl)propyl, 6-(2-methylcyclopropyl)hexyl, 2-ethylcyclopropane, 2-propertyliability, 2-hexyltrichlorosilane, cyclobutylmethyl, 2-methylcyclobutane, cyclopentylmethyl, 2-cyclopentylmethyl, 2-methylcyclopentanol, 2-(2-methylcyclopentene)ethyl, 2-ethylcyclopentadienyl, cyclohexylmethyl, 2-cyclohexylethyl, 2-methylcyclohexylamine, 2-(2-methylcyclohexyl)ethyl or cyclopentylmethyl, preferably group cyclopropylmethyl, 2-cyclopropylethyl, 2-methylcyclopropyl ethyl, 2-(2-methylcyclopropyl)ethyl, 2-ethylcyclopropane, cyclobutylmethyl, 2-methylcyclobutane, cyclopentylmethyl, 2-methylcyclopentanol, cyclohexylmethyl or 2-methylcyclohexylamine preferred group cyclopropylmethyl, 2-methylcyclopropyl, 2-ethylcyclopropane, cyclobutylmethyl, 2-methylcyclobutane, cyclopentylmethyl or 2-methylcyclohexylamine, more preferably group cyclopropylmethyl, 2-methylcyclopropyl, cyclopentylmethyl or 2-methylcyclohexylamine, even more preferably cyclopropylmethyl or 2-methylcyclopropyl group, and most preferably 2-methylcyclopropyl group.

(C2-C6)-Aliphatic acyl group, (C2-C6)-aliphatic acyloxymethyl group in the definition of R3represents, for example, acetyl, propionyl, butyryloxy, isobutyryloxy, valerino, isovaleryl or hexanoyl group, preferably - (C2-C4)-aliphatic acyl group, preferably - (C2-C3)-aliphatic acyl group, and most preferably acetyl group.

(C1-C6-Alkoxygroup Deputy aryl group or (C1-C6-alkoxygroup halogen-(C1-C6-alkoxygroup Deputy aryl group in the definition of R3 and R4or (C1-C6-alkoxygroup (C1-C6)-alkoxycarbonylmethyl group and (C1-C6)-alkoxycarbonyl group in the definition of R3represents, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy or hexyloxy, preferably -(C1-C4)-alkoxygroup, preferably a methoxy group or ethoxypropan, and most preferably a methoxy group.

Halogen atom included in the definition of R1, R3and R4represents, for example, fluorine atom, chlorine, bromine or iodine, preferably fluorine atom, chlorine or bromine, preferably fluorine atom or chlorine.

(C6-C10)-Aryl group optionally substituted (C6-C10)-aryl group in the definition of R3or optionally substituted (C6-C10)-aryl group in the definition of R4represents, for example, phenyl or naftalina group, preferably phenyl group.

The number of the substituents aryl group is, for example, from 1 to 5, preferably 1-3, preferably 1 or 2, and most preferably one.

Preferred (C6-C10)-aryl group, which optionally may be substituted by substituents selected from the group SOS is oasa from (C 1-C6)-alkyl, (C1-C6)-alkoxy and halogen, in the definition of R3represents, for example, a phenyl group, were, dimetilfenil, methoxyphenyl, acid, forfinal, chlorophenyl, bromophenyl, differenl, chlorophenyl, dichlorophenyl, naphthyl, Meilahti, methoxyethyl, fornetti, chloronaphthyl or panaftel, preferably a phenyl group, were, methoxyphenyl, forfinal or chlorophenyl, most preferably phenyl or methylphenyl group.

Preferred (C6-C10)-aryl group, which optionally may be substituted by substituents selected from the group consisting of (C1-C6)-alkyl, halogen-(C1-C6)-alkyl, (C1-C6)-alkoxy, halogen-(C1-C6)-alkoxy and halogen, in the definition of R4represents, for example, a phenyl group, were, triptoreline, methoxyphenyl, trifloromethyl, deformational, forfinal, chlorophenyl, bromophenyl, differenl, chlorophenyl, dichlorophenyl, tryptophanyl, trichlorophenyl, naphthyl, Meilahti, methoxyethyl, fornetti, chloronaphthyl or panaftel, preferably the phenyl group, 4-were, 4-triptoreline, 4-methoxyphenyl, 4-trifloromethyl, 4-deformational, 2-, 3 - or 4-forfinal, 2-, 3 - or 4-chlorophenyl, 4-bromophenyl, 2,4 - or 2,6-differenl, 4-the ENT-2-forfinal, 2-chloro-4-forfinal, 2,4 - or 2,6-dichlorophenyl, 2,4,6-tryptophanyl or 2,4,6-trichlorphenol, more preferably group 4-forfinal, 4-chlorophenyl, 2,4-differenl, 2,6-differenl, 4-chloro-2-forfinal, 2-chloro-4-forfinal, 2,4-dichlorophenyl or 2,6-dichlorophenyl, and most preferably 4-florfenicol, 2,4-differenly or 4-chloraniline group.

The preferred group is an oxygen atom or a sulfur atom; more preferred oxygen atom.

The compound of formula (I) of this invention can exist as optical isomers due to the presence of asymmetric(s) atom(s) or in the form of geometrical isomers due to the presence of double(s) connection(s) or a cyclic structure. The present invention covers the individual isomers and mixtures of such isomers.

Pharmaceutically acceptable salts of compounds of formula (I) are additive salts of the acids. Examples of such salts are, for example, salts of halogen acids, such as hydrohloride, hydrochloride, hydrobromide, hydroiodide; nitrate; perchlorate; sulfates; phosphates; carbonates; and (C1-C6)-alkyl sulphonates, which optionally can be substituted by fluorine atoms, such as methanesulfonate, triftoratsetata, econsultancy, pentafluoroethanesulfonyl, propanesulfonate, butanesulfonate, pentanesulfonate, hexanesulfonate, (C6-C10

The compounds of formula (I) of this invention or their salts may exist in the form of hydrates. The present invention includes hydrates.

Preferred compounds of formula (I) are (1) compounds where R1is a (C2-C4)-alkenylphenol group, (C3-C4)-alkenylphenol group substituted by fluorine or chlorine, (C3-C6)-cycloalkyl group, which optionally may be substituted (C1-C2)-alkyl, or (C3-C6-cycloalkyl-(C1-C2)-alkyl group which may be substituted (C1-C2)-alkyl;

(2) compounds where R1is a (C3-C4)-alkenylphenol group, 3-chloro-2-propenyloxy group, 3,3-debtor-2-propenyloxy group, 3,3-dichloro-2-propenyloxy group, cyclopropyl group, 2-methylcyclopropyl group, 2-ethylcyclopropane group, cyclobutyl group, cyclopentyl group, 2-methylcyclopentanol group, tsiklogeksilnogo group, 2-m is testiclejenna group, cyclopropylmethyl group, 2-methylcyclopropyl group, 2-ethylcyclopentadienyl group, cyclobutylmethyl group, 2-methylcyclopentadienyl group, cyclopentylmethyl group or 2-methylcyclohexylamine group;

(3) compounds, where R1is a 2-propenyloxy group, 2-butenyloxy group, cyclopropyl group, 2-methylcyclopropyl group, cyclopentyloxy group, 2-methylcyclopentanol group, tsiklogeksilnogo group, 2-methylcyclohexyl group, cyclopropylmethyl group, 2-methylcyclopropyl group, cyclopentylmethyl group or 2-methylcyclohexylamine group;

(4) compounds, where R1is a 2-propenyloxy group, 2-butenyloxy group, cyclopropyl group, 2-methylcyclopropyl group, cyclopropylmethyl group or 2-methylcyclopropyl group;

(5) compounds, where R1is a 2-butenyloxy group, cyclopropylmethyl group or 2-methylcyclopropyl group;

(6) compounds, where R2is a (C1-C4)-alkyl group;

(7) compounds, where R2is a (C1-C2)-alkyl group;

(8) compounds, where R2represents a methyl group;

(9) compounds, where R3represents hydroxymethylene the group, (C2-C6)-aliphatic acyloxymethyl group, benzoyloxymethyl group, which optionally can be substituted stands, methoxy, fluorine or chlorine, (C1-C4)-alkoxycarbonylmethyl group, formyl group, carboxyl group, (C1-C4)-alkoxycarbonyl group or vinyloxycarbonyl group, which optionally can be substituted stands, methoxy, fluorine or chlorine;

(10) compounds, where R3represents hydroxymethylene group, (C2-C6)-aliphatic acyloxymethyl group, benzoyloxymethyl group, (C1-C2)-alkoxycarbonylmethyl group, formyl group, carboxyl group, (C1-C2)-alkoxycarbonyl group or vinyloxycarbonyl group;

(11) compounds, where R3represents hydroxymethylene group, (C2-C4)-aliphatic acyloxymethyl group, (C1-C2)-alkoxycarbonylmethyl group, formyl group, carboxyl group or (C1-C2)-alkoxycarbonyl group;

(12) compounds, where R3represents hydroxymethylene group, (C2-C3)-aliphatic acyloxymethyl group, formyl group or a carboxyl group;

(13) compounds, where R3is own the th hydroxymethylene group or acetoxymethyl group;

(14) compounds, where R4represents a phenyl group substituted by 1-3 substituents selected from the group consisting of (C1-C4)-alkyl, halogen-(C1-C4)-alkyl, (C1-C4)-alkoxy, halogen-(C1-C4)-alkoxy, fluorine, chlorine and bromine;

(15) compounds, where R4represents a phenyl group substituted by 1-3 substituents selected from the group consisting of methyl, trifloromethyl, methoxy, triptoreline, deformedarse, fluorine, chlorine and bromine;

(16) compounds, where R4represents a phenyl group substituted in position(s)selected(s) from the group consisting of positions 2, 4 and 6 of the phenyl group, 1 or 2 substituents selected from the group consisting of fluorine and chlorine;

(17) compounds, where R4represents a phenyl group substituted in position 4, the provisions of the 2.4 or the provisions of 2,6 phenyl groups, 1 or 2 substituents selected from the group consisting of fluorine and chlorine;

(18) compounds, where a represents an oxygen atom or a sulfur atom; and

(19) compounds, where a is an oxygen atom.

In each group of the above sections(1)-(5), (6)-(8), (9)-(13), (14)-(17) or (18)-(19), the larger the number of the section, especially preferably a compound described in this section and, similarly, in the group of sections (20)-(24), described below. Connect the tion, where R1, R2, R3, R4and a randomly chosen group of sections(1)-(5), (6)-(8), (9)-(13), (14)-(17) or (18)-(19), respectively, are also preferred.

Such compounds are, for example, the following:

(20) compounds, where R1is a (C2-C4)-alkenylphenol group, (C3-C4)-alkenylphenol group substituted by fluorine or chlorine, (C3-C6)-cycloalkyl group, which optionally may be substituted (C1-C2)-alkyl, or (C3-C6-cycloalkyl-(C1-C2)-alkyl group which may be substituted (C1-C2)-alkyl,

R2is a (C1-C4)-alkyl group,

R3represents hydroxymethylene group, (C2-C6)-aliphatic acyloxymethyl group, benzoyloxymethyl group, which optionally can be substituted stands, methoxy, fluorine or chlorine, (C1-C4)-alkoxycarbonylmethyl group, formyl group, carboxyl group, (C1-C4)-alkoxycarbonyl group or vinyloxycarbonyl group, which optionally can be substituted stands, methoxy, fluorine or chlorine,

R4represents a phenyl group substituted by 1-3 substituents selected from the group consisting of (C -C4)-alkyl, halogen-(C1-C4)-alkyl, (C1-C4)-alkoxy, halogen-(C1-C4)-alkoxy, fluorine, chlorine and bromine,

And represents an oxygen atom or a sulfur atom;

(21) compounds, where R1is a (C3-C4)-alkenylphenol group, 3-chloro-2-propenyloxy group, 3,3-debtor-2-propenyloxy group, 3,3-dichloro-2-propenyloxy group, cyclopropyl group, 2-methylcyclopropyl group, 2-ethylcyclopropane group, cyclobutyl group, cyclopentyl group, 2-methylcyclopentanol group, tsiklogeksilnogo group, 2-methylcyclohexyl group, cyclopropylmethyl group, 2-methylcyclopropyl group, 2-ethylcyclopentadienyl group, cyclobutylmethyl group, 2-methylcyclopentadienyl group, cyclopentylmethyl group or 2-methylcyclohexylamine group,

R2is a (C1-C4)-alkyl group,

R3represents hydroxymethylene group, (C2-C6)-aliphatic acyloxymethyl group, benzoyloxymethyl group, (C1-C2)-alkoxycarbonylmethyl group, formyl group, carboxyl group, (C1-C2)-alkoxycarbonyl group or vinyloxycarbonyl group,

R4represents a phenyl group substituted by 1-3 mandated what teli, selected from the group consisting of methyl, trifloromethyl, methoxy, triptoreline, deformedarse, fluorine, chlorine and bromine,

And represents an oxygen atom or a sulfur atom;

(22) compounds, where R1is a 2-propenyloxy group, 2-butenyloxy group, cyclopropyl group, 2-methylcyclopropyl group, cyclopentyloxy group, 2-methylcyclopentanol group, tsiklogeksilnogo group, 2-methylcyclohexyl group, cyclopropylmethyl group, 2-methylcyclopropyl group, cyclopentylmethyl group or 2-methylcyclohexylamine group,

R2is a (C1-C2)-alkyl group,

R3represents hydroxymethylene group, (C2-C4)-aliphatic acyloxymethyl group, (C1-C2)-alkoxycarbonylmethyl group, formyl group, carboxyl group or (C1-C2)-alkoxycarbonyl group,

R4represents a phenyl group substituted in position(s)selected(s) from the group consisting of positions 2, 4 and 6 of the phenyl group, 1 or 2 substituents selected from the group consisting of fluorine and chlorine,

And represents an oxygen atom;

(23) compounds, where R1is a 2-propenyloxy group, 2-butenyloxy group, cyclopropyl group, 2-methylcyclo who saw the group cyclopropylmethyl group or 2-methylcyclopropyl group,

R2is a (C1-C2)-alkyl group,

R3represents hydroxymethylene group, (C2-C3)-aliphatic acyloxymethyl group, formyl group or a carboxyl group,

R4represents a phenyl group substituted in position(s)selected(s) from the group consisting of positions 2, 4 and 6 of the phenyl group, 1 or 2 substituents selected from the group consisting of fluorine and chlorine, And is an oxygen atom; and (24) compounds, where R1is a 2-butenyloxy group, cyclopropylmethyl group or 2-methylcyclopropyl group, R2represents a methyl group, R3represents hydroxymethylene group or acetoxymethyl group,

R4represents a phenyl group substituted in position 4, the provisions of the 2.4 or the provisions of 2,6 phenyl groups, 1 or 2 substituents selected from the group consisting of fluorine and chlorine,

And represents the oxygen atom.

Examples of preferred compounds of formula (I) can be compounds listed in table 1.

Table 1

In table 1 the following abbreviations are used and the seat is of:

No. Conn.-so no connection is specified as an example,

AC is acetyl, VI - butyl, VIc- cyclobutyl, Bur - butyryl, Et is ethyl, NHc- cyclohexyl. Me is methyl, RPc- cyclopentyl, Ph is phenyl, Pr is propyl, Prp - propionyl, Prc- cyclopropyl.

In table 1, the preferred compounds are the compounds listed under the numbers

2, 4, 8, 9, 17, 19, 20, 21, 22, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 56, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 82, 90, 93, 95, 105, 106, 114, 116, 120, 121, 129, 132, 134, 138, 140, 142, 144, 146, 167, 178, 188, 192, 196, 200, 216, 225, 233, 237, 241, 245, 264, 277, 286, 290, 294, 298, 306, 307, 310, 311, 317, 323, 326, 329, 332, 345, 351, 357, 360, 363, 366, 373, 377, 381, 383, 385, 387, 394, 411, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 430, 433, 436, 439, 442, 449, 450, 451, 452, 453, 454, 455, 456, 457, 458, 461, 467, 470, 473, 476, 478, 480, 481, 482, 483, 484, 485, 486, 487, 488, 492, 494, 496, 498, 503, 504, 505, 506, 507, 508, 512, 514, 516, 518, 539, 542, 548, 558, 562, 564, 566, 583, 585, 589, 592, 594, 595, 596, 597, 598, 600, 602, 604, 606, 607, 608, 625, 626, 627, 633, 634, 665, 666, 667, 668, 669, 670, 671, 672, 675, 676, 681, 682, 683, 684, 685, 686, 702, 703, 704, 705, 706, 707, 723, 724, 725, 726, 727, 728, 834, 846, 858, 862, 889, 901, 930, 939, 990, 1014, 1018, 1072, 1090, 1094, 1113, 1117, 1133, 1136, 1148, 1149, 1159, 1163, 1164, 1165, 1167, 1169, 1171, 1173, 1175, 1177, 1181, 1185, 1189 and 1193.

More preferred are the compounds listed under the numbers

9, 19, 20, 22, 25, 32, 33, 40, 41, 43, 47, 48, 59, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 82, 93, 95, 105, 106, 114, 116, 120, 121, 134, 138, 142, 146, 167, 178, 311, 317, 416, 417, 420, 421, 427, 436, 439, 442, 450, 451, 454, 455, 461, 485, 506, 508, 589, 592, 594, 595, 596, 602, 606, 625, 633, 665, 666, 681, 682, 834, 846, 889, 1090, 1113, 1133, 1163, 1164,1165, 1167, 1169, 1171, 1173, 1175 and 1177.

Further, more preferred are the compounds listed under the numbers 9, 20, 22, 32, 33, 41, 43, 47, 48, 61, 63, 65, 69, 71, 73, 95, 106, 121, 421, 427, 455, 589, 594, 602, 606, 625, 1165 and 1169.

Even more preferred are the compounds listed under the numbers 22, 33, 43, 48, 106, 121, 421, 455 and 594.

Most preferred are

the connection specified under No. 22: 1-(2-butenyl)-7-(4-forbindelse)-3-hydroxymethyl-2-methylpyrrole[2,3-d]pyridazin,

the connection specified under number 33: 7-(4-forbindelse)-3-hydroxide Tyl-2-methyl-1-(2-methylcyclopropyl)pyrrolo[2,3-d]pyridazin,

the connection specified under number 43: 1-(2-butenyl)-7-(2,4-deferasirox)-3-hydroxymethyl-2-methylpyrrole[2,3-d]pyridazin,

the connection specified number 48: 7-(2,4-deferasirox)-3-hydroxymethyl-2-methyl-1-(2-methylcyclopropyl)pyrrolo[2,3-d]pyridazin,

the connection specified number 106: 3-acetoxymethyl-7-(4-forbindelse)-2-methyl-1-(2-methylcyclopropyl)pyrrolo[2,3-d]pyridazin, and

the connection specified number 121: 3-acetoxymethyl-7-(2,4-deferasirox)-2-methyl-1-(2-methylcyclopropyl)pyrrolo[2,3-d]pyridazin.

In addition, of the above preferred compounds are 1-[(1S,2S)-2-methylcyclopropyl] derivatives.

Pyrrolopyridine derivatives of the formula (I) can be obtained according to the following method.

In the above reaction scheme, R1, R2, R4and a have the meanings specified above.

Stage 1 represents a method for obtaining compounds of formula (Ia) and is carried out by reacting the compounds of formula (II) with an oxidizing agent in an inert solvent.

Used oxidising agent is, for example, the oxidizing agent, with which the methyl group can be converted into hydroxymethylene group, such as cerium(IV)ammoniumnitrate, acetate, manganese(III) or selenium dioxide, preferably, the cerium(IV)ammoniumnitrate. The amount of oxidizing agent is from 1.5 to 10 (preferably 2-6) moles to one mole of the compounds of formula (II).

Used inert solvent has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the source of the substance to a certain extent. Such a solvent is, for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; carboxylic acid or carboxylic acid anhydride, for example acetic acid, acetic anhydride, propionic acid or benzoic acid; water; or the mixture; and preferred carboxylic acid, carboxylic acid anhydride, carboxylic acid containing water, or a mixture of carboxylic acid anhydride and carboxylic acids; more preferred acetic acid, acetic anhydride, acetic acid containing water, or a mixture of acetic acid and acetic anhydride.

The reaction temperature usually ranges from 0°to 150°With (preferably from room temperature to 100°). The reaction time varies depending on the reaction temperature and other factors, but ranges from 30 minutes to 20 hours (preferably from 1 hour to 10 hours).

When in stage 1 as the inert solvent used carboxylic acid or carboxylic acid anhydride, in some cases, you can receive the product, esterified carboxylic acid hydroxymethylene group of compound (Ia). Esterified compound hydrolyzing the usual way and get the compound of formula (Ia). For example, the esterified compound is treated with a base (e.g. alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or carbonate of an alkali metal such as sodium carbonate, potassium carbonate; the preferred alkali metal hydroxide, and most preferred lithium hydroxide) at 0°S-100°With (prefer is Ino, at 10°S-50° (C) during the period from 10 minutes to 10 hours (preferably from 20 minutes to 5 hours) in an inert solvent containing water (for example, in alcohol containing water, such as methanol containing water or ethanol containing water), and obtain the connection formula (Ia).

The compound of formula (Id), which is a compound of formula (I), where R3is a (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbamoyl group, which optionally may be substituted by substituents selected from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy and halogen, or (C1-C6)-alkoxycarbonylmethyl group, can be obtained by acylation of compounds of formula (Ia).

In the formula (Id) R5is (C2-C6)-aliphatic acyl group, (C6-C10)-arylcarbamoyl group, which optionally may be substituted by substituents selected from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy and halogen, or (C1-C6)-alkoxycarbonyl group, and R1, R2, R4and a have the meanings specified above.

Allermuir reagent is, for example, (C2-C6)-the aliphatic halog anhydrid, such as acetylchloride, acetylmuramic, propionitrile, propenylboronic, butyrylcholine, isobutyrate, valerianic or hexanoate; anhydride (C2-C6)-aliphatic carboxylic acids, such as acetic anhydride, propionic anhydride or hexanoic anhydride; and (C6-C10-arylcarbamoyl, which optionally may be substituted by substituents selected from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy and halogen, such as benzoyl chloride, benzylbromide, trouillard, truarray, methoxybenzophenone, chlorobenzylchloride, tormentilla or aftercare; or (C1-C6-alkoxycarbonylmethyl, such as methoxycarbonylamino, ethoxycarbonylphenyl, ethoxycarbonylphenyl, propoxycarbonyl, butoxycarbonyl, ventilatsiooniloorist or hexyloxybenzoic; preferred (C2-C6)-aliphatic acid chloride, (C6-C10-arylcarboxamide, which optionally may be substituted by substituents selected from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy and halogen, or (C1-C6-alkoxycarbonylmethyl.

Used the base is, for example, alkali metal amide such as lithium amide, sodium amide or the ID of potassium; carbonate of an alkali metal such as lithium carbonate, sodium carbonate or potassium carbonate; alcoholate alkali metal such as lithium methylate, sodium methylate, sodium ethylate or tert-butyl potassium; or an organic amine, such as triethylamine, tributylamine, diisopropylethylamine, N-ethylmorpholine, pyridine, picoline, 4-(N,N-dimethylamino)pyridine, quinoline, N,N-dimethylaniline, N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); preferred organic amine, and the most preferred triethylamine or pyridine.

Used inert solvent has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the source of the substance to a certain extent. Such a solvent is, for example, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; or mixtures thereof; and the preferred halogenated hydrocarbon or a simple ester; and the most preferred methylene chloride, chloroform, diethyl ether or tetrahydrofuran is.

The reaction temperature usually ranges from 0°to 100°With (preferably, from 10°C to 50°). The reaction time varies depending on the reaction temperature and other factors, but is generally from 10 minutes to 100 hours (preferably from 30 minutes to 5 hours).

Stage 2 represents a method for obtaining compounds of formula (Ib) and is carried out by reacting the compounds of formula (Ia) with an oxidant in an inert solvent.

Used oxidizing agent is, for example, an oxidizer, which hydroxymethylene group can be converted into a formyl group, such as manganese dioxide, chlorproma pyridinium (RRC), pyridinium dichromate (PDC) or a mixture of dimethyl sulfoxide and acid anhydride (for example, an anhydride of an aliphatic carboxylic acid, which optionally may be substituted with halogen, such as acetic anhydride, triperoxonane anhydride or propionic anhydride; the preferred acetic anhydride or triperoxonane anhydride); preferably manganese dioxide. The amount of oxidizing agent generally ranges from 1 to 50 (preferably from 2 to 30 moles to one mole of the compounds of formula (Ia).

Used inert solvent has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the source of the substance to determine the Noi degree. Such a solvent is, for example, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; or mixtures thereof; and the preferred halogenated hydrocarbon; and most preferred methylene chloride.

The reaction temperature usually ranges from 0°to 150°With (preferably from room temperature to 100°). The reaction time varies depending on the reaction temperature and other factors, but ranges from 30 minutes to 40 hours (preferably from 1 hour to 20 hours).

Stage 3 represents the method of obtaining the compounds of formula (IC) and is carried out by reacting the compounds of formula (Ib) with an oxidant in an inert solvent.

Used oxidizing agent is, for example, the oxidizing agent, with which the formyl group can be converted into a carboxyl group, such as silver oxide, chlorproma pyridinium (RRC) or pyridinium dichromate (PDC); preferably silver oxide. The amount of oxidizing agent generally ranges from 1 to 20 (preferably from 2 to 10 moles to one mole of the compound form is s (Ib). When the oxidant is used, silver oxide, it is preferable to use a silver oxide, obtained by the interaction of silver nitrate with an alkali metal hydroxide (preferably sodium hydroxide).

Used inert solvent has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the source of the substance to a certain extent. Such a solvent is, for example, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; an alcohol such as methanol or ethanol; carboxylic acid such as acetic acid, propionic acid or benzoic acid; water; or mixtures thereof; and the preferred alcohol, alcohol containing water, carboxylic acid, carboxylic acid containing water, or water, and the preferred alcohol containing water; and most preferred is ethanol containing water.

The reaction temperature usually ranges from 0°to 150°With (preferably from room temperature to 100°). The reaction time varies depending on the reaction temperature and other factors, but is about the 1 hour to 72 hours (preferably, from 12 hours to 48 hours).

The compound of formula (I)representing the compound of formula (I), where R3is a (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxyalkyl group, which optionally may be substituted by substituents selected from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy and halogen, can be obtained by esterification of compounds of formula (Ic).

In the formula (Ie) R6is (C1-C6)-alkyl group or (C6-C10)-aryl group, which optionally may be substituted by substituents selected from the group consisting of (C1-C6)-alkyl, (C1-C6)-alkoxy and halogen, and R1, R2, R4and a have the meanings specified above.

The etherification is carried out by interaction of the compounds of formula (Ic) with a halogenation agent in an inert solvent with the formation of gelegenheid carboxylic acid with subsequent interaction of gelegenheid carboxylic acid derivative of the alcohol or phenol in the presence of a base in an inert solvent. Both stages of the reaction can be performed in one reactor, where the compound of formula (Ic) interacts with a halogenation agent, and if necessary, you can remove actuarial from the reaction mixture.

Used halogenation agent is, for example, thionylchloride, such as thionyl chloride, thienylboronic, or a phosphorus halide, such as trichloride phosphorus, pentachloride phosphorus oxychloride phosphorus or oxybromide phosphorus; predpochtitelno - thionyl chloride or phosphorus oxychloride.

The inert solvent used in the interaction of the compounds of formula (IC) with a halogenation agent, has no particular restrictions, provided that it has no adverse effect on the reaction and can dissolve the source of the substance to a certain extent. Such a solvent is, for example, aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; or mixtures thereof; and preferred a simple ether; and the most preferred diethyl ether or tetrahydrofuran.

The reaction temperature usually ranges from 0°to 100°With (preferably, from 10°C to 50°). The reaction time varies depending on the reaction temperature and other factors, but is generally from 10 minutes to 10 hours (preferably from 30 minutes to 5 hours is impressive.

The inert solvent used in the interaction gelegenheid carboxylic acid derivative of the alcohol or phenol, is a solvent, which is described for the interaction of the compounds of formula (IC) with a halogenation agent. The reaction temperature and the time required for communication are in the same interval, which is described for the interaction of the compounds of formula (IC) with a halogenation agent.

Each of the above stages, each desired compound can be isolated from the reaction mixture by the conventional procedures. For example, this can be achieved 1) by filtration of the reaction mixture when the reaction mixture has an insoluble substance, with subsequent evaporation of the solvent from the filtrate; or 1) the concentration of the reaction mixture, (2) adding water to the residue, followed by distribution between water and an appropriate organic solvent, immiscible with water, 3) osushivaniya extract over anhydrous magnesium sulfate, etc. with subsequent 4) the concentration of the extract. The desired compound can, if necessary, to clear advanced conventional procedures such as recrystallization, column chromatography, etc.

The compound of formula (I) can be converted to its pharmaceutically acceptable salt by treatment with acid according obiomimetico. For example, the desired salt can be obtained by the coupling of compounds of formula (I) with an acid in an inert solvent (preferably, a simple ether, such as diethyl ether, tetrahydrofuran or dioxane; an alcohol such as methanol, ethanol or propanol; or a halogenated hydrocarbon, such as methylene chloride or chloroform) at room temperature for 5 minutes to 1 hour, followed by evaporation of solvent.

The original compound of formula (II) is known or can be easily obtained by interaction of a pyrrole of the formula (III) with the compound of the formula R1-X (IV) according to a known method (see, for example, the publication of the patent application of Japan Hei 7-247285).

In the above formula, R7is (C1-C6)-alkyl group, R2matter mentioned above, X represents a halogen atom (preferably chlorine atom or bromine)and R1has the values listed above.

Compounds of formulas (III) and (IV) are also known or can easily be obtained by known methods (see, for example, the publication of the patent application of Japan Hei 7-247825; Monatschefte fur Chemie (1973), 104, 925; J. Chem. Soc., Perkin. Trans. II (1979), 287, etc).

In addition, you can obtain each desired optically active compound of the formula (I) and (IV) (for example, form 1S, 2S) by the optical splitting Reznichenko forms of compliance is adequate compound (a mixture of 1S, 2S-shape and 1R, 2R-forms, etc). Optical splitting can be done by selecting the appropriate method of the conventional methods such as chromatography on a column of optical splitting, preferential crystallization and cleavage mixture diastereoisomeric salts.

[Industrial applicability]

The compounds of formula (I) of this invention or their pharmaceutically acceptable salts find a strong inhibitory activity against the secretion of gastric juice, protective activity against gastric mucosa and strong antibacterial activity against Helicobacter pylori, and they discover excellent properties as a remedy. The compounds of formula (I) or their pharmaceutically acceptable salts are useful as preventive or therapeutic agents in the case of ulcerative diseases such as peptic ulcer, acute or chronic gastric ulcer, gastritis, reflux esophagitis, gastro-esophageal reflux, dyspepsia, hyperacidity of the gastric juice, the syndrome of Zollinger-Ellison etc. or as a prophylactic or therapeutic agents in the case of bacterial infections caused by Helicobacter pylori.

When applied as a preventive or therapeutic agent in the case of the diseases mentioned above, the compound of formula (I) or its pharmaceutically acceptable salt as the active ingredient) can be entered by themselves (in pure form), or they can be part of the pharmaceutical composition. The pharmaceutical composition was prepared by mixing the active ingredient with appropriate pharmaceutically acceptable excipients, diluents and the like, followed by obtaining a composition in the form of tablets, capsules, granules, powders or syrups and the like, for oral administration, or injections, etc. for parenteral administration, preferably oral administration).

The receipt of such pharmaceutical compositions is carried out according to General methods known to experts in the art, using additives, such as excipient, binder, baking powder, lubricating agent, stabilizer, corrigent, diluent and solvent for injection.

Excipient is, for example, derived sugars, such as lactose, sucrose, glucose, mannitol or sorbitol; a derivative of starch, such as corn starch, potato starch, α-Brahmadatta or carboximetilkrahmal; derivative of cellulose such as crystalline cellulose, nizkozameshhennoj hydroxypropylcellulose, hypromellose, carboxymethylcellulose, calcixerollic or sodium carboxymethyl cellulose with internal bridging ties; Arabian gum; dextrin; pullulan; silicate derivative is, such as light silicic acid anhydride, synthetic aluminum silicate or alumino-metasilicate magnesium phosphonate, such as calcium phosphonate; carbonate such as calcium carbonate; sulfate such as calcium sulfate; and the like

The binder is, for example, one of the excipients described above; gelatin; polyvinylpyrrolidone; macrogol (trademark), etc.

Baking powder, represents, for example, one of the excipients described above; chemically modified starch or a derivative of cellulose, such as nitrocresols or natrocarbonatite; polyvinylpyrrolidone with bridge connections, etc.

Lubricating agent is, for example, talc; stearic acid; salt of the metal and of stearic acid such as calcium stearate or magnesium stearate; colloidal silica; waxes such as beeswax and spermaceti; boric acid; glycol; carboxylic acid such as fumaric acid or adipic acid; carboxylate sodium, such as sodium benzoate; a sulfate such as sodium sulfate; leucine; lauryl sulphate, such as sodium lauryl sulfate or lauryl sulfate, magnesium; silicic acid, for example, silicic acid anhydride or silicic acid hydrate; one of the derivatives of starch, described above in connection with the excipients; and so on

With habilitator represents for example, p-oxybenzoates derivative, such as methylparaben or propylparaben; alcohol, such as chlorobutanol, benzyl alcohol or phenethyl alcohol; benzylaniline; a derivative of phenol, such as phenol or cresol; thimerosal; dehydroacetic acid; sorbic acid; and the like

Corrigent represents, for example, a sweetener, a substance that gives the sour taste, or perfume, which usually are used; and so on

The solvent for injection is, for example, water, ethanol, glycerin, etc.

Suitable dosage levels depend on the state of the disease, patient's age, etc. but, as a rule, suitable dosage levels of active ingredient of the present invention is from 1 mg (preferably 5 mg to 1000 mg (preferably 500 mg) in the case of oral administration and from 0.1 mg (preferably 1 mg) to 500 mg (preferably, 300 mg) in the case of intravenous administration on the standard dose per day for an adult, respectively. Dosages above, is injected, preferably, one to six times a day, depending on the state of illness.

The best way of carrying out the invention

The following examples, reference examples, examples, test examples and compositions are intended to further explain the present invention and are not intended for the OTF is to limit the scope of invention.

Example 1

3-Acetoxymethyl-7-(4-forbindelse)-2-methyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrolo[2,3-d]pyridazin

To a solution of 7-(4-forbindelse)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrolo[2,3-d]pyridazine (0,679 g, 2.00 mmol) in acetic acid (40 ml) at room temperature add the cerium(IV)ammoniumnitrate (6,58 g, 12,0 mmol). The mixture was stirred at 60°C for 3 hours, poured into water and extracted with ethyl acetate.

The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The remainder chromatographic on a column of silica gel using as eluent hexane/ethyl acetate (1/1) and receive the oil which crystallized from hexane to obtain specified in the connection header (0,255 g, 28%) as a pale yellow crystalline substance.

Melting point 122-123°C.

Mass spectrum (CI, m/z): 398 (M++1).

The NMR spectrum (CDCl3that δ ppm): 0.13-0.20 (m, 1H), 0.37-0.44 (m, 1H), 0.61-0.68 (m, 1H), 0.84-0.91 (m, 1H), 0.90 (d, J=5.9 Hz, 3H), 2.05 (s, 3H), 2.48 (s, 3H), 4.14 (DD; J=14.6 Hz, 7.3 Hz, 1H), 4.31 (DD, J=14.6 Hz, 6.3 Hz, 1H), 5.27 (s, 2H), 5.65 (d, J=12.0 Hz, 1H), 5.70 (d, J=12.0 Hz, 1H), 7.05-7.12 (m, 2H), 7.48-7.53 (m, 2H), 9.12 (1H).

Example 2

7-(4-Forbindelse)-3-hydroxymethyl-2-methyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrolo[2,3-d]pyridazin

To a solution of 7-(4-forbindelse)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopentadienyl[2,3-d]pyridazine (67,9 g, 200 mmol) in acetic acid (800 ml) at room temperature add the cerium(IV)ammoniumnitrate (329 g, 600 mmol). The mixture was stirred at 55°C for 8 hours, poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. To the residue is added methanol (500 ml) and 2 n aqueous solution of lithium hydroxide (160 ml), and the mixture is stirred at room temperature for 40 minutes. The reaction mixture is neutralized 1 n hydrochloric acid and the methanol is evaporated in vacuum. The remaining mixture is extracted with chloroform. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The remainder chromatographic on a column of silica gel using as eluent ethyl acetate and a mixture of ethyl acetate/methanol (9/1) and receive a crystalline substance, which is washed with ethyl acetate, getting named the title compound (24.6 g, 35%) as a pale yellow crystalline substance.

Melting point 128-129°C.

Mass spectrum (CI, m/z): 356 (M++1).

The NMR spectrum (CDCl3that δ ppm): 0.10-0.16 (m, 1H), 0.34-0.40 (m, 1H), 0.58-0.68 (m, 1H), 0.77-0.86 (m, 1H), 0.87 (d, J=5.9 Hz, 3H), 2.44 (s, 3H), 4.09 (DD, J=14.6 Hz, 7.3 Hz, 1H), 4.26 (DD; J=14.6 Hz, 6.3 Hz, 1H), 4.82 (s, 2H), 5.57 (d, J=11.7 Hz, 1H), 5.62 (d, J=11.7 Hz, 1H), 7.04-7.09 (m, 2H), 7.7 (DD; J=8.8 Hz, 5.4 Hz, 2H), 9.07 (s, 1H).

Optical rotation [α]D20=+18,2° (C=1.00, the Meon).

Example 3

7-(4-Forbindelse)-3-formyl-2-methyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrolo[2,3-d]pyridazin

To a solution of 7-(4-forbindelse)-3-hydroxymethyl-2-methyl-1-[(1S,23)-2-methylcyclopropyl]pyrrolo[2,3-d]pyridazine (64,3 g, 181 mmol) in methylene chloride (900 ml) at room temperature is added activated manganese dioxide (472 g, 5.43 mol). The mixture is stirred at room temperature for 18 hours. The reaction mixture was filtered through celite (trade mark)and the filtrate concentrated in vacuo. The crude crystalline substance (of 45.7 g) washed with ethyl acetate and hexane and get named in the title compound (44,3 g, 69%) as a pale yellow crystalline substance.

Melting point 138,5-139,5°C.

Mass spectrum (CI, m/z): 354 (M++1).

The NMR spectrum (CDCl3that δ ppm): 0.19-0.26 (m, 1H), 0.40-0.47 (m, 1H), 0.71-0.78 (m, 1H), 0.84-0.91 (m, 1H), 0.92 (d, J=5.9 Hz, 3H), 2.75 (s, 3H), 4.19 (DD; J=14.6 Hz, 7.1 Hz, 1H), 4.35 (DD; J=14.6 Hz, 6.6 Hz, 1H), 5.67 (d, J=12.0 Hz, 1H), 5.73 (d, J=12.0 Hz, 1H), 7.07-7.14 (m, 2H), 7.51 (DD; J=Q. 5 Hz, 5.4 Hz, 2H), 9.63 (s, 1H), 10.22 (s, 1H).

Optical rotation [α]D20=+20,4° (C=1.00, the Meon).

Example 4

3-carboxy-7-(4-forbindelse)-2-methyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrolo[2,3-d]pyridazin

To the silver nitrate solution of 0.85 g, 5 mmol) in water (2.5 ml) is dobavlaut aqueous 2 n solution of lithium hydroxide (3 ml), and then a solution of 7-(4-forbindelse)-3-formyl-2-methyl-1-[(1S,2S)-2-methylcyclopropyl]-pyrrolo[2,3-d]pyridazine (0,177 g, 0.5 mmol) in ethanol (10 ml). The mixture is stirred at room temperature for 48 hours. To the reaction mixture was added 1 n hydrochloric acid (3 ml) and the resulting mixture was filtered through celite (trademark). Celite (trademark) washed with ethanol (30 ml). To the combined filtrates, water is added and the resulting mixture extracted with chloroform. The extract is dried over anhydrous magnesium sulfate and concentrated in vacuo. The remainder chromatographic on a column of silica gel using as eluent a mixture of chloroform/isopropanol (19/1), getting named the title compound (0,094 g, 51%) as a pale yellow crystalline substance.

Melting point 170-225°C.

Mass spectrum (CI, m/z): 370 (M++1).

The NMR spectrum (CDCl3that δ h/m): 0.20-0.25 (m, 1H), 0.40-0.46 (m, 1H), 0.63-0.69 (m, 1H), 0.86-0.92 (m, 1H), 0.91 (d, J=5.9 Hz, 3H), 2.86 (s, 3H), 3.60 (Ushs., 1H), 4.26 (DD; J=14.7 Hz, 7.3 Hz, 1H), 4.40 (DD; J=14.7 Hz, 6.8 Hz, 1H), 5.67 (d, J=11.7 Hz, 1H), 5.72 (d, J=11.7 Hz, 1H), 7.08-7.14 (m, 2H), 7.53 (DD, J=8.8 Hz, 5.4 Hz, 2H), 9.88 (Ushs., 1H).

Optical rotation [α]D20=+15,8° (C=1.00, the Meon).

Reference example 1

7-(4-Forbindelse)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrolo[2,3-d]pyridazin

(a) Methyl-3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrole-2-Carbo is Silat

To a solution of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate (5,79 g, 31.9 per mmol) and 18-crown-6 (0,41 g, 1.55 mmol) in tetrahydrofuran (130 ml) is added tert-butyl potassium (3,49 g of 35.1 mmol) and the mixture is stirred at room temperature for 1 hour. After adding to the reaction mixture dropwise over 30 minutes at 50°WITH (1S,2S)-2-methylcyclopentanone (5,71 g, to 38.3 mmol) the mixture is refluxed for 3 hours. To the mixture add tert-butyl potassium (0.36 g, up 3.22 mmol) and (1S, 2S)-2-methylcyclopentanone (0,48 g, is 3.21 mmol) and the resulting mixture heated for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract is washed with water and saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is removed in vacuum and get the desired connection (compared to 8.26 g, 100%) as a pale brown oil.

Mass spectrum (CI, m/z: 250 (M++1).

The NMR spectrum (CDCl3that δ h/m): 0.25 (dt; J=8 Hz, 5 Hz, 1H), 0.48 (dt; J=8 Hz, 5 Hz, 1H), 0.71-0.80 (m, 1H), 0.82-0.89 (m, 1H), 1.00 (d, J=6 Hz, 3H), 2.20 (s, 3H), 2.26 (s, 3H), 3.89 (s, 3H), 4.25 (d, J=7 Hz, 2H), 10.43 (s, 1H).

Optical rotation [α]D20=+17,6° (C=1,02, EtOH).

(b) 2,3-Dimethyl-1-[(1S,2S)-2-methylcyclopropyl]-6,7-dihydropyrrolo[2,3-d]pyridazin-7-he

To a solution of methyl 3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrol-2-carboxyla is a (of 7.96 g, for 31.9 mmol) in acetic acid (38 ml) at room temperature add hydrazinehydrate (1.92 g, 38.4 mmol) and the mixture was stirred at 90°C for 1 hour. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into ice water. Rich crystalline substance is collected by filtration, washed with water and dissolved in a mixture of chloroform and methanol (9:1). The organic layer is separated, washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. The solvent is removed in vacuo and to the residue is added a mixture of toluene and hexane. Precipitated precipitated substance is collected by filtration and obtain the target compound (7,02 g, 95,0%) as pale yellow-white powder.

Mass spectrum (CI, m/z): 232 (M++1).

The NMR spectrum (CDCl3that δ ppm): 0.22 (dt; J=8 Hz, 5 Hz, 1H), 0.64 (dt; J=8 Hz, 5 Hz, 1H), 0.86-0.95 (m, 2H), 0.98 (d, J=5 Hz, 3H), 2.21 (s, 3H), 2.35 (s, 3H), 4.44 (d, J=7 Hz, 2H), 8.05 (s, 1H), 9.97 (s, 1H).

Optical rotation [α]D20=+11,2° (C=0,50, EtOH).

(C) 7-Chloro-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]pirollo[2,3-d]pyridazin

To 2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]-6,7-dihydropyrrolo[2,3-d]pyridazin-7-ONU (6,95 g, to 30.1 mmol) is added phosphorus oxychloride (55 ml, 590 mmol) and the mixture was stirred at 90°C for 3.5 hours. After completion of the reaction, the reaction mixture was cooled to room is temperature and poured into ice water. The aqueous solution is neutralized with 5 n aqueous solution of sodium hydroxide and extracted with methylene chloride. The extract is washed with water, dried over anhydrous magnesium sulfate and then concentrated in vacuo. To the residue add hexane and precipitated precipitated substance is collected by filtration, obtaining the target compound (6,90 g, 92,0%) as a pale yellow powder.

Mass spectrum (CI, m/z: 250 (M++1).

The NMR spectrum (CDCl3that δ ppm): 0.29 (dt; J=8 Hz, 5 Hz, 1H), 0.54 (dt; J=8 Hz, 5 Hz, 1H), 0.73-1.02 (m, 5H), 2.30 (s, 3H), 2.43 (s, 3H), 4.44 (d, J=6 Hz, 2H), 9.15 (s, 1H).

Optical rotation [α]D20=+12,3° (C=1,01, EtOH).

(d) 7-(4-Forbindelse)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]pirollo[2,3-d]pyridazin

To a solution of sodium hydride (0.26 g, the 10.8 mmol) in tetrahydrofuran (6 ml) add a solution of p-fermentelos alcohol (1.45 g, 11.5 mmol) in tetrahydrofuran (2 ml) and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture at room temperature is added dropwise a solution of 7-chloro-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]pirollo[2,3-d]pyridazine (2.50 g, 10.0 mmol) in tetrahydrofuran (13 ml) and the mixture refluxed for 3 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over betwo the major magnesium sulfate and then concentrated in vacuo. To the concentrated solution was added hexane and precipitated precipitated substance is collected by filtration and then recrystallized from a mixture of ethyl acetate and hexane, getting named the title compound (2.25 g, 66,4%) as a pale brown crystalline substance.

TPL 114-115°C.

Mass spectrum (CI, m/z): 340 (M++1).

1H-NMR spectrum (CDCl3that δ ppm): 0.14 (dt; J=8 Hz, 5 Hz, 1H), 0.39 (dt; J=8 Hz, 5 Hz, 1H), 0.59-0.65 (m, 1H), 0.76-0.85 (m, 1H), 0.89 (d, J=6 Hz, 3H), 2.26 (s, 3H), 2.36 (s, 3H), 4.13 (DD; J=15 Hz, 7 Hz, 1H), 4.27 (DD; J=15 Hz, 6 Hz, 1H), 5.63 (d, J=12 Hz, 1H), 5.68 (d, J=12 Hz, 1H), 7.05-7.12 (m, 2H), 7.47-7.52 (m, 2H), 8.96 (s, 1H).

Optical rotation [α]D20=+17,9° (C=0,50, EtOH).

Reference example 2 Methyl-3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrole-2-carboxylate

(a) Methyl-4,5-dimethyl-1-[(E)-2-methylcyclopropyl]pyrrole-2-carboxylate

To a solution of methyl-4,5-dimethylpyrrole-2-carboxylate (25,02 g, 163 mmol) and 18-crown-6 (3,19 g, 12.1 mmol) in tetrahydrofuran (150 ml) is added tert-butyl potassium (18,33 g, 164 mmol) and the mixture is stirred at room temperature for 1 hour. To the resulting mixture add a solution of (E)-2-methylcyclopentanone (racemate, 12,70 g of 85.2 mmol) and the mixture refluxed for 7 hours. After completion of the reaction, the reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The remainder chromatographic on column using toluene as eluent and get the desired compound (racemate, 13,50 g, 71,6%) as a brown oil.

Mass spectrum (CI, m/z): 222 (M++1).

The NMR spectrum (CDCl3that δ h/m): 0.20 (dt; J=8 Hz, 5 Hz, 1H), 0.48 (dt; J=8 Hz, 5 Hz, 1H), 0.67-0.93 (m, 2H), 0.98 (d, J=6 Hz, 3H), 2.01 (s, 3H), 2.18 (s, 3H), 3.76 (s, 3H), 4.21 (d, J=7 Hz, 2H), 6.76 (s, 1H).

(b) Methyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]-pyrrole-2-carboxylate

Methyl-4,5-dimethyl-1-[(E)-2-methylcyclopropyl]pyrrole-2-carboxylate (10,00 g) chromatographic by liquid chromatography high pressure and get named in the title [(S,S)]-form of compound (3.33 g) and [(R,R)]-form compounds (of 3.97 g), which is the antipode [(S,S)]-form of the connection.

The separation conditions:

column CHIRALCEL OJ, 50⊘×500 mm, Daicel Chemical Industries, Ltd.;

eluent hexane/2-propanol = 1000/1;

the flow rate of 25 ml per minute.

Named in the title [(S,S)]-connection form

Mass spectrum (CI, m/z): 222 (M++1).

The NMR spectrum (CDCl3that δ h/m): 0.20 (dt; J=8 Hz, 5 Hz, 1H), 0.48 (dt; J=8 Hz, 5 Hz, 1H), 0.66-0.80 (m, 1H), 0.82-0.91 (m, 1H), 0.98 (d, J=6 Hz, 3H), 2.01 (s, 3H), 2.18 (s, 3H), 3.76 (s, 3H), 4.21 (d, J=7 Hz, 2H), 6.76 (s, 1H).

Optical rotation [α]D20=+17,6° (=To 1.00, EtOH).

Antipodal [(R,R)]-connection form

Mass spectrum (CI, m/z): 222 (M++).

The NMR spectrum (CDCl3that δ h/m): 0.20 (dt; J=8 Hz, 5 Hz, 1H), 0.48 (dt; J=8 Hz, 5 Hz, 1H), 0.66-0.80 (m, 1H), 0.82-0.91 (m, 1H), 0.98 (d, J=6 Hz, 3H), 2.01 (s, 3H), 2.18 (s, 3H), 3.77 (s, 3H), 4.21 (d, J=7 Hz, 2H), 6.76 (s, 1H).

Optical rotation [α]D20=-17,0° (C=1,01, EtOH).

(C) Methyl-3-formyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrole-2-carboxylate

To a solution of dimethylformamide (1.10 g, 15 mmol) in toluene (2 ml) is added phosphorus oxychloride (2.15 g, 14 mmol) and the mixture is stirred at room temperature for 30 minutes. To the mixture add a solution of methyl-4,5-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrole-2-carboxylate (of 2.21 g, 10 mmol) in toluene (6 ml) and the mixture was stirred at 80°C for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into ice water and neutralized with a saturated aqueous solution of sodium bicarbonate. The organic layer is separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated in vacuo.

The remainder chromatographic on column using as eluent a mixture of ethyl acetate/hexane (10/1) and get named in the title compound (1,95 g, 78,2%) as a pale yellow oil.

Reference example 3

7-(4-Forbindelse)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrolo[2,3-d]pyridazin

(a) 7-(4-Forbindelse)--[(E)-2-methylcyclopropyl]-2,3-dimethylpyrrole[2,3-d]pyridazin (racemate)

Carry out the reaction in a manner similar to the method described in reference example 1, using (E)-2-methylcyclopentanone (racemate) instead of (1S,2S)-2-methylcyclopentanone and get the desired connection (56%).

TPL 120-122°C.

Mass spectrum (CI, m/z): 340 (M++1).

1H-NMR spectrum (CDCl3that δ ppm): 0.14 (dt; J=8 Hz, 5 Hz, 1H), 0.39 (dt; J=8 Hz, 5 Hz, 1H), 0.59-0.65 (m, 1H), 0.76-0.85 (m, 1H), 0.89 (d, J=6 Hz, 3H), 2.26 (s, 3H), 2.36 (s, 3H), 4.13 (DD; J=15 Hz, 7 Hz, 1H), 4.27 (DD; J=15 Hz, 6 Hz, 1H), 5.63 (d, J=12 Hz, 1H), 5.68 (d, J=12 Hz, 1H), 7.05-7.12 (m, 2H), 7.47-7.52 (m, 2H), 8.96 (s, 1H).

(b) 7-(4-Forbindelse)-2,3-dimethyl-1-[(1S,2S)-2-methylcyclopropyl]pyrrolo[2,3-d]pyridazin

7-(4-Forbindelse)-1-[(E)-2-methylcyclopropyl]-2,3-dimethylpyrrole[2,3-d]pyridazin (racemate, 25 g) chromatographic by liquid chromatography high pressure and recrystallized from ethyl acetate, getting named in the title [(S,S)]-form compounds (8,54 g) and [(R,R)]-form compounds (7,60 g), which is the opposite of [(S,S)]-form of the connection.

The separation conditions:

column CHIRALCEL OJ, 50⊘×500 mm, Daicel Chemical Industries, Ltd.;

eluent hexane/ethanol = 90/10;

the flow rate of 25 ml per minute.

Named in the title [(3,3)]-connection form

TPL 114-115°C.

Mass spectrum (CI, m/z): 340 (M++1).

1H-NMR spectrum (CDCl3that δ ppm): 0.14 (dt; J=8 Hz, 5 Hz, 1H), 0.39 (dt; J=8 Hz, 5 Hz, 1H), 0.59-0.65 (m, 1H), 0.76-0.5 (m, 1H), 0.89 (d, J=6 Hz, 3H), 2.26 (s, 3H), 2.36 (s, 3H), 4.13 (DD; J=15 Hz, 7 Hz, 1H), 4.27 (DD; J=15 Hz, 6 Hz, 1H), 5.63 (d, J=12 Hz, 1H), 5.68 (d, J=12.2 Hz, 1H), 7.05-7.12 (m, 2H), 7.47-7.52 (m, 2H), 8.96 (s, 1H).

Optical rotation [α]D20=+19,0° (C=0.99, and the Meon).

Antipodal [(R,R)]-connection form

TPL 114-115°C.

Mass spectrum (CI, m/z): 340 (M++1).

The NMR spectrum (CDCl3that δ h/m): 0.15 (dt; J=8 Hz, 5 Hz, 1H), 0.39 (dt; J=8 Hz, 5 Hz, 1H), 0.58-0.66 (m, 1H), 0.78-0.85 (m, 1H), 0.89 (d, J=6 Hz, 3H), 2.26 (s, 3H), 2.37 (s, 3H), 4.13 (DD; J=15 Hz, 7 Hz, 1H), 4.27 (DD; J=15 Hz, 6 Hz, 1H), 5.63 (d, J=12 Hz, 1H), 5.68 (d, J=12 Hz, 1H), 7.06-7.11 (m, 2H), 7.49-7.52 (m, 2H), 8.97 (s, 1H).

Optical rotation [α]D20=-18,8° (C=0,98, Meon).

Example test 1

Test the activity of the proton-potassium-adenosinetriphosphatase

(N+·+-ATPase)

As of the preparation of the proton-potassium-adenosinetriphosphatase use microsomal fraction obtained according to the method of Sachs et al. [J. Bio. Chem., 251, 7690 (1976)] by homogenizing fresh layer of the mucous membrane of the stomach of the pig and subsequent ultracentrifugation homogenate in the density gradient. Solution (10 µl) of the test compound in dimethyl sulfoxide is added to 0.75 ml of 70 mm buffer Tris-hydrochloric acid (5 mm magnesium chloride, 20 mm potassium chloride, pH 6,85)containing 30-80 µg/ml of enzyme in the reagent to the protein concentration. The mixture is incubated with shaking 200 times/min at 37&#HWS within 45 minutes. The enzymatic reaction start by adding 0.25 ml of 8 mm solution of districtdistrict. After this enzymatic reaction is continued for 20 minutes, add 1 ml 10% trichloroacetic acid and activated charcoal (100 mg) to terminate the reaction. The reaction mixture was centrifuged (at 4°C and 3000 rpm for 15 minutes). Inorganic phosphoric acid formed by the hydrolysis of ATP in the supernatant determine colorimetrically method Yoda et al. [Biochem. Biophys. Res. Commun., 40, 880 (1970)]. Also determine the amount of inorganic phosphoric acid in the reaction mixture, free from potassium chloride. By subtracting this amount from the amount of inorganic phosphoric acid in the presence of potassium chloride to determine the proton-potassium-adenosine-triphosphatase (N+·+-ATPase) activity. The degree of inhibition (%) is determined from the values of the activity of control and activity values with the test compound at each concentration, whereby determine the concentration of 50% inhibition (IC50µg/ml) in respect of the proton-potassium-adenosinetriphosphatase. As a result, the compound of example 2 has a concentration of 50% inhibition (IC50) of 0.015 μg/ml, showing excellent activity.

Sample test 2

Test for inhibition of secretion Gelu is full of juice in rats

After the rats survive without food during the night, they do abdominal incision in the midline, are ligated and their gatekeepers under anesthesia with ether. The stomach and duodenum are returned to their original position in the body and then close the part of the abdominal incision. The test compound (0.3 to 10 mg/ml) suspended in an aqueous solution containing 0.5% of sodium carboxymethyl cellulose and 0.4% tween-80 (trademark). The resulting suspension (1 ml/kg body weight) administered to rats orally via a stomach tube. Four hours after ligation rats killed by inhalation of gaseous CO2. They do abdominal incision for removal of the stomach. Stomach contents collected in a glass graduated centrifuge tube. After centrifugation measure the amount (ml) of the supernatant and the amount (ml) of sediment. Sediment in excess of 0.5 ml are considered as faeces and exclude from the results. Supernatant (100 μl) was poured into a test tube. To the solution was added distilled water (4 ml) and the solution titrated to pH 7.0 with 0.01 n solution of sodium hydroxide. Standard hydrochloric acid solution obtained by adding 4 ml of distilled water to 100 μl of 0.1 n hydrochloric acid, titrated in the same way. Each parameter is calculated in accordance with the following EQ the values:

(1) the concentration of acid in the gastric juice (mEq/l)=a/b×100;

A: amount (ml) of sodium hydroxide solution required for the titration of 100 μl of the supernatant;

B: amount (ml) of sodium hydroxide solution required for the titration of 100 μl of 0.1 n hydrochloric acid;

(2) the Output of gastric juice (mgecw/h) = amount (ml) supertint gastric juice × the concentration of the acid in the gastric juice (mEq/l)/4.

(3) the degree of inhibition (%)=(C-D)/C×100

With - AO (mgecw/hour) group, which has introduced the media;

D - AO (mgecw/hour) group, which injected the connection.

The dose for 50% inhibition (ID50) is determined according to the method of least squares from the curve, the degree of inhibition is dose-dependent, on which lay the degree of inhibition at each dose against the logarithm of the dose.

Confidence interval at 95% determined according to the equation Fieller. As a result, the compound of example 2 reveals excellent activity, ie, ID50below 10 mg/kg

Example test 3

Antibacterial action against Helicobacter pylori

Antibacterial activity of the compounds of the invention appreciate using strains 9470, 9472 and 9474 Helicobacter pylori, and determining the MIC (minimum inhibitory concentration) of compounds according to the invention in relation to Helicobacter pylori.

Helicobacter pylori is cultivated by passage on p is anseth within 4 days. The environment is obtained by dissolving agar Brain Heart Infusion (product of Difco Laboratories) in the prescribed amount of distilled water, sterilize by autoclaving, add horse blood (product of Nippon Seibutsu Zairyo) to obtain a concentration of 7% and the mixture is then utverjdayut.

In microaerophilic conditions Helicobacter pylori grown at 37°within 4 days, suspended in physiological solution and get it a viable number of about 108CFU/ml Then the suspension is diluted 100 times, and a portion (about 10 µl) of the diluted suspension inoculant on Wednesday to determine the MIC. The medium used to determine the MIC, has the same composition as the medium for pre-cultivation. The compound of the present invention is dissolved in dimethyl sulfoxide (DMSO) and carry out a twofold serial dilution of sterilized water. After mixing the solution and the environment in the ratio of 1:99 the cured product in a Petri dish is used as a medium for determination of MIC. As for the pre-cultivation, Helicobacter pylori cultured at 37°C for 3 days in microaerophilic conditions. After completion of cultivation in the inoculated portion visually see the growth of bacteria. The minimum concentration of the compounds of this invention, in which the growth of bacteria do not see, is designated as MIC (μg/ml). Connection example the 2 detects excellent antibacterial activity, i.e. his MIC is less than 12.5 mg/ml

Example compositions 1

Tablets

The compound of example 230.0 mg
Lactose144, 0mm mg
Corn starch25.0 mg
Magnesium stearate1.0 mg
Total:200.0 mg

Get the tablet using the above ingredients. The components are mixed and pressed on the machine for tabletting, getting a tablet weight of 200 mg If needed on the tablet can be coated, for example, to obtain a tablet with a sugar coating.

[Effect of the invention]

The compounds of formula (I) or their pharmaceutically acceptable salts find a strong inhibitory activity against the secretion of gastric juice, protective activity against gastric mucosa and strong antibacterial activity against Helicobacter pylori, and they have excellent properties as a remedy. The compounds of formula (I) or their pharmaceutically acceptable salts are useful as therapeutic agents, particularly as a preventive or therapeutic remedies in case of ulcerative diseases such as peptic ulcer, acute or chronic gastric ulcer, gastritis, reflux Asia is it gastro-esophageal reflux, dyspepsia, gastric hyperacidity or syndrome Zollinger-Ellison, etc. or prophylactic or therapeutic agents in the case of bacterial infections resulting from Helicobacter pylori.

1. Pyrrolopyridine derived the following formula

where R1is (C3-C7-cycloalkyl-(C1-C6)-alkyl group, which optionally may be substituted (C1-C6)-alkyl group;

R2is (C1-C6)-alkyl group;

R3is hydroxymethylene group, (C2-C6)-aliphatic acyloxymethyl group, (C6-C10)-arylcarbamoyl group, (C1-C6)-alkoxycarbonylmethyl group, formyl group, carboxyl group, (C1-C6)-alkoxycarbonyl group or (C6-C10)-aryloxyalkyl group;

R4is (C6-C10)-aryl group, which optionally may be substituted by substituents selected from the group consisting of (C1-C6)-alkyl groups, halogen(C1-C6)-alkyl groups, (C1-C6)-alkoxygroup, halogen-(C1-C6)-alkoxygroup and halogen atoms; and

And represent the screens aminogroup, an oxygen atom or a sulfur atom,

or its pharmaceutically acceptable salt.

2. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claim 1, where R1is a (C3-C6-cycloalkyl-(C1-C2)-alkyl group which may be substituted (C1-C2)-alkyl group.

3. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claim 1, where R1represents cyclopropylmethyl group, 2-methylcyclopropyl, 2-ethylcyclopentadienyl group, cyclobutylmethyl group, 2-methylcyclopentadienyl group, cyclopentylmethyl group or 2-methylcyclohexylamine group.

4. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claim 1, where R1represents cyclopropylmethyl group, 2-methylcyclopropyl group, cyclopentylmethyl group or 2-methylcyclohexylamine group.

5. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claim 1, where R1represents cyclopropylmethyl group or 2-methylcyclopropyl group.

6. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claim 1, where R1is a 2-methylcyclopropyl group.

7. Pyrrolo iridaceae derivative or its pharmaceutically acceptable salt according to claims 1-6, where R2is a (C1-C4)-alkyl group.

8. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1-6, where R2is a (C1-C2)-alkyl group.

9. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1-6, where R2represents a methyl group.

10. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1 to 9, where R3represents hydroxymethylene group, (C2-C6)-aliphatic acyloxymethyl group, benzoyloxymethyl group, (C1-C4)-alkoxycarbonylmethyl group, formyl group, carboxyl group, (C1-C4)-alkoxycarbonyl group or vinyloxycarbonyl group.

11. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1 to 9, where R3represents hydroxymethylene group, (C2-C6)-aliphatic acyloxymethyl group, benzoyloxymethyl group, (C1-C2)-alkoxycarbonylmethyl group, formyl group, carboxyl group, (C1-C2)-alkoxycarbonyl group or vinyloxycarbonyl group.

12. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1-9, RG is R 3represents hydroxymethylene group, (C2-C4)-aliphatic acyloxymethyl group, (C1-C2)-alkoxycarbonylmethyl group, formyl group, carboxyl group or (C1-C2)-alkoxycarbonyl group.

13. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1 to 9, where R3represents hydroxymethylene group, (C2-C3)-aliphatic acyloxymethyl group, formyl group or a carboxyl group.

14. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1 to 9, where R3represents hydroxymethylene group or acetoxymethyl group.

15. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1 to 14, where R4represents a phenyl group substituted by 1-3 substituents selected from the group consisting of (C1-C4)-alkyl groups, halogen-(C1-C4)-alkyl groups, (C1-C4)-alkoxygroup, halogen-(C1-C4)-alkoxygroup, fluorine, chlorine and bromine.

16. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1 to 14, where R4represents a phenyl group substituted by 1-3 substituents selected from the group consisting of methyl group, trip armadillos group, metoxygroup, cryptometer, dipterocarp, fluorine, chlorine and bromine.

17. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1 to 14, where R4represents a phenyl group substituted in position(s)selected(s) from the group consisting of positions 2, 4 and 6 of the phenyl group, 1 or 2 substituents selected from the group consisting of fluorine and chlorine.

18. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1 to 14, where R4represents a phenyl group substituted in position 4, positions 2, 4, or positions 2, 6 phenyl groups, 1 or 2 substituents selected from the group consisting of fluorine and chlorine.

19. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1 to 18, where a represents an oxygen atom or a sulfur atom.

20. Pyrrolopyridine derivative or its pharmaceutically acceptable salt according to claims 1 to 18, where a represents an oxygen atom.

21. Pyrrolopyridine derivative according to claim 1, selected from the group which consists of 7-(4-forbindelse)-3-hydroxymethyl-2-methyl-1-(2-methylcyclopropyl)pyrrolo[2,3-d]pyridazine, 3-acetoxymethyl-7-(4-forbindelse)-2-methyl-1-(2-methylcyclopropyl)pyrrolo[2,3-d]pyridazin or its pharmaceutically acceptable salt.

22. Pyrrolopyridine derived or what about the pharmaceutically acceptable salt according to any one of claims 1 to 21, applicable for prophylaxis or treatment of peptic ulcer.

23. Pharmaceutical composition for use in the prevention or treatment of peptic ulcer, containing pyrrolopyridine derivative or its pharmaceutically acceptable salt according to any one of claims 1 to 21.

24. A method of prophylaxis or treatment of peptic ulcer disease involving the introduction of a warm-blooded animal a pharmaceutically effective amount pyrrolopyridine derivative or its pharmaceutically acceptable salt according to any one of claims 1 to 21.

25. The method according to paragraph 24, where the specified warm-blooded animal is a human.



 

Same patents:

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: compounds satisfying the formula I 1 are disclosed, wherein each R1 and R2 independently to one another are H, OH, OA or Hal; or R1 and R2 together are -O-CH2-O- or -O-CH2-CH2-O-; R3 and R4 are A-group; X - group monosubstituted with R8, R5 or R7; R5 is linear or branched C1-C10-alkylene, wherein one or two CH2-groups may be substituted with oxygen atom; R7 is phenyl or phenylmethyl; R8 is COOH, COOA, CONH2, CONHA, CON(A)2 or CN; F is C1-C6-alkyl; and Hal is F, Cl, Br, or I, as well as physiologically acceptable salts or solvates thereof. Methods for production of claimed compounds (I) and pharmaceutical composition containing the same also are disclosed. Said compounds and pharmaceutical composition have activity as phosphodiesterase V inhibitors and are useful in treatment of cardiovascular diseases and potency disorders.

EFFECT: pharmaceutically applicable compounds and compositions.

7 cl, 16 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to novel pyrasolbenzodiazepines of formula I 1 (in formula R1 is hydrogen, -NO2, -CN, halogen, -OR5, -COOR7, -CONR8R9, -NR10R11, NHCOR12, NHSO2R13; each R2 and R4 independently of one another are hydrogen, halogen, -NO2, -CF3; R3 is hydpegen, C3-C8-cycloalkyl, aryl, in particular C6-C10-aromatic group having 1 or 2 rings, 5-10-membered heteroaryl, having 1 or 2 rings and1-3 heteroatoms, selected from N, O, and S, -COOR7, CN, C2-C6-alkenyl, -CONR8R9 or C1-C6-alkyl optionally substituted with OR9-group, F or aryl as mentioned above; R5 is C1-C6-alkyl; R7 is hydrogen or C1-C6-alkyl; each independently of one another are hydrogen or C1-C6-alkyl optionally substituted with hydroxyl or NH2, or alternatively R8 and R9 together form morpholino group; each R10,R11 and R12 independently of one another are hydrogen or C1-C6-alkyl; R13 is C1-C6-alkyl optionally substituted with halogen or -NR14R15; each R14 and R15 independently of one another are hydrogen or C1-C6-alkyl optionally substituted with halogen; or alternatively -NR14R15 is morpholino group) or pharmaceutically acceptable salts thereof, as well as to certain pyrasolbenzodiazepine derivatives, thiolactam intermediates for production of compound (I) and pharmaceutical compositions containing the same. Compound and pharmaceutical composition of present invention are cycline-dependent kinase (CDK2) inhibitors and antiproliferation agents used in treatment or controlling disorders associated with cell proliferation, in particular breast, colon, lung and/or prostate tumors.

EFFECT: new antiproliferation agents.

20 cl, 12 tbl, 8 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to improved synthesis method of pyrlindone hydrochloride having formula (I) 1. Method features intramolecular cyclization of 6-methyl-1-(2-chloroethyl-imino)-1,2,3,4-tetrahydrocarbazole hydrochloride of formula IV 2 at 80°-140°C with alkali agent in presence of phase transfer catalyst to provide 1,2,5,6-tetrahydro-8-methyl-pyrazine[3,2,1-j,k]-4H-carbazole of formula VI 3 followed by reduction at 80°-120°C. Method of present invention makes in possible to produce compound of formula I with yield nearly 70 % and purity more than 99 %.

EFFECT: method of high yield with reduced amount of alkali agent and phase transfer catalyst.

7 cl, 2 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to a new derivative of bicyclic heteroaromatic compound of the general formula (I) or its pharmaceutically acceptable salt eliciting agonistic activity with respect to luteinizing hormone (LH). Compounds can be used for preparing medicinal agents for control ability for conception. In compounds of the general formula (I) R1 represents R7 wherein R7 represents (C6-C10)-aryl optionally substituted with halogen atom at ortho- and/or meta-position; NHR8, OR8 wherein R8 means (C1-C8)-alkyl that can be substituted with halogen atom, (C1-C8)-alkylcarbonyl, (C1-C8)-alkylcarbonyloxy-group, phenyl, (C6-C10)-arylcarbonylamino-group, 5-methyl-2-phenylimidazol-4-yl, (C6)-heterocycloalkyl wherein 1-2 heteroatoms are taken among nitrogen and oxygen atoms, ethyloxycarbonylmethylthio-(C1-C4)-alkoxy-group, amino-group, (C6-C7)-heteroaryl; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R2 represents (C1-C8)-alkyl or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; or (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; R3 represents (C1-C8)-alkyl possibly substituted with (C6-C14)-aryl possibly substituted with halogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkoxycarbonyl, mono- or tri-(C6-C10)-cycloalkyl, (C6-C10)-aryl, (C5-C6)-heteroaryl comprising nitrogen, oxygen or sulfur atom as a heteroatom; (C5-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; (C3-C8)-cycloalkyl, (C2-C7)-heterocycloalkyl comprising 2 heteroatoms taking among nitrogen or oxygen atom; or (C6-C10)-aryl optionally substituted with one or more substitutes taken among (C1-C8)-alkoxy-group; X represents sulfur atom (S) or N(R4); Y represents nitrogen atom (N); R4 represents (C1-C8)-alkyl, phenyl-(C1-C8)-alkyl; or X represents sulfur atom (S), and Y represents CH; Z represents NH2 or OH; A represents sulfur (S), oxygen atom (O) or a bond. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable properties of compounds and composition.

14 cl, 1 tbl, 119 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, chemical technology, herbicides.

SUBSTANCE: invention describes a method for preparing compounds of the formula (I):

wherein each R1, R2, R3 means independently of one another (C-C6)-alkyl; R can represent also pyridyl; R4 and R5 in common with nitrogen atoms to which they are joined form unsaturated 5-8-membered heterocyclic ring that can be broken by oxygen atom; G means hydrogen atom. Method involves interaction of compound of the formula (II):

wherein R1, R2 and R3 have above given values; R6 is a group RR9N-; R7 is a group R10R11N-; each among R8, R, R10 and R11 means independently of one another hydrogen atom or (C1-C6)-alkyl in inert organic solvent being optionally with the presence of a base with compound of the formula (IV) ,

(IVa)

or (IVb) ,

wherein R4 and R have above given values; H x Hal means hydrogen halide. The prepared compound of the formula (I) wherein G represents ammonium cation is converted to the corresponding compound of the formula (I) by treatment with Brensted's acid wherein G represents hydrogen atom. Also, invention describes compound of the formula (II) wherein R1, R2, R3, R6 and R7 have above indicated values.

EFFECT: improved preparing method.

9 cl, 12 ex

The invention relates to imidazole derivative of the formula (I)

or its pharmaceutically acceptable salt

The invention relates to organic chemistry and can find application in medicine

The invention relates to heterocyclic compounds with substituted phenyl group of formula Ior its pharmaceutically acceptable salt, in which R1represents a C1-C6alkyl; R2represents a C1-C6alkyl; R3represents H or halogen andrepresents a substituted heterocycle, as defined in paragraph 1 of the claims; and X represents NH or O

The invention relates to organic chemistry and can find application in medicine

The invention relates to organic chemistry, in particular to the compounds representing amide of the formula I:

in which * denotes an asymmetric carbon atom; R1and R2independently from each other represent a hydrogen atom or halogen, amino, hydroxyamino-, nitro-, cyano-, sulfamidihappo, (ness.)alkyl, -OR5, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl; R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms; R4means (O)other40or unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom of the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist on the ring angle is found (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR7, -(CH2)n-C(O)OTHER6, -C(O)-C(O)OR8and -(CH2)n-OTHER6or its pharmaceutically acceptable salts

The invention relates to organic chemistry and can find application in medicine

The invention relates to a new inhibitor of serine proteases of the formula (I):

in which J is an R1, R1-SO2-, R3OOC-(CHR2)p- or (R2aR2b)N-CO-(CHR2)P-;D is an amino acid of formula-NH-CHR1-C(O) -, or-NR4-CH[(CH2)qC(O)OR1]-C(O)-; E is-NR2-CH2or fragment

R1selected from (1-12C)alkyl, (3-12C)cycloalkyl and (3-12C)cycloalkyl(1-6C)alkylene, groups which are optionally substituted (3-12C)cycloalkyl, and from (14-20C)(biaryl)alkyl; each of R2, R2Aand R2bindependently selected from H, (1-8C)alkyl, (3-8C)cycloalkyl and (6-14C)aryl; R3has the same values, which is defined for R2; R4represents H; X and Y are CH; m is 1 or 2; p is 1, 2 or 3; q is 1, 2 or 3; t is 2, 3 or 4; or N-alkoxycarbonyl-substituted derivative; and/or its pharmaceutically acceptable salt additive and/or MES

The invention relates to new physiologically active substituted oxazolo[4,5-d]pyridazine General formula (1), (2) or (3) and combinatorial library designed to search among them physiologically active substances, compounds leaders and candidates (drug-candidates) on the basis of screening

The invention relates to a derivative phthalazine General formula (I) or their pharmaceutically acceptable salts, or hydrates, where R1and R2are the same or different from each other and each represents a halogen atom, a C1-C4alkyl group which may be substituted by a halogen atom, a hydroxyl group or a C1-C4alkoxygroup, which may be substituted by a halogen atom, or cyano; X represents a cyano, a halogen atom, hydroxyimino, optional O-substituted C1-C4alkyl group, or a heteroaryl group selected from thiazoline, thienyl, pyrazolidine, triazolinones and tetrazolyl groups that may be substituted WITH1-C4alkyl group; Y represents a cyclic amino group (i) - (v) described in paragraph 1 of the claims; (vi) etinilnoy or ethyl group substituted WITH1-C4alkyl group, which, in turn, replaced by a number of deputies referred to in paragraph 1 of the claims; (vii) optionally substituted phenyl group; (viii) pyridyloxy or thiazolidine group

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantane of the general formula:

wherein m = 1 or 2; each R1 represents independently hydrogen atom; A represents C(O)NH or NHC(O); Ar represents the group:

or

wherein X represents a bond, oxygen atom or group CO, (CH2)1-6, CH=, O(CH2)1-6, O(CH2)2-6O, O(CH2)2-3O(CH2)1-3, CR'(OH), NR5, (CH2)1-6NR5, CONR5, S(O)n, S(O)nCH2, CH2S(O)n wherein n = 0, 1 or 2; R' represents hydrogen atom; one of R2 and R3 represents halogen atom, nitro-group, (C1-C6)-alkyl; and another is taken among R2 and R3 and represents hydrogen or halogen atom; either R4 represents 3-9-membered saturated or unsaturated aliphatic heterocyclic ring system comprising one or two nitrogen atoms and oxygen atom optionally being heterocyclic ring system is substituted optionally with one or more substitutes taken independently among hydroxyl atoms, (C1-C6)-alkyl, (C1-C6)-hydroxyalkyl, -NR6R7, -(CH2)rNR6R7; or R4 represents 3-8-membered saturated carbocyclic ring system substituted with one or more substitutes taken independently among -NR6R7, -(CH2)NR6R7 wherein r = 1; R5 represents hydrogen atom; R6 and R7 each represents independently hydrogen atom or (C1-C6)-alkyl, or (C2-C6)-hydroxyalkyl group eliciting antagonistic effect with respect to R2X7-receptors. Also, invention describes a method for their preparing, pharmaceutical composition comprising thereof, a method for preparing the pharmaceutical composition and their applying in therapy for treatment of rheumatic arthritis and obstructive diseases of respiratory ways.

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

13 cl, 88 ex

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