Derivatives pyrrolopyridine, methods for their production, antiulcer tool

 

(57) Abstract:

Describes the new derivatives pyrrolopyridine having General formula (I), where the values of R1-R5, m, n, A, X specified in paragraph 1 of the formula. Derivatives pyrrolopyridine have high activity, inhibiting the secretion of gastric juice, activity, protects the mucous membrane of the stomach antibacterial activity against Helicobacter Pylori, and so the derivative can be used as a preventive or therapeutic agent for the prevention or treatment of peptic ulcer disease. Describes how they obtain and antiulcer agent. 4 C. and 23 C.p. f-crystals, 3 PL.

The invention relates to a derivative pyrrolopyridine or their pharmaceutically acceptable salts, with high activity, inhibiting the secretion of gastric juice; activity, protects the mucous membrane of the stomach; and high antibacterial activity against Helicobacter pylori; and antiulcer agent containing the derivative or salt as an active ingredient.

It is known that practical ulcer occurs when the imbalance between factors razreshau treatment of stomach ulcers is important suppression of secretion of gastric juice, one of the factors that destroy the lining of the stomach. Up to the present time in clinics in the quality of medicines, is effective for inhibiting the secretion of gastric juice, has been widely used anticholinergics and antagonists histamine H2receptors, such as cimetidine, etc., However, the possibility of relapse when the drug is removed antagonist histamine H2receptors after long-term use is a serious problem. Although it is believed that the recurrence of ulcers caused by the reduction of protective factors in the area of the mucous membrane of the stomach, however, was recently revealed their relationship to Helicobacter pylori. Accordingly it would be desirable to obtain such an antiulcer agent, which would be a strong inhibitor of gastric secretion (i.e., destructive factor), would contribute to the protection of the gastric mucosa and had high antibacterial activity against Helicobacter pylori.

Among the derivatives of pyrrolopyridine having the activity of inhibiting the secretion of gastric juice and protective activity against gastric mucosa, it is known, for example, the connection shown below (WO91/17164, WO92/06979, WO93/08190 EDINENIE with higher activity.

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To solve the above problems, the authors present invention for many years he conducted a thorough investigation relating to the synthesis of derivatives pyrrolopyridine and their pharmacological activity and is aimed at developing highly effective antiulcer agents that have a strong effect, inhibiting the secretion of gastric juice (i.e., destructive factor), a protective effect against gastric mucosa and high antibacterial activity against Helicobacter pylori. As a result of these studies it was found that derivatives pyrrolopyridine having certain substituents, possess high antibacterially activity against Helicobacter pylori, as well as high activity, inhibiting the secretion of gastric juice and protective activity against the gastric mucosa, based on which we developed the present invention.

Derivatives pyrrolopyridine of the present invention have the General formula:

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In this formula, R1represents a C2-C6-alkenylphenol group, halogen-C2-C6-alkenylphenol group, C6-C10-aryl-C2-C6-alkenylphenol group, C26is an alkyl group, (C5-C7-cycloalkenyl) -C1-C6is an alkyl group, or halogen-C1-C6is an alkyl group;

R2and R3may be the same or different and each represents a hydrogen atom, a C1-C6is an alkyl group, or a C6-C10-aryl group;

R4represents a hydrogen atom, or a C1-C6is an alkyl group;

R5represents a C6-C10-aryl group, or a 5-10 membered heteroaryl group, where the heteroatom or heteroatoms) selected from nitrogen atoms, oxygen and sulfur;

A represents a C1-C3-alkylenes group;

X represents an imino(NH) group, oxygen atom, sulfur atom or methylene group;

m = 0 or 1; and

n = 0 or 1.

C2-C6-alkenylphenol group or a C2-C6-alkenylphenol halogen-C2-C6-alkenylphenol group and C6-C10aryl-C2-C6-alkenylphenol groups included in the definition of R1may be, for example, vinyl, 1-protanilla, 2-protanilla, isopropylene, 1-bucinellina, 2-bucinellina, 3-bucinellina, 1-methyl-1-protanilla, 1-methyl-2-protanilla, 2-methyl-1-propanediyl-2-bucinellina, 3-methyl-2-bucinellina, 1-examilia, 2-examilia, propane-1,2-dianiline, butane-1,2-dianiline, pentane-1,2-dianiline, or hexane-1,2-Danilina group; and preferably, C2-C5-Alchemilla group (in particular, vinyl, 1-protanilla, 2-protanilla, isopropylene, 1-bucinellina, 2-bucinellina, 3-bucinellina, 2-methyl-2-protanilla, 2-penttila, 3-penttila, 3-methyl-2-bucinellina, or propane-1,2-Danilina group); and more preferably C3-C4-Alchemilla group (in particular, 1-protanilla, 2-protanilla, 1-bucinellina, 2-bucinellina or 2-methyl-2-protanilla group).

Halogen-C2-C6-alkenylphenol group included in the definition of R1may be, for example, 2,2-debtor-vinyl, 3-fluoro-2-protanilla, 2-chloro-2-protanilla, 3-chloro-2-protanilla, 3-bromo-2-protanilla, 3-iodine-2-protanilla, 3,3-debtor-2-protanilla; 2,3-dichloro-2-protanilla; 3,3-dichloro-2-protanilla; 2,3-dibromo-2-protanilla; 3,3-dibromo-2-protanilla; 4,4,4-Cryptor-2-bucinellina; 5-fluoro-2-penttila; or 6-fluoro-2-hexylamine group; and preferably, 3-chloro-2-protanilla, 3,3-dichloro-2-protanilla, or 4,4,4-Cryptor-2-bucinellina group.

C6-C10-aryl part (C6-C10are, included in the definition of R2, R3and R5may be, for example, phenyl group or naftalina group, preferably phenyl group. This group may, but is not necessary to have a Deputy (deputies) on the ring, and such substituents may be, for example, C1-C6is an alkyl group, as defined below; C1-C6-alkoxy group such as methoxy, ethoxy-, propoxy-, isopropoxy, butoxy, isobutoxy, pentox or hexyloxy group; halogen atom such as fluorine atom, chlorine, bromine, or iodine; halogen-(C1-C6is an alkyl group, such as vermeil, chloromethyl, deformity, trifluoromethyl, 2-foretel, 2-chloroethyl, 2-bromacil, 2-codetel, 2,2,2-triptorelin, 3-forprofit, 4-terbutyl, 5-terpencil, or 6-forhekset; or halogen-(C1-C6-alkoxy group, such as formatosi, deformedarse, triptoreline-, 2-floratone, 2-chloroethoxy-, 2-iodoxy-, 2,2,2-triptoreline-, 3-forproperty-, 4-forbooks-, 5-fermentasi-, or 6-perhexiline group; preferably, C1-C4is an alkyl group, a C1-C4-alkoxy group, halogen atom, or a halogen-C1-C4is an alkyl group, and more preferably, methyl group, methoxy group, a fluorine atom or, chlorine, trifluoromethyl or deformedarse group (especially fluorine or chlorine) milking group within the definition of R5.

(C6-C10aryl)-C2-C6-alkenylphenol group included in the definition of R1may be, for example, 2-phenylethenyl, 3-phenyl-2-propenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 6-phenyl-5-hexenyl, 3-were-2-propenyl, 3-methoxyphenyl-2-propenyl, 3-forfinal-2-propenyl, 3-chlorophenyl-2-propenyl, or 3-naphthyl-2-propenyl; preferably 3-phenyl-2-propenyl, 4-phenyl-3-butenyl, 5-phenyl-4-pentenyl, 3-were-2-propenyl, 3-methoxyphenyl-2-propenyl, 3-forfinal-2-propenyl, 3-chlorophenyl-2-propenyl, or 3-naphthyl-2-propenyl; and more preferably 3-phenyl-2-propenyl.

C2-C6is an alkyl group, leading to the definition of R1may be, for example, etinilnoy, 2-proponila, 2-Butyrina 2-penicilina, or 2-hexylamine group, preferably C2-C4is an alkyl group, and more preferably 2-proponila group.

C3-C7-cycloalkyl group or a C3-C7-cycloalkyl part (C3-C7-cycloalkyl)-C1-C6is an alkyl group within the definition of R1may be, for example, cyclopropyl, cyclobutyl, C is positive cyclopropyl. This group may have, but not necessarily, the Deputy (or deputies) on the ring; and such Deputy may be, for example, C1-C6is an alkyl group, as defined below; preferably C1-C4is an alkyl group; more preferably a methyl or ethyl group; and especially preferably a methyl group.

(C3-C7-cycloalkyl)-C1-C6is an alkyl group included in the definition of R1may be, for example, cyclopropylmethyl, methylcyclopropyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, methylcyclohexylamine, cycloheptylmethyl, 2-cyclopropylethyl, 3-cyclopropylmethyl, 4-cyclopropylmethyl, 5-cyclopropylmethyl, or 6-cyclopropylethyl; preferably cyclopropylmethyl, 2-methylcyclopropyl, or cyclohexylmethyl; and especially preferably cyclopropylmethyl, or 2-methylcyclopropyl.

(C5-C7)-cycloalkenyl)-C1-C6is an alkyl group included in the definition of R1may be, for example, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, 2-cyclopentadienyl, 3-cyclopentylpropionyl, 4-cyclopentylmethyl, 5-cyclopentadienyl, 6 - cyclopentyloxy, 2-cyclohexenylmethyl, 3 tikikpina-1-ylmethyl or cyclohexen-1-ylmethyl; and more preferably cyclopenten-1-ylmethyl.

Halogen-C1-C6is an alkyl group included in the definition of R1may be, for example, vermeil, chloromethyl, deformity, trifluoromethyl, 2-foretel, 2-chloroethyl, 2-bromacil, 2-codetel, 2,2-dottorati, 2,2,2-triptorelin, 3-forprofit, 4-terbutyl, 5-terpencil, or 6-forhekset; preferably halogen-C1-C4is an alkyl group; more preferably deformity, 2-foretel, 2-chloroethyl, 2-bromacil, 2-codetel, 2,2-dottorati, 2,2,2-triptorelin, 3-forprofit, or 4-terbutyl; and particularly preferably 2,2,2-triptorelin or 3-forproper.

C1-C6is an alkyl group included in the definition of R2, R3and R4may be, for example, methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, pencilina or exilda group, preferably C1-C4is an alkyl group, more preferably a methyl or ethyl group; and especially preferably a methyl group.

5-10-membered heteroaryl group having heteroatoms selected from nitrogen atoms, oxygen and sulfur, and which is included in the definition of R5may be, for example, pyrrolyl, indolyl, furyl, benzofuran, thienyl, benzothiazolyl, imidazolyl, benzimidazolyl, pyrazolyl, benzimidazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, pyridyl, hinely, ethanolic, pyrimidinyl, pyrazinyl or pyridazinyl; preferably furyl, thienyl, oxazolyl, benzoxazolyl, thiazolyl, benzothiazolyl, imidazolyl, benzimidazolyl, 1,3,4-oxadiazolyl, 1,3,4-thiadiazolyl, pyridyl, pyrazinyl, or pyridazinyl; and more preferably furyl, thienyl, or pyridyl. This heteroaryl group may have a Deputy (deputies) on the ring; and, Deputy 5-6 membered heteroclite may be, for example, C1-C6is an alkyl group or halogen atom defined above; and especially preferably methyl, fluorine, or chlorine; and the substituents on the phenyl ring may be the same group mentioned above in the definition of aryl groups.

C1-C3-alkalinous group in the definition of A can be, for example, methylene, ethylene, propylene or trimethylene group; and preferably a methylene group.

X is preferably an oxygen atom, a sulfur atom or a methylene group; more preferably an oxygen atom or a methylene group; and particularly preferably an oxygen atom.

m PR is predpochtitelno 0.

The compound of General formula (1) described above, may be converted, if necessary, its pharmaceutically acceptable salt. Such salts can be preferably salt accession acid, for example, galoidovodorodov, such as forgert, chlorhydrate, bromohydrin, or loggedout; nitrate; perchlorate; a sulfate; a phosphate; a carbonate; C1-C4-alkylsulfonate, such as methanesulfonate, triftorbyenzola, or econsultant; C1-C10-arylsulfonate, such as bansilalpet or p-toluensulfonate; carboxylate, such as acetate, propionate, butyrate, benzoate, fumarate, succinate, citrate, tartrate, oxalate, malonate, or maleate; or a salt of the amino acids, such as glutamate or aspart. In addition, the scope of the present invention includes any hydrate of Compound (I).

In some cases, the compound (I) can exist as optical isomers due to the presence of the molecule in the asymmetric atom (or atoms) of carbon; and/or in the form of geometrical isomers due to the presence in the molecule of the double bond (or bonds). Scope of the present invention includes all of these stereoisomers and mixtures thereof.

The preferred compounds of General Farlow group; C3-C4-alkenylphenol group substituted by fluorine, chlorine, or bromine; C6aryl-C3-C5-alkenylphenol group; C3-C4-alkylamino group; cyclopropyl group; C3-C6-cycloserine group; or halogen-(C1-C4is an alkyl group;

(2) the compound in which R1represents a C2-C5-alkenylphenol group; C3-C4-alkenylphenol group substituted by fluorine or chlorine; 3-(C6aryl)-2-propenyloxy group; 2-propenyloxy group; cyclopropylmethyl group; 2-methylcyclopropyl group; cyclopenten-1-ylmethylene group; or fluorine-C2-C3is an alkyl group;

(3) the compound in which R1is a 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 2-methyl-2-propanol, propane-1,2-dienyl, 3-phenyl-2-propenyl, 2-PROPYNYL, cyclopropylmethyl, 2-methylcyclopropyl, cyclopenten-1-ylmethyl, 2,2,2-triptorelin, or 3-forproper;

(4) the compound in which R1is a 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 2-methyl-2-propenyl, 3-phenyl-2-propenyl, cyclopropylmethyl, or 2-methylcyclopropyl;

(5) the compound in which R2and R3may be the same or different, and each of them before the group in which R2and R3may be the same or different and each represents a hydrogen atom, a C1-C3is an alkyl group, or phenyl group;

(7) a compound in which R2and R3may be the same or different and each represents a hydrogen atom, a C1-C2is an alkyl group;

(8) the compound in which R2and R3are identical and represent a methyl group;

(9) a compound in which R4represents a hydrogen atom or a C1-C4is an alkyl group;

(10) the compound in which R4represents a hydrogen atom or a C1-C2is an alkyl group;

(11) a compound in which R4represents a hydrogen atom;

(12) a compound in which R5represents a phenyl group; optionally substituted C1-C4is an alkyl group, a C1-C4-alkoxy group, halogen, halogen-C1-C4is an alkyl group or halogen-C1-C4-alkoxy-group; naftalina group; follow group, thienyl group, oxazolidinyl group, benzoxazolyl group, thiazole group, benzothiazolyl group; imidazolidinyl se; personilnya group; or pyridazinyl group;

(13) the compound in which R5represents a phenyl group, optionally substituted methyl group, methoxy group, fluorine, chlorine, permatile group, triptorelin group, formatosi group, or deformedarse group; follow group, thienyl group, oxazolidinyl group, benzoxazolyl group, thiazolidine group, benzimidazolyl group, or pyridyloxy group;

(14) the compound in which R5represents a phenyl group, optionally substituted methyl group, methoxy group, fluorine, chlorine, permatile group, triptorelin group, formatosi group, or deformedarse group; follow group; thienyl group; or pyridyloxy group;

(15) the compound in which R5represents a phenyl group, optionally substituted by fluorine, chlorine, triptorelin group, or deformedarse-group;

(16) the compound in which R5represents a phenyl group, optionally substituted by fluorine or chlorine;

(17) a compound in which A represents a methylene group;

(18) the compound in which X is an atom ka, an oxygen atom or methylene group;

(20) the compound in which X represents an oxygen atom;

(21) the compound in which m = 0; and

(22) the compound in which n = 0.

In addition, any of the above combinations, namely, (1) - (4), (5) - (8), (9) - (11), from(12) - (16), (17), (18) - (20), (21) and (22) can be preferred connection, such as:

(23) a compound in which:

R1represents a C2-C5-alkenylphenol group; C3-C4-alkenylphenol group substituted by fluorine, chlorine, or bromine; C6-aryl-C3-C5-alkenylphenol group; C3-C4-alkylamino group; cyclopropyl group; C3-C6-cycloalkylation group; or halogen-(C1-C4is an alkyl group;

R2and R3may be the same or different and each represents a hydrogen atom, a C1-C4is an alkyl group, or a C6-aryl group;

R4represents a hydrogen atom, or a C1-C4is an alkyl group;

R5represents a phenyl group, optionally substituted C1-C4is an alkyl group, a C1-C4-alkoxy group, halogen, halogen-C1-C4-alkyl is y; oxazolidinyl group; benzoxazolyl group; thiazolidine group; benzothiazolyl group; imidazolidinyl group; benzimidazolyl group; 1,3,4-oxadiazolyl group; 1,3,4-thiadiazolyl group; pyridyloxy group; personilnya group; or pyridazinyl group;

A represents a methylene group;

X represents an oxygen atom, a sulfur atom or methylene group; and

If n = 1 then m = 0;

(24) a compound in which:

R1represents a C2-C5-alkenylphenol group; C3-C4-alkenylphenol group substituted by fluorine or chlorine; 3-(C6-aryl)-2-propenyloxy group 2-propenyloxy group" cyclopropyl group; cyclopropylmethyl group; 2-methylcyclopropyl group; cyclopenten-1-ylmethylene group; or fluorine-C2-C3is an alkyl group;

R2and R3may be the same or different and each represents a hydrogen atom, a C1-C3is an alkyl group, or phenyl group;

R4represents a hydrogen atom, or a C1-C2is an alkyl group;

R5represents a phenyl group, optionally substituted methyl group, methoxy group, ft is th; follow group; thienyl group; oxazolidinyl group; benzoxazolyl group; thiazolidine group; benzothiazolyl group; imidazolidinyl group; benzimidazolyl group; or pyridyloxy group;

A represents a methylene group;

X represents an oxygen atom, a sulfur atom or methylene group; and

m = 0;

(25) a compound in which:

R1is a 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 2-methyl-2-propenyloxy, propane-1,2-dianilino, 3-phenyl-2-propenyloxy, 2-propenyloxy, cyclopropylmethyl, 2-methylcyclopropyl, cyclopenten-1-ylmethylene, 2,2,2-triptorelin, or 3-forproperty group;

R2and R3may be the same or different and each represents a hydrogen atom or a C1-C2is an alkyl group;

R4represents a hydrogen atom or a C1-C2is an alkyl group;

R5represents a phenyl group, optionally substituted by fluorine, chlorine, triptorelin group or deformedarse-group;

A represents a methylene group;

X represents an oxygen atom or methylene group;

m = 0; and

n = 0; is, 2-butenyloxy, 2-methyl-2-propenyloxy, 3-phenyl-2-propenyloxy, cyclopropylmethyl, or 2-methylcyclopropyl group;

R2and R3may be the same or different, and each represents a methyl group;

R4represents a hydrogen atom;

R5represents a phenyl group, optionally substituted by fluorine or chlorine;

A represents a methylene group;

X represents an oxygen atom;

m = 0; and

n = 0.

In Tables 1, 2 and 3 presents examples of typical compounds of the present invention, however, the scope of the present invention is not limited to these compounds. The compounds listed in Tables 1, 2 and 3, have the structure of Compound (1-1), Compound (1-2) and the Compound (1-3), respectively.

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In Tables 1, 2, 3 we used the following abbreviations:

Benzimidz: benzimidazolyl group

Benzoxaz: benzoxazolyl group

Benzothiaz: benzothiazolyl group

Bu: bucilina group

Buc: cyclobutyl group

Bui: isobutylene group

Bus: second-bucilina group

But: tert-bucilina group

Et: ethyl group

Fur: furilla group
HpC: cyclopentenone group

Your image: imidazolidine group

Me: methyl group

Naph: naftalina group

Oxaz: oxazolidine group

Pntec: cyclopentenone group

Ph: phenyl group

Pn: pencilina group

Pnc: cyclopentenone group

Pr: sawn group

Prc: cyclopropyl group

Pri: ISO-propyl group

Pyr: Peregrina group

Pyraz: piratininga group

Pyridz: pyridazinyl group

TDA: thiadiazolidine group

Thi: thienyl group

Thiaz: thiazolidine group

Of the above compounds, preferred are the following compounds: NN

1-1, 1-2, 1-3, 1-6, 1-11, 1-13, 1-18, 1 -19, 1-24, 1-36, 1-37, 1-38, 1-39, 1-40, 1-42, 1-45, 1-48, 1-51, 1-59, 1-62, 1-68, 1-69, 1-70, 1-71, 1-76, 1-77, 1-78, 1-79, 1-80, 1-81, 1-94, 1-99, 1-111, 1-112, 1-115, 1-120, 1-126, 1-129, 1-134, 1-137, 1-146, 1-153, 1-154, 1-155, 1-156, 1-169, 1-186, 1-187, 1-195, 1-198, 1-201, 1-204, 1-209, 1-226, 1-227, 1-229, 1-231, 1-232, 1-234, 1-236, 1-237, 1-239, 1-241, 1-242, 1-244, 1-246, 1-247, 1-249, 1-251, 1-252, 1-259, 1-260, 1-263, 1-278, 1-293, 1-308, 1-323, 1-338, 1-353, 1-368, 1-383, 1-398, 1-413, 1-428, 1-445, 1-447, 1-449, 1-451, 1-458, 1-460, 1-461, 1-462, 1-464, 1-466, 1-473, 1-475, 1-478, 1-488, 1-490, 1-492, 1-493, 1-503, 1-504, 1-505, 1-506, 1-507, 1-523, 1-524, 1-526, 1-539, 1-540, 1-619, 1-623, 1-631, 1-632, 1-644, 1-653, 1-656, 1-664, 1-669, 1-672, 1-678, 1-725, 1-726, 1-728, 1-729, 1-734, 2-3, 2-4, 2-5, 2-6, 2-8, 2-13, 2-14, 2-16, 2-17, 2-21, 2-24, 2-25, 2-28, 2-36, 2-38, 2-41, 2-44, 2-50, 2-522-147, 2-148, 2-156, 2-164, 2-165, 2-168, 2-170, 2-171, 2-173, 2-175, 2-183, 2-184, 2-185, 2-186, 2-187, 2-188, 3-59, 3-60, 3-68, 3-76, 3-77, 3-80, 3-82, 3-83, 3-99, 3-100 and 3-101;

more preferred are the following compounds: NN 1-1, 1-3, 1-6, 1-11, 1-13, 1-18, 1-19, 1-39, 1-40, 1-42, 1-45, 1-48, 1-51, 1-59, 1-62, 1-68, 1-69, 1-70, 1-71, 1-77, 1-78, 1-81, 1-86, 1-94, 1-126, 1-129, 1-153, 1-156, 1-226, 1-231, 1-232, 1-236, 1-241, 1-259, 1-263, 1-323, 1-413, 1-445, 1-447, 1-449, 1-451, 1-458, 1-460, 1-462, 1-464, 1-466, 1-492, 1-505, 1-507, 1-523, 1-524, 1-526, 1-539, 1-540, 1-619, 1-623, 1-631, 1-632, 1-644, 1-653, 1-656, 1-664, 1-669, 1-672, 1-678, 1-725, 1-726, 1-728, 1-729, 2-3, 2-4, 2-5, 2-6, 2-8, 2-13, 2-14, 2-16, 2-17, 2-21, 2-24, 2-25, 2-28, 2-36, 2-41, 2-44, 2-50, 2-53, 2-54, 2-56, 2-57, 2-59, 2-76, 2-93, 2-94, 2-95, 2-96, 2-97, 2-98, 2-119, 2-120, 2-126, 2-127, 2-128, 2-130, 2-138, 2-139, 2-140, 2-142, 2-143, 2-148, 2-164, 2-165, 2-168, 2-171, 2-187, 3-60, 3-76, 3-77, 3-83, 3-99, 3-100 and 101;

most preferred are the following compounds: NN 1-3, 1-6, 1-11, 1-13, 1-19, 1-39, 1-40, 1-42, 1-45, 1-51, 1-59, 1-70, 1-77, 1-78, 1-81, 1-126, 1-153, 1-156, 1-226, 1-231, 1-232, 1-236, 1-323, 1-445, 1-447, 1-449, 1-451, 1-460, 1-462, 1-464, 1-466, 1-505, 1-523, 1-524, 1-526, 1-539, 1-540, 1-619, 1-623, 1-631, 1-632, 1-644, 1-653, 1-656, 1-664, 1-669, 1-672, 1-678, 1-725, 1-726, 1-728, 2-4, 2-5, 2-16, 2-24, 2-25, 2-28, 2-36, 2-41, 2-44, 2-50, 2-53, 2-56, 2-76, 2-93, 2-95, 2-97, 2-98, 2-119, 2-120, 2-148, 2-164, 2-165, 2-168, 2-171, 2-187, 3-60, 3-77 and 3-83; and particularly preferred compounds are:

The compound N 1-6: 1-(2-butenyl)-7-benzyloxy-2,3-dimethyl-pyrrolo[2,6-d] pyridazin;

The compound N 1-11: 7-benzyloxy-2,3-dimethyl-1-(2-methyl-2-propenyl pyrrolo[2,6-d]pyridazin;

The compound N 1-45: 7-benzyloxy-2,3-dimethy role[2,6-d]pyridazin;

The compound N 1-77: 7-(4-forbindelse)-2,3-dimethyl-1-(1-propenyl)pyrrolo[2,3-d]pyridazin;

The compound N 1-78: 7-(4-forbindelse)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

The compound N 1-81: 1-(2-butenyl-7-(4-forbindelse)-2,3-dimethylpyrrole[2,3-d]pyridazin;

Compound 1-126 N: 1-cyclopropylmethyl-7-(4-forbindelse)-2,3-dimethylpyrrole[2,3-d]pyridazin;

The compound N 1-153: 7-(2,4-deferasirox)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

The compound N 1-156: 1-(2-butenyl)-7-(2,4-deferasirox)-2,3-dimethylpyrrole[2,3-d]pyridazin;

Compound 1-226 N: 7-(4-chlorobenzoyloxy)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

The compound N 1-231: 7-(2,4-dichloraniline)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

Connection 1-232 N: 1-(2-butenyl)-7-(2,4-dichloraniline)-2,3-dimethylpyrrole[2,3-d]pyridazin;

The compound N 1-236: 7-(2-forbindelse)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

The compound N 1-323: 1-(2-Butenyl)-3-ethyl-7-(4-forbindelse)-2-methylpyrrole[2,3-d]pyridazin;

The compound N 1-445: 7-(4-forbesii)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

Connection 1-460 N: 1-(2-butenyl)-7-(4-forbesii)-2,3-dimethylpyrrole[2,3-d]pyridazin;

The compound N 1-462: 1-(2-butenyl)-7-(2,4-diferentially)-2,3-BR>
The compound N 1-524: 1-(2-butenyl)-7-(4-chloro-6-forbindelse)-2,3-dimethylpyrrole[2,3-d]pyridazin;

The compound N 1-539: 7-(4-forbindelse)-2,3-dimethyl-1-(2-methylcyclopropyl) pyrrolo[2,3-d]pyridazin;

The compound N 1-540: 7-(2,4-deferasirox)-2,3-dimethyl-1-(2-methylcyclopropyl) pyrrolo[2,3-d]pyridazin;

The compound N 1-631: 2,3-dimethyl-7-phenethyl-1-(2-propenyl)-pyrrolo[2,3-d] pyridazin;

The compound N 1-632: 1-(2-butenyl)2,3-dimethyl-7-phenethyl-pyrrolo[2,3-d] pyridazin;

The compound N 1-653: 7-(4-florfenicol)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

The compound N 1-656: 1-(2-butenyl)-7-(4-forfinal)-2,3-dimethylpyrrole[2,3-d]pyridazin;

The compound N 1-664: 1-cyclopropylmethyl-7-(4-florfenicol)-2,3-dimethylpyrrole[2,3-d]pyridazin;

The compound N 1-669: 7-(2,4-divertenti)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,6-d]pyridazin;

The compound N 1-672: 1-(2-butenyl)-7-(2,4-divertenti)-2,3-dimethylpyrrole[2,3-d]pyridazin;

The compound N 1-678: 1-cyclopropylmethyl-7-(2,4-divertenti)-2,3-dimethylpyrrole[2,3-d]pyridazin;

The compound N 1-725: 7-(4-florfenicol)-2,3-dimethyl-1-(2-methylcyclopropyl) pyrrolo[2,3-d]pyridazin;

The compound N 1-726: 7-(2,4-divertenti)-2,3-dimethyl-1-(2-methylcyclopropyl)pyrrolo[2,3-d] pyridazin;

The compound N 1-728: 2,3-dimethyl-1-(2-IU methylpyrrole[2,3-d]pyridazin-5-oxide;

The compound N 2-44: 1-(2-butenyl)-7-(2,4-deferasirox)-2,3-dimethylpyrrole[2,3-d]pyridazin-5-oxide;

The compound N 2-171: 1-(2-butenyl)-7-(2,4-divertenti)-2,3-dimethylpyrrole[2,3-d]pyridazin-5-oxide; and

The compound N 3-83: 1-(2-butenyl)-7-(2,4-divertenti)-2,3-dimethylpyrrole[2,3-d]pyridazin-6-oxide.

Derivatives pyrrolopyridine of the present invention can be easily obtained by, systematized in the following reaction scheme:

< / BR>
< / BR>
< / BR>
B above formulas:

R1, R2, R3, R4, R5and A are defined above;

Xarepresents an imino group, an oxygen atom or a sulfur atom;

Y represents a halogen atom (preferably, chlorine atom, bromine atom, or iodine);

Z represents a halogen atom (preferably chlorine atom, bromine, or iodine); C1-C4-alkanesulfonyl group optionally substituted by an atom (or atoms), halogen (such as methanesulfonate, econsultancy, propanesulfonate, butanesulfonate, tripterocalyx, or trichlorocarbanilide); C6-C10-arylsulfonate group (such as benzosulfimide or p-toluensulfonate group); or a halogen-usloviy, that m' and n' are not O at the same time.

Method A provides for compounds of formulas (Ia) and (Ib), i.e. of formula (I), where X represents aminogroup, an oxygen atom or a sulfur atom.

In Stage A1 obtain the connection formula (Ia), i.e. of formula (I), where X represents an imino group, an oxygen atom or a sulfur atom, and n = 0, by reaction of compounds of General formula (II) with a compound of General formula (III) in a solvent or without solvent, in the presence or absence of a base.

The base used in this stage may be, for example, alkali metal hydride such as lithium hydride, sodium hydride, or potassium hydride; amides of alkali metals such as lithium amide, sodium amide or potassium amide; carbonates of alkali metals such as sodium carbonate, potassium carbonate, or lithium carbonate, alkoxides of alkali metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium, or ataxic lithium; or organic amines such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, picoline, 4-(N, N-dimethylamino)pyridine; 2,6-di(tert-butyl)-4-methylpyridin; quinoline; N,N-dimethylaniline, N,N-diethylaniline; 1,5-diabetico [4.3.0] non-5-ene (DBN); 1,4-diazabicyclo[2.2.2 the La (especially tert-piperonyl potassium). This reaction proceeds in the absence of base. For more efficient completion of the reaction, it can be carried out in the presence of salts of Quaternary ammonium bases, such as chloride of benzyltriethylammonium or tetrabutylammonium chloride, or crown ethers such as 18-crown-6 or dibenzo-18-crown-6, etc.

The nature of the solvent used in this stage is not critical, provided that the solvent does not adversely influence the reaction. Examples of suitable solvents can serve as aliphatic hydrocarbons, such as hexane, heptane, ligroin, or petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons,

such as dichloromethane, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene, or dichlorobenzene; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or dimethyl ether of diethylene glycol; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone or cyclohexanone; NITRILES, such as acetonitrile, or Isobutanol; amides, such as formamide, dimethylformamide, dimethylacetamide, N - methyl-2-pyrrolidone, or triamide, R organic solvents; however, preferred are ethers (particularly tetrahydrofuran or dioxane ).

The compound of formula (Ia) can also be obtained by reaction of compounds of formula (III), where Xa represents an oxygen atom or sulfur, with an alkali metal (preferably sodium) in the presence of a solvent (preferably, a simple ether) to obtain the corresponding alcoholate or thiolate, and subsequent reaction of the resulting product with the compound of the formula (II).

The reaction temperature is usually from 0o250oC (preferably from room temperature to 200oC). The time required for the reaction varies depending on the reaction temperature and other factors and ranges from 1 minute to 50 hours, preferably, from 5 minutes to 30 hours).

In the case when the reagent is used as a compound of the formula (II), where R1represents alkenylphenol or alkyl groups, the compound obtained of the formula (Ia) can then be transformed into isomer by isomerization.

After completion of the reaction, the desired compound of formula (Ia) can be isolated from the reaction mixture by standard methods. For example, one such method; and distillation of the solvent under reduced pressure; or, after removal of the solvent under reduced pressure, adding water to the residue; the extraction is not miscible with water, an organic solvent, such as ethyl acetate; drying the extract with anhydrous magnesium sulfate, or so forth; and finally, the distillation of the solvent. If necessary, the resulting product may be purified by standard methods such as recrystallization, column chromatography, etc.

In Stage A2, the compound of formula (Ib), i.e. the compound of formula (I), where X represents an imino group, an oxygen atom or a sulfur atom, m = m' and n = n' (m' and n' are defined above), get through the reaction of compounds of formula (Ia) with an oxidant in the presence of an inert solvent.

Examples of suitable oxidizing agents can serve nagkalat such as peracetic acid, natantia acid, or m-chlorbenzene acid; hydrogen peroxide; or a salt of an alkali metal, such as meta-perchlorate sodium meta-periodate sodium or meta-periodate potassium; preferably, nagkalat or hydrogen peroxide; and particularly preferably, m-chlorbenzene acid.

The nature of the solvent used at this stage, is not the crucial is to meet the initial connection to a certain degree. Examples of suitable solvents are hydrocarbons, such as hexane, benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, dichloromethane, chlorobenzene or dichlorobenzene; alcohols such as methanol, ethanol, propanol or butanol; esters such as ethyl acetate, butyl acetate or ethylpropane; carboxylic acids, such as acetic acid or propionic acid; water; and mixtures of two or more of these solvents; however, preferred are halogenated hydrocarbon (particularly dichloromethane or chloroform), or carboxylic acids (especially acetic acid).

The reaction temperature is usually -20 to 150oC (preferably from 0o100oC). The time required for the reaction varies depending on the reaction temperature and other factors, but usually, it is from 10 minutes to 5 hours, preferably from 20 minutes to 2 hours).

After completion of the reaction, the desired compound of formula (Ib) can be isolated from the reaction mixture by standard methods. For example, one such technique involves removing insoluble substances (if present) is of Italia under reduced pressure, adding water to the residue; the extraction is not mixed with water with an organic solvent such as ethyl acetate; drying the extract with anhydrous magnesium sulfate, or so forth; and finally, the distillation of the solvent. If necessary, the resulting product may be purified by standard methods such as recrystallization, column chromatography, etc.

Method B is an alternative method of obtaining the compounds of formula (Ia).

In Stage B1, the compound of formula (Ib) are obtained by reaction of compounds of General formula (IV) with a compound of General formula (V) in an inert solvent or without solvent, in the presence or absence of a base. This reaction can be carried out in a manner analogous to the method of carrying out the reaction in Stage A1 Method A.

Method C involves the production of compounds of formula (Ic) and (Id), i.e. compounds of formula (I), where X represents a methylene group.

In Stage C1, the compound of formula (Ic) are obtained by reaction of compounds of formula (VI) with hydrazine or its hydrate in an inert solvent.

In this stage can be used as a solvent, in fact, of any nature, provided that it has no adverse Vozdvizhenka are ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, or dimethyl ether of diethylene glycol; alcohols, such as methanol, ethanol, propanol or butanol; carboxylic acids, such as acetic acid or propionic acid; amides, such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone or triamide hexamethylphosphoric acid; amines, such as triethylamine or pyridine; and water; however, the preferred solvents are alcohols (especially ethanol) or carboxylic acids (especially acetic acid).

The reaction temperature is usually from -50oC to 150oC (preferably from -10o100oC). The time required for the reaction varies depending on the reaction temperature and other factors, but usually, it is from 10 minutes to 12 hours (preferably from 30 minutes to 5 hours).

After completion of the reaction, the desired compound of formula (Ic) can be isolated from the reaction mixture by standard means. For example, one such method involves removing insoluble substances (if present) by standard filtration; and the distillation of the solvent at lower deshima of water with an organic solvent, such as ethyl acetate; drying the extract with anhydrous magnesium sulfate, or so forth; and finally, the distillation of the solvent. If necessary, the resulting product may be purified by standard methods such as recrystallization, column chromatography, etc.

In Stage C2, the compound of formula (Id), i.e. the compound of formula (I), where X represents a methylene group, m = m' and n = n' (m' and n' are defined above), get through the reaction of compounds of formula (Ic) with an oxidant in the presence of an inert solvent; moreover, this stage can be carried out in a manner analogous to the method of stage A2.

The initial compounds of the formula (II), (IV) and (VI) can be easily obtained by, arranged in the following pattern:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
In the above formulas: R1, R2, R3, R4, R5, A, Xa, Y and Z are defined above;

R6represents a C1-C6is an alkyl group;

R7represents aminosidine group, preferably tert-butoxycarbonyl group; C6-arylmethyl group, such as benzyl p-methoxybenzyl or p-brombenzene group; or (C6-arylethoxysilanes GPU; and

M represents an alkali metal such as lithium, sodium or potassium (preferably sodium).

Method D provides for compounds of formula (II).

In Stage D1, the compound of General formula (VIII) are obtained by reaction of compounds of General formula (VII) with a reagent of Vilsmeier, such as phosphorus oxychloride - dimethylformamide, oxybromide phosphorus - dimethylformamide, or oxalicacid - dimethylformamide in an inert solvent (for example, a halogenated hydrocarbon, such as dichloromethane, chloroform, carbon tetrachloride or 1,2-dichloroethane; or amide, such as dimethylformamide) at a temperature of from -10o150oC (preferably from 0o100oC) during the period of time from 15 minutes to 12 hours (preferably from 30 minutes to 5 hours).

In Stage D2, the compound of General formula (X) are obtained by reaction of compounds of formula (VIII) with a compound of General formula (IX) in an inert solvent (for example, aromatic hydrocarbons such as benzene or toluene; halogenated hydrocarbons, such as dichloromethane or chloroform; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran or dioxane; alcohols, such as metalman or pyridine) in the presence of a base (for example, organic amine such as triethylamine or pyridine) at a temperature of from 10o150oC (preferably from 0o50oC) during the period from 30 minutes to 24 hours (preferably from 1 hour to 10 hours).

In Stage D3 receives the connection of General formula (XI). The compound of formula (XI), where R4is a hydrogen atom, can be obtained by reaction of compounds of formula (X) with the reaction of Vilsmeier in a manner analogous to the method of carrying out the reaction in Stage D1. The compound of formula (XI), where R4represents a C1-C6is an alkyl group, can be obtained by reaction of compounds of formula (X) with an acid anhydride or halogenerator formula

(Ra4CO)2O or Ra4COY

(where Y is defined above, and Ra4represents a C1-C6is an alkyl group) in an inert solvent (e.g. an aromatic hydrocarbon such as benzene, toluene or nitro benzene; halogenated hydrocarbon, such as dichloromethane, harmatan, chloroform, carbon tetrachloride or 1,2-dichloroethane; or carbon disulfide in the presence of a Lewis acid (e.g. aluminum chloride, tin chloride (4) or zinc chloride) at a temperature of from 10o

In Stage D4, the compound of General formula (XII) are obtained by reaction of compounds of formula (XI) with hydrazine or its hydrate in an inert solvent in a manner analogous to the method of carrying out the reaction in Stage C1 of the method C described above.

In Stage D5 compound of formula (III) are obtained by reaction of compounds of formula (XII) with a halogenation reagent (such as phosphorus oxychloride, oxybromide phosphorus, accelerated, thionyl chloride, pentachloride phosphorus or pentabromide phosphorus) in an inert solvent (for example, halogenosilanes hydrocarbon, such as dichloromethane or chloroform; simple ether, such as diethyl ether, tetrahydrofuran or dioxane; amide, such as dimethylformamide or dimethylacetamide; or a sulfoxide such as dimethyl sulfoxide) or without solvent, at temperatures from 10o150oC (preferably from 50o120oC) during the period of time from 30 minutes to 12 hours (preferably from 1 hour to 5 hours).

Method E provides for compounds of formula (IV). In Stage E1, the compound of General formula (Xa) are obtained by reaction of compounds of General formula (VIII) with a compound of General formula (IXa) in a manner analogous to the way Allow (Xb) by removing aminosidine group of compounds of formula (Xa).

If aminosidine group is tert-butoxycarbonyl group, this group can be removed by treatment with acid (for example, inorganic acid such as hydrogen chloride, hydrochloric acid, sulfuric acid or nitric acid; or an organic acid such as acetic acid, triperoxonane acid, methanesulfonate acid or p-toluensulfonate acid) in an inert solvent (for example, halogenated hydrocarbon, such as dichloromethane, chloroform or carbon tetrachloride; or simply ether, such as tetrahydrofuran or dioxane) at a temperature of from -10o100oC (preferably from -5o50oC) during the period of time from 5 minutes to 48 hours (preferably from 30 minutes to 10 hours).

If aminosidine group is C6arylmethylidene or C6armletaccessory group, this group can be removed by reaction with hydrogen at a pressure of from 1 to 10 atmospheres in the presence of a catalyst (such as palladium-on-charcoal, palladium black, platinum oxide, platinum black, or etc., and preferably palladium-on-coal) in an inert solvent (e.g. an alcohol, such as methanol, ethanol or isoproterenol) at a temperature of from 0o100oC (preferably from 20oup to 70oC) during the time from 5 minutes to 48 hours (preferably from 1 hour to 24 hours).

In Stage E3 compound of General formula (XIa) is obtained by acylation of compounds of formula (Xb) in a manner analogous to the method of carrying out the reaction in Stage D3 Method described above.

In Stage E4, the compound of General formula (XIIa) are obtained by reaction of compounds of formula (XIa) with hydrazine or its hydrate in a manner analogous to the method of carrying out the reaction in Stage C1 of the Method C described above.

In Stage E5 compound of General formula (IIa) are obtained by reaction of compounds of formula (XIIa) with a halogenation reagent in a manner analogous to the method of carrying out the reaction in Stage D5 Method D described above.

In Stage E6 compound of General formula (IV) are obtained by reaction of compounds of formula (IIa) with the compound of the formula (III) in a manner analogous to the method of carrying out the reaction in Stage A1 to Method A described above.

Method F provides for compounds of formula (Xc), which is an intermediate compound in Method E, that is, the compound (Xb), where each of R2and R3is a methyl group.

BEM General formula (XIII) in an inert solvent (for example, in a hydrocarbon solvent such as hexane, benzene or toluene: simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; or amide, such as dimethylformamide or dimethylacetamide) in the presence of a base (e.g. alkali metals such as lithium, sodium or potassium; hydrides of alkali metals such as lithium hydride, sodium hydride or potassium hydride, amides of alkali metals such as lithium amide, sodium amide or potassium amide; or alkoxides of alkali metals, such as ataxic lithium, sodium methoxide, ethoxide or sodium tert-piperonyl potassium) at a temperature of from 10o100oC (preferably from 0o50oC) during the period of time from 30 minutes to 48 hours (preferably from 2 to 20 hours).

In Stage F2 compound of General formula (XVI) are obtained by reaction of compounds of General formula (XV) with a nitrile of an alkali metal (e.g. sodium nitrile, nitrile sodium, potassium or nitrile, etc.) in an inert solvent (for example, in a simple ether, such as diethyl ether, tetrahydrofuran, dioxide or dimethoxyethane; carboxylic acid such as acetic acid or propionic kislotoupornyh solvent) at a temperature of from - 20o50oC (preferably from 0o20oC) during the period of time from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours).

In Stage F3 compound of formula (Xc) are obtained by reaction of compounds of formula (XVI) with the compound of the formula (XIV) in an inert solvent (for example, in a simple ether, such as diethyl ether, tetrahydrofuran, dioxane or dimethoxyethane; carboxylic acid such as acetic acid or propionic acid; amide, such as dimethylformamide or dimethylacetamide; water or in mixtures of two or more of these solvents) in the presence of a reducing agent (for example, zinc, tin, iron, or etc.) at a temperature of 20o150oC (preferably from 50o100oC) during the period of time from 30 minutes to 10 hours (preferably from 1 hour to 5 hours).

Method G is an alternative method of obtaining the compounds of formula (XI), which is an intermediate compound in Method D.

In G1 Phase compound of formula (XI) are obtained by reaction of compounds of General formula (XIa) with the compound of the formula (V) in a manner analogous to the method of carrying out the reaction in Stage B1 of the Method B described above.

In Stage H2 compound of General formula (XX) are obtained by reaction of compounds of formula (XIX) with a compound of formula (V) in a manner analogous to the method of carrying out the reaction in Stage B1 of the Method B described above.

In Stage H3 receive the compound of General formula (VI). The compound of formula (VI), where R4is a hydrogen atom, can be obtained by reaction of compounds of formula (XX) with a reagent of Vilsmeier in a manner analogous to the method of carrying out the reaction in Stage D1 Method D described above. Connection formally the compounds of formula (XX) with the compound, having the formula (Ra4CO)2O or Ra4COY (where Ra4and Y defined above), in a manner analogous to the method of carrying out the reaction in Stage D3 Method D described above, and the subsequent reaction of the obtained product with a reagent of Vilsmeier in a manner analogous to the method of carrying out the reaction in Stage D1 Method D described above.

Method I involves obtaining the compounds of formula (IX), which is a starting compound in Method D.

In Stage II, the compound of formula (IX) are obtained by reaction of compounds of General formula (XXI) with a compound of General formula (XXII) in an inert solvent (for example, in a hydrocarbon solvent such as hexane, benzene or toluene; halogenated hydrocarbon solvent such as dichloromethane or chloroform; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane or dimethoxyethane; a ketone such as methyl ethyl ketone or acetone; amide, such as dimethylformamide or dimethylacetamide; or a sulfoxide such as dimethyl sulfoxide) in the presence or in the absence of a base (e.g. carbonate of an alkali metal such as lithium carbonate, sodium carbonate, or potassium carbonate;in picoline or 4-(N,N-dimethylamino)pyridine) at a temperature of from -10o150oC (preferably from 0oC to 100oC) during the period of time from 30 minutes to 48 hours (preferably from 1 hour to 20 hours).

Method J provides for compounds of General formula (IXa), which is a starting compound in Method E.

In Stage J1 compound of formula (IXa) are obtained by reaction of compounds of General formula (XXIII) with a compound of General formula (XXIV) in a manner analogous to the method of carrying out the reaction in Stage II Method I described above.

The compound of formula (Ia), (Ib), (Ic), (Id), (II), (VI), (X), (XI) or (XII), where R1represents halogenating group, can be dehydrohalogenated, if necessary, by treatment with base (e.g. an organic amine such as DBN, DBU, DABCO, or etc.) in an inert solvent (for example, a simple ether, such as diethyl ether, tetrahydrofuran or dioxane) at a temperature of from 0o150oC (preferably from 50o100oC) during the period of time from 30 minutes to 20 hours (preferably from 1 hour to 10 hours) to obtain alkenylphenol derived.

After completion of the reaction every need soedinenie: remove insoluble substances, if they are present, by standard filtration, and distillation of the solvent under reduced pressure; or after removal of the solvent under reduced pressure, adding water to the residue, extraction is not miscible with water with an organic solvent such as ethyl acetate, drying of the extract with anhydrous magnesium sulfate and so on; finally, the distillation of the solvent. If necessary, the resulting product may be purified by standard methods such as recrystallization, column chromatography, etc.

Derivatives pyrrolopyridine of the present invention have a high activity, suppressing the secretion of gastric juice; protective activity in relation to the gastric mucosa; and antibacterial activity against Helicobacter pylori. Therefore, these derivatives can be used as preventive and therapeutic agents for the prevention or treatment of peptic ulcer diseases, such as peptic ulcer, acute or chronic gastric ulcer, duodenal ulcer, gastritis, reflux esophagitis, gastrointestinal areflexia, dispersion, increased acidity of gastric juice, syndrome Zollinger - Ellison and so on; as well as profilactics is DSTV against Helicobacter pylori.

As mentioned above, derivatives pyrrolopyridine (I) of the present invention have a high activity, suppressing the secretion of gastric juice, and so on, and so they are a valuable prophylactic or therapeutic means for the prevention or treatment of peptic ulcer disease. Derivatives pyrrolopyridine (I) used as a preventive or therapeutic agents for the prevention or treatment of peptic ulcer disease, may be withdrawn orally, e.g. in the form of tablets, capsules, granules, powders, syrups, etc.; or parenterally, e.g. by injection. These drugs can be obtained by conventional methods using appropriate additives, including fillers such as lactose, mannitol, corn starch, crystalline cellulose, etc.,; binding agents such as derivatives of cellulose, Arabic gum, gelatin, etc. ; disintegrators such as calcium carboxymethyl cellulose, etc.; oiling agents, such as talc, magnesium stearate, etc. stabilizatory; corrigentov; solvents for injection, such as water, ethanol, glycerol, etc., the Dose may vary depending on the symptoms, the patient's age and so on , but the OS is set entered as a single or divided doses).

The present invention is illustrated in more detail by the following Examples, Comparative examples and Experimental examples. However, these examples should not be construed as limiting the scope of the invention.

Example 1

1-(2-Butenyl)-7-(4-forbindelse)-2,3-dimethylpyrrole[2,3-d] pyridazin

To a solution of 0.48 g (0,0038 mmol) 4-fermentelos alcohol and 0.08 g (0,0003 mol) of 18-crown-6 in 30 ml of tetrahydrofuran was added 0.85 grams (0,0076 mol) of tert-butyl potassium and the resulting mixture was stirred 10 min at room temperature. Then to the mixture was added 0.45 g (0,0019 mol of 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d] pyridazine and stirred for 8 hours at room temperature. After completion of the reaction, the reaction mixture was poured into ice water and the aqueous mixture was extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate, and the solvent is kept at reduced pressure. The residue was purified by column chromatography, elwira mixture (4:1) toluene and ethyl acetate. The obtained oily substance was led in hexane and received 0.39 g of 1-(2-butenyl)-7-(4-forbindelse)-2,3-dimethylpyrrole [2,3-d] pyridazine (CIS/Tran-13/87) as light brown powder. So pl.: 93 - 103oC. Mass spectrum (Cl, m/z) : 326 (M,10 - to 5.58 (m, 2H), 5,67 (s, 2H), 7,00 for 7.12 (m, 2H), 7,41 - rate of 7.54 (m, 2H), 8,97 (s, 1H).

Elemental analysis for C17H20FN3O (%);

Calculated: C 70,17; H 6,07; N 12,91;

Found: C 70,20; H 6318; N 12,84.

Example 2

7-Benzyloxy-2,3-dimethyl-1-(3-methyl-2-butenyl)pyrrolo[2,3-d] pyridazin

The target compound in the form of a white powder with a yield of 6.2% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(3-methyl-2-butenyl)pyrrolo-[2,3-d]-pyridazine and benzyl alcohol.

So pl.: 104 - 105oC. Mass spectrum (Cl, m/z): 322 (M++ 1).

The NMR spectrum (CDCl3million d): 1,60 (s, 3H), and 1.63 (s, 3H) and 2.26 (s, 3H), of 2.33 (s, 3H), to 4.98 (d, J = 6 Hz, 2H), 5,11 (t, J = 6 Hz, 2H), 5,73 (s, 2H), 7,30 - 7,42 (m, 3H), 7,50 - of 7.55 (m, 2H), 8,99 (s, 1H).

Elemental analysis for C20H23N3O: (%):

Calculated: C 74,74; H 7,21; N 13,07;

Found: C 74,74; H 7,28; N 12,99.

Example 3

7-Benzyloxy-2,3-dimethyl-1-(2-propenyl)pyrrolo [2,3-d] pyridazin

The target compound in the form of a white powder with a yield of 63.2% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d] pyridazine and benzyl alcohol.

So pl.: 115 - 116oC. Mass spectrum (Cl, m/z): 294 (M++1).

The NMR spectrum (CDCl3million d): of 2.27 (s, 3H), of 2.30 (s, 3H), br4.61 (d, J = 16 Hz 18H19N3O: (%):

Calculated: C 73,70; H 6,53; N 14,32;

Found: C 73,69; H 6,29; N 14,14.

Example 4.

7-Benzyloxy-1-cyclopropylmethyl-2,3-dimethylpyrrole[2,3-d] pyridazin

The target compound in the form of a white powder with a yield of 69.2% was obtained by the method described in Example 1, using 7-chloro-1-cyclopropylmethyl-2,3-dimethylpyrrole[2,3-d]-pyridazine and benzyl alcohol.

So pl.: 123-124oC.

Mass spectrum (Cl, m/z): 308 (M + 1).

The NMR spectrum (CDCl3) (million days ) : 0,21 - of 0.45 (m, 4H), 1.06 a - to 1.21 (m, 1H), 2,28 (s, 3H), 2,39 (s, 3H), 4,24 (d, J = 8 Hz, 2H), 5,70 (s, 2H), 7,29 - 7,56 (m, 5H), 8,99 (s, 1H).

Elemental analysis for C19H21N3O (%):

Calculated: C 74,24; H 6,89; N 13,67

Found: C 74,42; H 6,90; N 13,66.

Example 5

7-Benzyloxy-1-(2-butenyl)-2,3-dimethylpyrrole[2,3-d]pyridazin

The target compound (CIS/TRANS = 21/79) as pale-brown crystals with a yield of 78.6% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d]pyridazine (CIS/TRANS = 18/82) and benzyl alcohol.

So pl.: 81-84oC.

Mass spectrum (Cl, m/z): 308 (M + 1).

The NMR spectrum (CDCl3(million days): 1,50 - of 1.56 (m, 3H), of 2.25 (s, 3H), 2,31 (s, 3H), 4,79 - 4,91 (m, 1,58 H), equal to 4.97 is 5.07 (m, 0,42 H), 5,10 - 5,61 (m, 2H), 5,71 (s, 2H), 7,27 - 7,

Found: C 74,14; H 6,97; N 13,57.

Example 6.

7-Benzyloxy-2,3-dimethyl-1-(3-phenyl-2-propenyl)pyrrolo [2,3-d]pyridazin

The target compound (TRANS) in the form of pale brown crystals with a yield of 85.4% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(3-phenyl-2-propenyl)pyrrolo[2,3-d]pyridazine (TRANS) and benzyl alcohol.

So pl. 132-134oC.

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

The NMR spectrum (CDCl3(million days): 2,28 (s, 3H), is 2.37 (s, 3H), 5,10 (d, J = 5 Hz, 2H), 5,71 (s, 2H), 6,07 (d, J = 16 Hz, 1H), 6.22 per (dt., J = 16 Hz, 5 Hz, 1H), 7,10 - of 7.55 (m, 10H), and 9.0 (s, 1H).

Elemental analysis for C24H23N3O (%):

Calculated: C 78,02; H 6,27; N 11,37

Found: C 78,09; H 6,28; N 11,32.

Example 7

7-(4-forbindelse)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d] pyridazin

The target compound as a white powder with a yield of 22.1 per cent was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 4-fermentelos alcohol.

So pl., 125 - 126oC.

Mass spectrum (Cl, m/z): 312 (M++ 1).

The NMR spectrum (CDCl3(million days): of 2.27 (s, 3H), of 2.30 (s, 3H), to 4.62 (d, J = 14 Hz, 1H), 4,90 is equal to 4.97 (m, 2H), 5,07 (d, J = 10 Hz, 1H), 5,65 (s, 2H), 5,81 - 5,96 (m, 1H), 7,01 - 7,11 (m, 2H), 7,43 - 7,42 (m, 2H), 8,99 (s, 1H) is: C 69,23; H 5,94; N 13,45.

Example 8

7-(3-forbindelse)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d] pyridazin

The target compound as white helplearn crystals with 71.4% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d] pyridazine and 3-fermentelos alcohol.

So pl.: 85-86oC.

Mass spectrum (Cl, m/z): 312 (M++ 1).

The NMR spectrum (CDCl3(million days): 2,28 (s, 3H), 2,31 (s, 3H), 4,63 (d, J 14 Hz, 1H), 4,94 - 5,02 (m, 2H), 5,11 (d, J 10 Hz, 1H), 5,70 (s, 2H), 5,86 - 6,01 (m, 1H), 6,98-7,07 (m, 1H), 7,16 - 7,40 (m, 3H), of 9.00 (s, 1H).

Elemental analysis for C18H18FN3O (%):

Calculated: C 69,44; H of 5.83; N 13,50

Found: C 69,34; H Of 5.85; N 13,40.

Example 9

7-(2,4-Diferentiate)-2,3-dimethyl-1-(2-propenyl)pyrrolo [2,3-d]pyridazin

The target compound in the form of a white powder with a yield of 26.6% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 2,4-differenziava alcohol.

So pl. 125-126oC.

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

The NMR spectrum (CDCl3(million days): to 2.25 (s, 3H), of 2.30 (s, 3H), to 4.62 (d, J = 14 Hz, 1H), 4,90 (d, J = 5 Hz, 2H), of 5.05 (d, J = 10 Hz, 1H), 5,71 (s, 2H), 5,81 - 5,91 (m, 1H), 6,80 - of 6.90 (m, 2H), 7,51 - EUR 7.57 (m, 1H), 8,98 (C. 1H).

; to 5.21; N 12,74.

Example 10

7-(2-forbindelse)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d] pyridazin

The target compound in the form of a white powder with output = 74,8% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 4-fermentelos alcohol.

So pl., 83-84oC.

Mass spectrum (Cl, m/z): 312 (M++ 1).

The NMR spectrum (CDCl3(million days): to 2.25 (s, 3H), of 2.30 (s, 3H), 4,63 (d, J = 14 Hz, 1H), 4,89 - of 4.95 (m, 2H), 5,04 (d, J = 10 Hz, 1H), 5,77 (s, 2H), 5,81 - 5,95 (m, 1H),? 7.04 baby mortality - 7,19 (m, 2H), 7,27 - 7,38 (m, 1H), 7,51 - to 7.59 (m, 1H), 8,99 (s, 1H).

Elemental analysis for C18H18FN3O (%):

Calculated: C 69,44; H of 5.83; N 13,50

Found: C 69,42; H By 5.87; N 13,45.

Example 11

7-Benzyloxy-2,3-dimethyl-1-(2-pentenyl)pyrrolo[2,3-d] pyridazin

The target compound (TRANS) in the form of a white powder with a yield of 75,9% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-pentenyl)pyrrolo[2,3-d]pyridazine (TRANS) and benzyl alcohol.

So pl.: 92-93oC.

Mass spectrum (Cl, m/z): 322 (M++ 1).

The NMR spectrum (CDCl3(million days): of 0.95 (t, J = 12 Hz, 3H), 1,98 - 2,12 (m, 2H), and 2.26 (s, 3H), 2,31 (s, 3H), 4.92 in - 5,08 (m, 2H), 5,23 - of 5.34 (m, 1H), 5,39 - 5,52 (m, 1H), 5,71 (s, 2H), 7,28-of 7.55 (m, 5H), 8,96 (s, 1H).

Elemental Ana is example 12

7-(4-Chlorobenzoyloxy)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d] pyridazin

The target compound in the form of white crystals with a yield of 50.7% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 4-chlorobenzylamino alcohol.

So pl. 98-99oC.

Mass spectrum (Cl, m/z): 328 (M++ 3), 330 (M++ 3).

The NMR spectrum (CDCl3(million days): and 2.26 (s, 3H), 2,31 (s, 3H), to 4.62 (d, J = 14 Hz, 1H), 4,89 is equal to 4.97 (m, 2H), 5,09 (d, J = 10 Hz, 1H), to 5.66 (s, 2H), of 5.82 - 5,97 (m, 1H), 7,35 (d, J = 8 Hz. 2H), the 7.43 (d, J = 8 Hz, 2H), 8,99 (s, 1H).

Elemental analysis for C18H18ClN3O (%):

Calculated: C 65,95; H Of 5.53; N 12,82.

Found: C 65,95; H 5,56; N 12,78.

Example 13

7-Benzyloxy-2,3-dimethyl-1-vinylpyrrole[2,3-d]pyridazin

The target compound as a white powder with a yield of 59.7 per cent was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-vinylpyrrole[2,3-d]pyridazine and benzyl alcohol.

So pl., 85-86oC.

Mass spectrum (Cl, m/z): 280 (M++ 1).

The NMR spectrum (CDCl3(million days): 2,28 (s, 3H), 2,43 (s, 3H), 5,18 (d, J = 8 Hz, 1H), 5,22 (d, J = 17 Hz, 1H), 5,72 (c, 2H), 7.29 trend - EUR 7.57 (m, 6H). of 9.00 (s, 1H),

Elemental analysis for C17H17N3O (%):

Calculated: C 73,10; H 6,13; N 15,04

Found: R> The target compound in the form of white crystals with a yield of 89.3 per cent was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-methyl-2-propenyl)pyrrolo[2,3-d]pyridazine and benzyl alcohol.

So pl. 106-107oC.

Mass spectrum (Cl, m/z): 308 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,60 (s, 3H), 2.26 and (C. 6H), 4,01 (C. 1H), amounts to 4.76 (s, 1H), to 4.81 (s, 2H), to 5.66 (s, 2H), 7,30 - 7,51 (m, 5H), of 9.00 (s, 1H).

Elemental analysis for C19H21N3O (%):

Calculated: C 74,24; H 6,89; N 13,67

Found: C 74,18; H 6,92; N 13,67.

Example 15

7-Benzyloxy-2,3-dimethyl-1-(2,2,2-triptorelin)pyrrolo[2,3-d] pyridazin

The target compound in the form of a white powder with a yield of 65.2% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2,2,2-triptorelin)pyrrolo[2,3-d]pyridazine and benzyl alcohol.

So pl.: 83-84oC.

Mass spectrum (Cl, m/z): 336 (M++ 1).

The NMR spectrum (CDCl3(million days): of 2.27 (s, 3H), is 2.37 (s, 3H), 4,93 (sq, J = 9 Hz, 2H), 5,70 (s, 2H), 7,30 - 7,58 (m, 5H), 9,01 (s, 1H).

Elemental analysis for C17H16F3N3O (%):

Calculated: C 60,89; H to 4.81; N 12,53

Found: C 60,96; H Of 4.77; N 12,45.

Example 16

7-Benzyloxy-1-cyclopropyl-2,3-dimethylpyrrole[2,3-d]pyridazin

Target connection is chlorophyl-2,3-dimethylpyrrole[2,3-d]pyridazine and benzyl alcohol.

So pl.: 121-122oC.

Mass spectrum (Cl, m/z): 294 (M++ 1).

The NMR spectrum (CDCl3(million days): 0,87 - 1,10 (m, 4H), 2,22 (s, 3H), 2,43 (s, 3H), 3,18 of 3.28 (m, 1H), 5,69 (s, 2H), 7,30 - to 7.59 (m, 5H), of 8.95 (s, 1H).

Elemental analysis for C18H19N3O (%):

Calculated: C 73,69; H 6,53; N 14,33

Found: C 73,78; H 6,56; N 14,37.

Example 17

7-(2,4-Dichloraniline)-2,3-dimethyl-1-(2-propenyl)pyrrolo [2,3-d] pyridazin

The target compound in the form of white crystals with a yield of 76.5% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and 2,4-amyl-metacresol.

So pl. 98-99oC.

Mass spectrum (Cl, m/z): 361 (M+), 363 (M++ 2).

The NMR spectrum (CDCl3(million days): and 2.26 (s, 3H), 4,63 (d, J = 16 Hz, 1H), 4,91 - to 4.98 (m, 2H), 3,05 - 5,09 (d, J = 11 Hz, 1H), 5,77 (s, 2H), of 5.83 is 5.98 (m, 1H), 7,20 - 7,29 (m, 1H), 7,42 - 7,56 (m, 2H), 9,00 (s, 1H).

Elemental analysis for C18H17Cl2N3O (%):

Calculated: C 59,68; H to 4.73; N 11,60

Found: C 59,71; H 4,79; N To 11.52.

Example 18

7-Benzyloxy-1-(2-foradil)-2,3-dimethylpyrrole[2,3-d]pyridazin

The target compound in the form of white crystals with a yield 76,2% was obtained by the method described in Example 1, using 7-chloro-1-(2-foradil)-2,3-dimethylpent the P> + 1).

The NMR spectrum (CDCl3(million days): of 2.27 (s, 3H), of 2.35 (s, 3H), 4,51 (s, 2H), with 4.64 (dt., J = 21 Hz, 2H), 5,69 (s, 2H), 7,29 - 7,51 (m, 5H), 8,99 (s, 1H).

Elemental analysis for C17H18FN3O (%):

Calculated: C 68,21; H the 6.06; N 14,04

Found: C 68,05; H 6,09; N 14,03.

Example 19

7-Benzyloxy-1-)3-forproper)-2,3-dimethylpyrrole[2,3-d]pyridazin

The target compound in the form of white crystals with a yield of 71.2 percent was obtained by the method described in Example 1, using 7-chloro-1-(3-forproper)-2,3-dimethylpyrrole[2,3-d]pyridazine and benzyl alcohol.

So pl.: 100-101oC.

Mass spectrum (Cl, m/z): 314 (M++1).

The NMR spectrum (CdCl3(million days): 1,95-2,15 (m, 2H, in), 2.25 (s, 3H), of 2.35 (s, 3H), 4,23 (dt., J = 48 Hz, 6 Hz, 2H), and 4.40 (t, J= 8 Hz, 2H), 5,69 (s, 2H, 7,31-7,53 (m, 5H), 8,98 (s, 1H).

Elemental analysis for C18H20FN3O (%):

Calculated: C 68,99, H to 6.43; N 13,41

Found: C 69,05; H Of 6.52; N 13,20.

Example 20

7-Benzyloxy-1-(2,2-dottorati)-2,3-dimethylpyrrole [2,3-d]pyridazin

The target compound as a white powder with a yield of 71.6 per cent was obtained by the method described in Example 1, using 7-chloro-1-(2,2-dottorati)-2,3-dimethylpyrrole [2,3-d]pyridazine and benzyl alcohol.

So pl.: 128-131oC

Mass spectrum (Cl, m/z): 318 (M++1).

Elemental analysis for C17H17F2N3O (%):

Calculated: C 64,34; H of 5.40; N 13,24

Found: C 64,35; H 5,33; N 13,11.

Example 21

1-(2-Butenyl)-7-(2,4-dichloraniline)-2,3-dimethylpyrrole[2,3-d] pyridazin

The target compound (CIS/TRANS)=25/75) in the form of white crystals with access to 72.4% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethyl-pyrrolo[2,3-d] pyridazine (CIS/TRANS=21/79) and 2,4-amyl-metacresol.

So pl.: 133-134oC.

Mass spectrum (Cl, m/z): 376 (M++1), 378 (M++3), 380 (M++5).

The NMR spectrum (CDCl3(million days): 1,56-to 1.67 (m, 3H), and 2.26 (s, 3H), 2,32 (S, 3H), 4,82-4,89 (m, 1.5 H), 5,00-of 5.05 (m, 0.5 H), 5,16-a 5.25 (m, 0,75 H), 5,30 of 5.39 (m, 0,25 H), 5,47-the ceiling of 5.60 (m, 1H), 5,80 (s, 2H), 7,20-7,27 (m, 1H), 7,43 (s, 1H), 7,50-7,56 (m, 1H), 8,97 (s, 1H)

Elemental analysis for C19H19Cl2N3O (%):

Calculated: C 60,65; H 5,09; N 11,17

Found: C 60,76; H 5,10; N 11,14.

Example 22

1-(2-Butenyl)-7-(2,4-deferasirox)-2,3-dimethylpyrrole [2,3-d] pyridazin

The target compound (CIS/TRANS = 18/82) in the form of a pale yellow powder with a yield of 43.1% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole [2,3-d]pyridazine (CIS/TRANS = 21/79) and 2,4-differenziava alcohol.

Elemental analysis for C19H19F2N3O(%):

Calculated: 66.46; H 5,58; N 12,24

Found: C 66,56; H 5,56; N 12,15.

Example 23

7-Benzyloxy-1-cyclohexyl-2,3-dimethylpyrrole[2.3-d]pyridazin

The target compound in the form of a white powder with output = 92,8% was obtained by the method described in Example 1, using 7-chloro-1-cyclohexyl-2,3-dimethylpyrrole[2,3-d] pyridazine and benzyl alcohol.

So pl.: 174-177oC.

Mass spectrum (Cl, m/z): 336 (M++1).

The NMR spectrum (CDCl3(million days): 1,10-of 1.44 (m,2H), 1,48-of 2.08 (m, 4H), to 1.76 (s, 3H), 2.13 and at 2.59 (m, 4H), and 2.27 (s, 3H), 3,91-4,19 (m, 1H), 5,70 (s, 2H), 7,29-7,66 (m, 5H), of 8.95 (s, 1H).

Elemental analysis for C21H25N3O (%):

Calculated: C 75,19, H 7,51; N 12,53

Found: C 75,17; H 7,63; N 12,50.

Example 24

7-(4-forensics)-2,3-dimethyl-1-(3-phenyl-2-propenyl)pyrrolo [2,3-d[pyridazin

The target compound (TRANS) in the form of pale yellow crystals with a yield of 47.7% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(3-phenyl-2-propenyl)pyrrolo[2,3-d] pyridazine (TRANS) and 4-fermentelos alcohol.

So pl.: 124-126oC
< (C, 2H), 6,03 (d, J= 17 Hz, 1H), 6,20 (dt., J = 17 Hz, 5 Hz, 1H), 6,91-7,51 (m, 9H), of 9.00 (s, 1H).

Elemental analysis for C24H22FN3O (%):

Calculated: C 74,40, H 5,72; N 10,85

Found: C 74,65; H Of 5.75; N 10,75.

Example 25

2,3-Dimethyl-1-(2-propenyl)-7-(4-triftormetilfosfinov)pyrrolo [2,3-d] -pyridazin

The target compound in the form of pale yellow crystals with a yield of 52.5% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]-pyridazine and 4-triftormetilfosfinov alcohol.

So pl.: 95-96oC.

Mass spectrum (Cl, m/z): 362 (M++1).

The NMR spectrum (CDCl3(million days): of 2.27 (s, 3H), 2,32 (s, 3H), 4,63 (d, J= 16 Hz, 1H), 4,96 (d, J = 4 Hz, 2H), 5,10 (d, J= 10 Hz, 1H), of 5.75 (s, 2H), by 5.87-6,00 (m, 1H), 7,46 for 7.78 (m, 4H), of 9.00 (s, 1H).

Elemental analysis for C19H18F3N3O(%):

Calculated: C 63,15; H 5,02; N 11,63

Found: C 63,23; H 5,02; N 11,66.

Example 26

7-(4-forbindelse)-2,3-dimethyl-1-(2-methyl-2-propenyl)pyrrolo [2,3-d] pyridazin

The target compound in the form of a grayish-white powder with a yield of 38.7% was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-methyl-2-propenyl) pyrrolo[2,3-d] -pyridazine and 4-fermentelos alcohol.

So pl.: 118-120oC.

Man) 5,61 (s, 2H), 7,01-7,11 (m, 2H), 7,41-to 7.50 (m, 2H), 8,99 (s, 1H).

Elemental analysis for C19H20FN3O (%):

Calculated: C 70,13; H 6,20; N 12,91.

Found: C 70, 29; H 6,28; N 12,68.

Example 27

7-Benzyloxy-3-ethyl-2-methyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin

The target compound in the form of powder with output = 97,0% was obtained by the method described in Example 1, using 7-chloro-3-ethyl-2-methyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and benzyl alcohol.

So pl. 82-83oC.

Mass spectrum (Cl, m/z): 308 (M++1).

The NMR spectrum (CDCl3million d): 1,22 (t, J = 8 Hz, 3H), 2,32 (s, 3H), 2,73 (sq , J = 8 Hz, 2H), br4.61 (d, J = 18 Hz, 1H), 4,91-4,99 (m, 2H), 5,08 (d, J= 10 Hz, 1H), 5,70 (s, 2H), of 5.83-6,00 (m, 1H), 7,27-7,53 (m, 5H), 9,03 (s, 1H).

Elemental analysis for C19H21N3O(%):

Calculated: C 74,24; H 6,89; N 13,67.

Found: C 74,33; H 6,99; N 13,61.

Example 28

1-(2-Butenyl)-2,3-dimethyl-7-(2-thienylmethyl)pyrrolo[2,3-d] pyridazin

The target compound (CIS/TRANS = 20/80) in the form of a grayish-white powder with a yield of 20.6% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d] pyridazine (CIS/TRANS=20/80) and 2-thiophenemethyl.

So pl.: 72-75oC.

Mass spectrum ( Cl, m/z): 314 (M+= 1).

Elemental analysis for C17H19N3OS (%):

Calculated: C 65,15; H 6,11; N 13,41

Found: C 65,13; H 6,12; N 13,38.

Example 29

1-(2-Butenyl)-7-(4-forbindelse)-2,3-dimethylpyrrole[2,3-d] pyridazin

The target compound (CIS/TRANS=98/2) as pale-brown crystals with a yield of 59.3% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole[2.3-d] pyridazine (CIS/TRANS =94/6) and 4-fermentelos alcohol.

So pl.: 108-112oC.

Mass spectrum (Cl, m/z): 326 (M++1).

The NMR spectrum (CDCl3(million days): 1,58 by 1.68 (m, 3H), and 2.26 (s, 3H), 2,31 (s, 3H), of 4.83-4,89 (m 0,04 H), equal to 4.97-5,04 (m, 1,96 H) of 5.29-ceiling of 5.60 (m, 2H), of 5.68 (s, 2H), 7,00-7,52 (m, 4H), 8,97 (s, 1H).

Elemental analysis for C19H20FN3O (%):

Calculated: C 70,14; H 6,20; N 12,91

Found: C 69,95; H 6,22; N 12,90.

Example 30

7-Benzyloxy-1-(2-chloro-2-propenyl)-2,3-dimethylpyrrole [2,3-d]pyridazin

The target compound in the form of a white powder with a yield of 10.9% was obtained by the method described in Example 1, using 7-chloro-1-(2-chloro-2-propenyl)-2,3-dimethylpyrrole[2,3-d]pyridazine and benzyl alcohol.

So pl.: 88 - 90oC.

Mass spectrum (Cl, m/z): 374 (M++ 1), 330 (M+with, 1H).

Elemental analysis for C18H18ClN3O (%):

Calculated: C 65,95; H 5,54; N 12,82

Found: C Of 66.00; H 5,51; N 12,74.

Example 31

1-(2-Butenyl)-7-(4-differentoccasions)-2,3-dimethylpyrrole [2,2-d] pyridazin

The target compound (CIS/TRANS = 21/79) in the form of a white powder with a yield of 37.8% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d]pyridazine (CIS/TRANS = 20/80) and 4-differentoccasions alcohol.

So pl.: 109 - 110oC.

Mass spectrum (Cl, m/z): 328 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,56 by 1.68 (m, 3H), of 2.25 (s, 3H), of 2.33 (s, 3H), 4,84 - 4,89 (m, 1,58 H), 5,00 - 5,04 (m, 0,42 H), 5,14 - a 5.25 (m, H 0,79), 5,30 is 5.38 (m, 0,21 H), the 5.45 ceiling of 5.60 (m, 1H), 5,69 (s, 2H), of 6.52 (t, J = 51 Hz, 1H), 7,13 (doctor J = 8 Hz, 2H), 7,51 (doctor J = 8 Hz, 2H), 8,97 (s, 1H).

Elemental analysis for C20H21F2N3O2(%):

Calculated: C 64,43; H 5,67; N 11,25

Found: C 64,28; H To 5.57; N 11,32.

Example 32

1-(2-Butenyl)-2,3-dimethyl-7-(3-pyridylmethylene)pyrrolo [2,3-d]pyridazin

The target compound (CIS/TRANS = 22/78) as a pale yellow powder with a yield of 45.9 per cent was obtained by the method described in Example 1 using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d]pyridazine (CIS/TRANS = 20/80) and 3-pyridinemethanol.

Elemental analysis for C18H20N4O (%):

Calculated: C 70,11; H is 6.54; N 18,17

Found: C 69,83; H 6,51; N 18,08.

Example 33

1-(2-Butenyl)-2-ethyl-7-(4-forbindelse)-3-methylpyrrole [2,3-d]pyridazin

The target compound (TRANS) in the form of a white powder with a yield of 41.7% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2-ethyl-3-methylpyrrole[2,3-d] pyridazine (CIS/TRANS = 4/96) and 4-fermentelos alcohol.

So pl.: 74 - 76oC.

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

The NMR spectrum (CDCl3(million days): 1,20 (t, J = 8 Hz, 3H), 1,59 (D., J = 7 Hz, 3H), of 2.28 (s, 3H), 2,75 (sq, J = 8 Hz, 2H), 4,81 - of 4.90 (m, 2H), 5.08 to of 5.26 (m, 1H), 5,42 - to 5.57 (m, 1H), to 5.66 (s, 2H), 7,07 (t, J = 9 Hz, 2H), 7,49 (DD. J = 7 Hz and 9 Hz, 2H), 8,98 (s, 1H).

Elemental analysis for C20H22FN3O (%):

Calculated: C 70,77; H 6,53; N 12,38

Found: C 70,78; H 6,44; N 12,34.

Example 34

7-(4-Forbesii)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-3d] pyridazin

The target compound in the form of a pale yellow powder with a yield of 61.6% was obtained by the method described in Example 1, using 7-chloro-2,3-Dimas-spectrum (Cl, m/z): 328 (M++ 1).

The NMR spectrum (CDCl3(million days): of 2.27 (s, 3H), 2,31 (s, 3H), 4,48 (d, J = 16 Hz, 1H), 4.72 in (s, 2H), 5,00 - 5,10 (m, 2H), 5,12 (doctor J = 10 Hz, 1H), 5,88 - of 6.02 (m, 1H), 6.90 to - 7,00 (m, 2H), 7,37 - 7,47 (m, 2H), 9,07 (s, 1H).

Elemental analysis for C18H18FN3O (%):

Calculated: C 66,04; H 5,54; N 12,83

Found: C 66,45; H 5,54; N 12,58.

Example 35

1-Cyclopropylmethyl-7-(4-forbindelse)-2,3-dimethylpyrrole [2,3-d] pyridazin

The target compound as a white powder with a yield of 74.1 per cent was obtained by the method described in Example 1, using 7-chloro-1-cyclopropylmethyl-2,3-dimethylpyrrole[2,3-d]pyridazine and 4-fermentelos alcohol.

So pl.: 137 - 138oC.

Mass spectrum (Cl, m/z): 326 (M++ 3).

The NMR spectrum (CDCl3(million days): 0,21 is 0.27 (m, 2H), 0,38 - 0,45 (m, 2H), 1,05 - 1,20 (m, 1H), 2,28 (s, 3H), 2,39 (s, 3H), 4,22 (d, J = 8 Hz, 2H), to 5.66 (s, 2H), 7,05 for 7.12 (m, 2H), of 7.48 - 7,53 (m, 2H), 8,99 (s, 1H).

Elemental analysis for C19H20FN3O (%):

Calculated: C 70,13; H 6,20; N 12,91

Found: C 70,22; H 6,24; N 12,89.

Example 36

1-(2-Butenyl)-7-furfurylamine-2,3-dimethylpyrrole[2,3-d]pyridazin

The target compound (CIS/TRANS = 15/85) as a white colorless powder with a yield of 12.2% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-deletes-spectrum (Cl, m/z): 298 (M++ 3).

The NMR spectrum (CDCl3(million days): 1,58 - of 1.65 (m, 3H), of 2.25 (s, 3H), 2,32 (s, 3H), 4,82 - 4,84 (m, 1,64 H), 4,98 - 5,00 (m, H 0,36), 5,28 to 5.35 (m, 1H), 5,44 - 5,49 (m, 1H), to 5.66 (s, 2H), 6,38 - to 6.39 (m, 1H), 6,51 (s, 1H), 7,44 (s, 1H), 8,95 (s, 1H).

Elemental analysis for C17H19N3O2(%):

Calculated: C 68,67; H 6,44; N 14,13;

Found: C 68,45; H Of 6.52; N 14,14.

Example 37

1-Cyclohexylmethyl-7-(4-forbindelse)-2,3-dimethylpyrrole[2,3-d] pyridazin

The target compound in the form of a white powder with output = 45,6% was obtained by the method described in Example 1, using 7-chloro-1-cyclohexylmethyl-2,3-dimethylpyrrole[2,3-d]pyridazine and 4-fermentelos alcohol.

So pl.: 108 - 109oC.

Mass spectrum (Cl, m/z): 368 (M++ 1).

The NMR spectrum (CDCl3(million days): 0,77 - of 0.90 (m, 2H), 0,93 - of 1.09 (m, 3H), 1,24 - of 1.32 (m, 2H), 1.56 to to 1.67 (m, 4H), of 2.25 (s, 3H), 2,32 (s, 3H), 4,01 (d, J = 7 Hz, 2H), 5,63 (s, 2H), was 7.08 (t, J = 6 Hz, 2H), 7,50 (DD. J = 6 Hz, 3 Hz, 2H), 8,96 (s, 1H).

Elemental analysis for C22H26FN3O (%):

Calculated: C 71,90; H to 7.09; N 11,44

Found: C 71,71; H 7,05; N 11,19.

Example 38

1-(2-Butenyl)-7-(2,6-deferasirox)-2,3-dimethylpyrrole- [2,3-d] pyridazin

The target compound (CIS/TRANS = 22/78) in the form of a white powder with a yield of 58.3% was obtained by the method described in Example 1, with the.

So pl.: 85 - 94oC.

Mass spectrum (Cl, m/z): 344 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,46 - to 1.60 (m, 3H), and 2.26 (s, 3H), 2,31 (s, 3H), 4,65 - 4,79 (m, 1,56 H), a 4.86 - 4,94 (m, 044H),5,09-5,51 (m, 2H), 5,78 (s, 2H), 6.87 in-7,02 (m, 2H), 7,27-7,42 (m, 1H), 8,98 (s, 1H).

Elemental analysis for C19H19F2N3O (%):

Calculated: C 66,46; H 5,58; N 12,24

Found: C 66,13; H The 5.45; N 12,25.

Example 39

1-(2-Butenyl)-7-(3,5-deferasirox)-2,3-dimethylpyrrole[2,3-d] pyridazin

The target compound (CIS/TRANS= 29/71) in the form of a white powder with a yield of 41.6% were obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d]pyridazine (CIS/TRANS=24/76) and 3,5-differenziava alcohol.

So pl.: 78-84oC.

Mass spectrum (Cl, m/z): 344 (M++1).

The NMR spectrum (CDCl3(million days): 1,51 to 1.76 (m, 3H), and 2.27 (s, 3H), of 2.34 (s, 3H), of 4.83-4,96 (m, 1,42 H), 5,01-5,10 (m 0,58 H), 5,11-of 5.75 (m, 2H), 5,70 (s, 2H), 6,67-PC 6.82 (m, 1H), 6,93-7,10 (m, 2H), 9,98 (s, H).

Elemental analysis for C19H19F2N3O (%):

Calculated: C 66,46; H 5,58; N 12,24;

Found: C 66,28; H 5,58; N 12,20.

Example 40

1-(2-Butenyl)-7-(2-chloro-6-forbindelse)-2,3-dimethylpyrrole [2,3-d] pyridazin

The target compound (CIS/TRANS=21/79) as pale-brown powder with a yield of 57.6% polarons=24/76) and 2-chloro-6-fermentelos alcohol.

So pl.: 103-112oC.

Mass spectrum (Cl, m/z); 360 (M++1), 362 (M++3).

The NMR spectrum (CDCl3(million days): 1,41 is 1.58 (m, 3H), of 2.25 (s, 3H), of 2.30 (s, 3H), 4,66-of 4.77 (m, 1,58 H), 4,84 to 4.92 (m, 0,42 H), 5,03-5,51 (m, 2H), a 4.83 (s, 2H), 6,99 for 7.12 (m, 1H), 7,21-7,38 (m, 2H), 8,97 (s, 1H).

Elemental analysis for C19H19ClFN3O (%):

Calculated: C 63,42; H 5,32; N 11,68.

Found: C 63,52; H Of 5.34; N 11,60.

Example 41

7-Benzyloxy-1-(3,3-dichloro-2-propenyl)-2,3-dimethylpyrrole [2,3-d] pyridazin

To a suspension consisting of 0.29 grams (0,0011 mol) of 7-benzyloxy-2,3-dimethylpyrrole[2,3-d] pyridazine and 0.03 g (0.0001 mol) of 18-CZK in 8 ml of tetrahydrofuran, was added to 0.13 g (0,0011 mol) of potassium tert-butylate and the mixture was stirred at room temperature for 40 minutes. After adding 0,22 g (0,0011 mol) 3,3-dichloro-2-propylbromide, the resulting mixture was stirred for five minutes at room temperature. Then the reaction mixture was poured into a mixture of ice and water and the aqueous mixture was extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate, and the solvent is kept at reduced pressure. The residue was purified by column chromatography on silica gel, using as eluent a mixture of chloroform and methanol (20: 1), resulting in a received 0,090.: 149-151oC.

Mass spectrum (Cl, m/z): 362 (M++1), 364 (M++3), 366 (M++5).

The NMR spectrum (CDCl3(million days): and 2.26 (s, 3H), of 2.35 (s, 3H), of 5.06 (d, J=5 Hz, 2H), 5,72 (s, 2H), 5,90 (t, J=5 Hz, 1H), 7,29-7,58 (m, 5H) 8,99 (s, 1H).

Elemental analysis for C18H17Cl2N3O (%):

Calculated: C 59,68; H to 4.73; N 11,60;

Found: C 60,06; H 4,99; N 11,32.

Example 42

7-Benzyloxy-2,3-dimethyl-1-(2-PROPYNYL)pyrrolo[2,3-d]pyridazin

The target compound in the form of a pale yellow powder with a yield of 27.4 per cent was obtained by the method described in Example 41, using 7-benzyloxy-2,3-dimethylpyrrole[2,3-d]pyridazine and 3-bromo-1-propene.

So pl.: 116-117oC.

Mass spectrum (Cl, m/z): 292 (M++1).

The NMR spectrum (CDCl3million days); and 2.26 (s, 3H), of 2.30 to 2.35 (m, 1H), 2,44 (s, 3H), 5,18 (d, J=2 Hz, 2H), 5,74 (s, 2H), 7,30-7,44 (m, 3H), 7,53-to 7.61 (m, 2H), 9,00 (s, 1H).

Elemental analysis for C18H17N3O (%):

Calculated: C 74,20; H 5,88; N 14,42.

Found: C 73,88; H Of 5.85; N 14,36.

Example 43

1-(3-Chloro-2-propenyl)-7-(4-forbindelse)-2,3-dimethylpyrrole [2,3-d]pyridazin

The target compound (CIS/TRANS=1/1) as a pale yellow powder with a yield of 31.4% was obtained by the method described in Example 41, using 7-(4-forbindelse)-2,3-dimethylpyrrole[2,3-d] Piri +
+1), 348 (M++3).

The NMR spectrum (CDCl3(million days): 2,25 (s, 1.5 H), and 2.26 (s, 1.5 H) of 2.33 (s, 1.5 H), 4,89 - 4,91 (m, 1H), 5,15 - 5,17 (m, 1H), 5,64 - 6,14 (m, 4H),? 7.04 baby mortality for 7.12 (m, 2H),7,47 - to 7.50 (m, 2H), 8,98 (m, 1H).

Elemental analysis for C18H17ClFN3O 1/4H2O (%):

Calculated: C 61,72; H 5,04; N 11,99;

Found: C 61,83; H A 4.86; N 12,04.

Example 44

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

To a solution containing 1,02 g (0,0081 mol) 4-fermentelos alcohol and 0.12 g (0,00045 mol) of 18-crown-6 in 10 ml of tetrahydrofuran, was added of 1.62 g (0.014 mol) of potassium tert-butylate and the mixture was stirred at room temperature for 25 minutes. To this mixture, one drop of solution was added, consisting of 0,60 g (0,0027 mol) of 7-chloro-1-(2-propenyl)-2,3-dimethylpyrrole[2,3-d]pyridazine and 5 ml of tetrahydrofuran and the resulting mixture was stirred for 10 hours at room temperature. After completion of the reaction, the reaction mixture was poured into a mixture of ice and water and the aqueous mixture was extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate, and the solvent is kept at reduced pressure. The resulting residue was purified by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and Gex is) in the form of a pale yellow powder.

So pl.: 114 - 115oC.

Mass spectrum (Cl, m/z): 312 (M++1).

The NMR spectrum (CDCl3(million days): USD 1.43 (d, J = 8 Hz, 3H), of 2.25 (s, 3H), to 2.29 (s, 3H), 5,62 (s, 2H), 5,85 - 5,95 (m, 1H), 6,65 - of 6.71 (m, 1H), 7,02 - 7,10 (m, 2H), 7,43 - to 7.50 (m, 2H), 9,00 (s, 1H).

Elemental analysis for C18H18FN3O (%):

Calculated: C 69,44; H of 5.83; N 13,50;

Found: C 69,79; H 5,91; N 13,51.

Example 45

7-Benzyloxy-2,3-dimethyl-1-(propane-1,2-dienyl)pyrrolo [2,3-d]pyridazin

The target compound as pale brown crystals with a yield of 37.6 received by the method described in example 44, using 7-chloro-2,3-dimethyl-1-(2-PROPYNYL)pyrrolo[2,3-d]pyridazine and benzyl alcohol.

So pl.: 77 - 79oC.

Mass spectrum (Cl, m/z): 292 (M++1).

The NMR spectrum (CDCl3(million days): of 2.27 (s, 3H), 2,41 (s, 3H), lower than the 5.37 (s, 1H), of 5.40 (s, 1H), 5,73 (s, 2H), 7,28 - to 7.68 (m, 6H), 8,98 (s, 1H).

Elemental analysis for C18H17N3O (%):

Calculated: C 74,21; H of 5.89; N 14,42

Found: C 74,29; H 5,86; N 14,31.

Example 46

7 Benzylamino-2,3-dimethyl-1-(1-propenyl)pyrrolo[2,3-d] pyridazin

The target connection (trance in the form of a beige powder with a yield of 31.5% was obtained by the method described in example 44, using 7-chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazine and benzylamino>(million days): 1,44 - of 1.62 (m, 3H), of 2.20 (s, 3H), of 2.25 (s, 3H), 4,88 (D., J = 5 Hz, 2H), 5,11 - 5,22 (m, 1H), 6,03 - 6,14 (m, 1H), of 6.71 - of 6.78 (m, 1H), 7,20 - 7,42 (m, 5H), 8,83 (s, 1H).

Elemental analysis for C18H20N4(%):

Calculated: C 73,04; H 6,95; N 18,93

Found: C 73,53; H 6,99; N 18,83.

Example 47

1-(2-Butenyl)-7-(4-forbindelsen)-2,3-dimethylpyrrole [2,3-d]pyridazin

A solution containing 0.35 g (0,0015 mol) of 1-(2-butenyl)-7 - chloro-2,3-dimethylpyrrole[2,3-d] pyridazine dissolved in 3.5 ml of 4-forbindelsen, was heated at a temperature of 180oC for 2.5 hours. After completion of the reaction, the reaction mixture was left to cool to room temperature, and then poured into a mixture of ice and water; the aqueous mixture was extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate, and the solvent is kept at reduced pressure. The residue was purified by column chromatography on silica gel, using as eluent a mixture of chloroform and methanol (30:1), resulting in a received 0,22 g 1-(2-butenyl)-7-(4-forbindelsen)-2,3-dimethylpyrrole[2,3-d] pyridazine (CIS/TRANS= 1/4) in the form of a powder skin color.

So pl.: 135 - 138oC.

Mass spectrum (Cl, m/z): 325 (M++1).

The NMR spectrum (CDCl3: million days): 1,38 - of 1.41 (m, 0,6 H), 1,55 - to 1.59 (m, 2.4 H), 2,25 (c, C19H21FN4(%):

Calculated: C 70,35; H 6,53; N 17,27

Found: C 70,08; H 6,62; N 17,08.

Example 48

1-(2-Butenyl)-7-(4-chloro-2-forbindelse)-2,3-dimethylpyrrole [2,3-d] pyridazin

The target compound (CIS/TRANS= 24/76) in the form of a white powder with a yield of 63.8 per cent was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d] pyridazine (CIS/TRANS=24/76) and 4-chloro-2-fermentelos alcohol.

So pl.: 106 - 109oC.

Mass spectrum (Cl, m/z): 360 (M++1 ), 360 (M++3).

The NMR spectrum (CDCl3(million days): 1,59 (d, J = 6 Hz, 2,28 H) of 1.65 (d, J = 6 Hz, 0,72 H), 2,24 (s, 3H), of 2.30 (s, 3H), 4,82 (d, J = 6 Hz, 1,52 H), 4,99 (d, J = 6 Hz, H 0,48), 5,12 - the ceiling of 5.60 (m, 2H), 5,73 (s, 2H), 7,12 (d, J = 9 Hz, 2H), 7,51 (t, J = 9 Hz, 1H), 8,97 (s, 1H).

Elemental analysis for C19H19ClFN3O (%):

Calculated: C 63,42; H 5,32; N 11,68

Found: C 63,41; H 5,17; N 11,54.

Example 49

1-(2-Butenyl)-7-(2,6-DICHLOROSILANE)2,3-dimethylpyrrole [2,3-d]pyridazin

The target compound (CIS/TRANS=21:79) as a pale yellow powder with a yield of 83.5 per cent was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3 - dimethylpyrrole[2,3-d]pyridazine (CIS/TRANS=24/76) and 2,6-amyl-metacresol.

So pl.: 133 - 140oC.

Mass spectrum (Cl, m/z): 376 (71 (D., J = 6 Hz, 1,58 H), 4,89 (D., J = 6 Hz, 0,42 H), 5,02 - of 5.50 (m, 2H), 5,94 (s, 2H), 7,19 - 7,47 (m, 3H), 8,99 (s, 1H).

Elemental analysis for C19H19Cl2N3O (%):

Calculated: C 60,65; H 5,09; N 11,17

Found: C 60,53; H To 5.03; N 11,17.

Example 50

1-(2-Butenyl)-7-(4-forbesii)-2,3-dimethylpyrrole [2,3-d]pyridazin

The target compound (CIS/TRANS= 20: 80) as a pale yellow powder with a yield 64,9: was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d] pyridazine (CIS/TRANS=23/77) and 4-performanceone.

So pl.: 110 - 115oC.

Mass spectrum (Cl, m/z): 342 (M++1).

The NMR spectrum (CDCl3(million days): 1,58 - of 1.65 (m, 2.4 H), 1,73 - to 1.79 (m, 0,6 H in), 2.25 (s, 3H), 2,31 (s, 3H), 4,74 (s, 2H), 4,93 - 5,00 (m, 1,6 H), 5,07 - 5,33 (m, 1,4 H), 5,46 - 5,61 (m, 1H), 6,91 - 7,02 (m, 2H), 7,39 - of 7.48 (m, 2H), 9,06 (s, 1H).

Elemental analysis for C19H20FN3S (%):

Calculated: C 66,84; H 5,90; N 12,31.

Found: C 66,92; H 5,90; N 12,23.

Example 51

1-(2-Butenyl)-7-(2,4-diferentially)-2,3-dimethylpyrrole [2,3-d] pyridazin

The target compound (CIS/TRANS = 16:84) in the form of pale brown crystals with access to 39.0% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d] pyridazine (CIS/TRANS = 22/78) and 2,4-demr-spectrum (CDCl3(million days): 1,48 by 1.68 (m, 2,52 H), 1,71 and 1.80 (m, H 0,48), 2,24 (s, 3H), 2,31 (s, 3H), of 4.77 (s, 2H), 4,88 - of 5.68 (m, 4H), 6,65 - 6,84 (m, 2H), 7,47 - 7,63 (m, 1H), 9,06 (s, 1H).

Elemental analysis for C19H19F2N3S (%):

Calculated: C 63,49; H 5,33; N OF 11.69

Found: C 63,67; H 5,32; N 11,66.

Example 52

1-(2-Butenyl)-7-(2-chloro-6-forbesii)-2,3-dimethylpyrrole [2,3-d] pyridazin

The target compound (CIS/TRANS = 18:82) as pale-brown crystals with access to 70.1% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d] pyridazine (CIS/TRANS = 22/78) and 2-chloro-6-performanceone.

So pl.: 95 - 117oC.

Mass spectrum (Cl, m/z): 376 (M++1).

The NMR spectrum (CDCl3(million days): 1,51 - of 1.66 (m, 2,46 H), 1,67 - to 1.77 (m, 0,54 H), and 2.27 (s, 3H), 2,32 (s, 3H), 4,81 - 5,62 (m, 6H), 6,93 - 7,31 (m, 3H), which is 9.09 (s, 1H).

Elemental analysis for C19H19ClFN3S (%):

Calculated: C 60,71; H 5,09; N 11,18.

Found: C 60,79; H 5,13; N Is 11.11.

Example 53

1-(2-butenyl)-7-(2,4-dichlorbenzene)-2,3-dimethylpyrrole [2,3-d]pyridazin

The target compound (CIS/TRANS = 16:84) as pale-brown crystals with a yield of 63.2% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole(2,3-d] pyridazine (CIS/TRANS is.

The NMR spectrum (CDCl3(million days): 1,47 - of 1.81 (m, 3H), of 2.25 (s, 3H), 2,31 (s, 3H), around 4.85 (s, 2H), 4,91 - 5,02 (m, 1,68 H), 5,03 - 5,13 (m, 0,32 H), 5,13 - 5,64 (m, 2H), 7,07 - to 7.68 (m, 3H) and 9,05 (s, 1H).

Elemental analysis for C19H19Cl2N3S (%):

Calculated: C 58,16; H 4,88; N 10,71

Found: C 58,01; H To 4.87; N 10,69.

Example 54

1-(2-Butenyl)-2,3-dimethyl-7-(2-pyridyldithio)pyrrolo [2,3-d]pyridazin

The target compound (CIS/TRANS = 20/80) as a yellow oily substance with access to 64.8% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole [2,3-d]pyridazine (CIS/TRANS = 22/78) and 2-pyridylmethyl.

Mass spectrum (Cl, m/z): 325 (++1).

The NMR spectrum (CDCl3(million days): 1,50 (D., J = 8 Hz, H 2,4), or 1.77 (d, J = 8 Hz, 0.6 a (H), and 2.26 (s, 3H), 2,31 (s, 3H), 4.92 in (s, 2H), 4,96 - 5,04 (m, 1,6 H), 5,10 - 5,38 (m, 1,4 H), 5,48 - 5,63 (m, 1H), 7,09 - 7,17 (m, 1H), to 5.56 to 7.62 (m, 2H), 8,54 at 8.60 (m, 1H), 9,04 (s, 1H).

Elemental analysis for C18H20N4S 3/4H2O (%):

Calculated: C 63,97; H 6,41; N 16,58

Found: C 64,16; H 6,14; N 16,23.

Example 55

7-(4-Chlorobenzylthio)-2,3-dimethyl-1-(2-propenyl)pyrrolo [2,3-d]pyridazin

The target connection in the form of a yellow solid with a yield of 70.6 per cent was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-propenyl)Perm++1).

The NMR spectrum (CDCl3(million days): and 2.26 (s, 3H), of 2.30 (s, 3H), 4,58 (d, J = 14 Hz, 1H), 4,70 (s, 2H), 5,00 - 5,13 (m, 3H), by 5.87 - 6,01 (m, 1H), 7,19 - 7,27 (m, 2H), 7,35 - 7,42 (m, 2H), 9,07 (s, 1H).

Elemental analysis for C18H18ClN3S (%):

Calculated: C 62,87; H 5,28; N 12,22;

Found: C 62,90; H 5,44; N 12,00.

Example 56

1-(2-Butenyl)-3-ethyl-7-(4-forbindelse)-2-methylpyrrole [2,3-d] pyridazin

The target compound (CIS/TRANS = 22/78) in the form of a white powder with a yield of 63.1% was obtained by the method described in Example 1, using 1-(2-butenyl)-7-chloro-3-ethyl-2-methylpyrrole [2,3-d]pyridazine (CIS/TRANS = 26/74) and 4-fermentelos alcohol.

So pl.: 78 - 83oC.

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

The NMR spectrum (CDCl3(million days): 1,22 (t, J = 8 Hz, 3H), 1.56 to its 1.68 (m, 3H), 2,32 (s, 3H), 2,71 (sq, J = 8 Hz, 2H), 4,81 - 4,89 (m, 1,56 H), 5,02 (D. , J = 8 Hz, 0,44 H), 5,13 - of 5.29 (m, 1H), 5,42 - to 5.58 (m, 1H), 5,69 (s, 2H), 7,01 for 7.12 (m, 2H), 7,42 - of 7.55 (m, 2H), 9,01 (s, 1H).

Elemental analysis for C20H22FN3O (%):

Calculated: C 70,77; H 6,53; N 12,38

Found: C 70,75; H 6,56; N 12,40.

Example 57

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

The target compound (TRANS) in the form of a white powder with a yield of 91.6% was obtained by the method described in Example 1 with use of the Sabbath.

So pl.: 121-122oC.

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

The NMR spectrum (CDCl3(million days): 0,15 ( dt., J = 8 Hz, 4 Hz, 1H), 0,39 (dt. , J = 8 Hz, 4 Hz, 1H), 0,58 is 0.67 (m, 1H), from 0.76 to 0.85 (m, 1H), 0,90 (D., J = 7 Hz, 3H), and 2.27 (s, 3H), is 2.37 (s, 3H), 4,14 (DD., J = 15 Hz, 7 Hz, 1H), 4,28 (DD, J = 15 Hz, 7 Hz, 1H), 5,64 (D., J = 16 Hz, 1H), 5,68 (D., J = 16 Hz, 1H), 7,06 - 7,13 (m, 2H), of 7.48 - 7,53 ( m, 2H), 8,99 (s, 1H).

Elemental analysis for C20H22FN3O (%):

Calculated: C 70,77; F 6,53; N 12,38

Found: C 70,77; H To 6.57; N 12,37.

Example 58

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

The target compound (TRANS) in the form of a white powder with a yield of 63.8 per cent was obtained by the method described in Example 1, using 7-chloro-2,3-dimethyl-1-(2-methylcyclopropyl)pyrrolo [2,3-d]pyridazine and 2,4-differenziava alcohol.

So pl.: 101-102oC.

Mass spectrum (Cl, m/z): 358 (M++ 1).

The NMR spectrum (CDCl3(million days): 0,10 - 0,17 (m, 1H), 0,35 - 0,41 (m, 1H), of 0.59 to 0.63 (m, 1H), 0,78 is 0.86 (m, 1H), 0,89 (D., J = 7 Hz, 3H), and 2.26 (s, 3H), of 2.36 (s, 3H), 4,10 (DD., J = 15 Hz, 7 Hz, 1H), 4.26 deaths (DD, J = 15 Hz, 7 Hz, 1H), 5,67 is 5.77 (m, 2H), 6,84 - 6,92 6,84 - 6,92 (m, 2H), 7,54 to 7.62 (m, 1H), 8,97 (s, 1H).

Elemental analysis for C20H21F3N3O (%):

Calculated: C 67,20; F OF 5.92; N 11,76

Found: C 67,28; H 5,91; N 11,74.

Note the ANS = 14/86)) in the form of a white powder with a yield of 49.8% was obtained by the method, described in Example 1, using 1-(2-butenyl)-7-chloro-2-methyl-3-Pantelleria[2,3-d] pyridazine (CIS/TRANS = 20/80) and 4-fermentelos alcohol.

So pl.: 65-69oC.

Mass spectrum (Cl, m/z): 382 (M++ 1).

The NMR spectrum (CDCl3(million days): to 0.89 (t, J = 8 Hz, 3H), 1,21 - of 1.40 (m, 9H), of 2.33 (s, 3H), 2,68 (t, J = 8 Hz, 2H), 4,82 - 4,89 (m, 1,72 H), 5,02 (d, J = 8 Hz, 0,28 H), 5,07 - 5,24 (m, 1H), 5,43 - to 5.58 (m, 1H), to 5.66 (s, 2H), 7,02 for 7.12 (m, 2H), 7,45 - 7,52 (m, 2H), 8,99 (s, 1H).

Elemental analysis for C23H28FN3O (%):

Calculated: C 72,41; H 7,40, N 11,02.

Found: C 72,44; H 7,29; N 11,03.

Example 60

7-Benzyloxy-2,3-dimethyl-1-(4,4,4-Cryptor-2-butenyl) pyrrolo[2,3-d] pyridazin

The target compound in the form of pale yellow crystals with a yield of 20.7% was obtained by the method described in Example 41, using 7-benzyloxy-2,3-dimethylpyrrole[2,3-d]pyridazine and 4,4,4-Cryptor-2-butylmalonate.

So pl.: 138-140oC.

Mass spectrum ( Cl, m/z): 362 (M++ 1).

The NMR spectrum (CDCl3(million days): 2,28 (s, 3H), to 2.29 (s, 3H), 4,98 - 5,11 (m, 3H), to 5.66 (s, 2H), 6,37 - 6.48 in (m, 1H), 7,32 - to 7.50 (m, 5H), 9,01 (s, 1H).

Elemental analysis for C19H18F3N3O (%):

Calculated: C 63,15; H 5,02; N 11,63.

Found: C 63,21; H Is 5.06; N 11,59.

Example 61

7-Benzyloxy-eternity crystals with a yield of 8.0% was obtained by the method, described in Example 41, using 7-benzyloxy-2,3-dimethylpyrrole [2,3-d]pyridazine and 1,2,3-trichloro-1-propene

Mass spectrum (Cl, m/z/): 362 (M++ 1).

The NMR spectrum (CDCl3million days): 2,32 (s, 3H), 2,43 (s, 3H), of 5.15 (s, 2H), to 5.66 (s, 2H), 5,80 (s, 1H), 7,31-7,52 (m, 5H), 9,18 (s, 1H).

Example 62

1-(2-Butenyl)-7-(4-florfenicol)-2,3-dimethylpyrrole[2,3-d] pyridazin

To a solution containing 0.39 g (0,00113 mol) of 1-(2-butenyl)-2-[1-chloro-3-(4-forfinal)-1-propenyl] -3-formyl-4,5 - dimethylpyrrole and 7 ml of ethanol, was added 0.10 g (0,0020 mol of hydrazine hydrate and the resulting mixture was stirred for one hour at a temperature of 75oC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and then the concentrate was diluted with a mixture of ice and water. The aqueous mixture was extracted with 30 ml ethyl acetate. The combined extracts were washed with saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent is kept under reduced pressure and the resulting residue was purified by column chromatography on silica gel, using as eluent a mixture of chloroform and methanol (50:1), resulting in a received 0,23 g of target compound (CIS/TRANS = 22/78) as white powdery crystals.< million days): 1,60 - by 1.68 (m, 3H), of 2.30 (s, 3H), of 2.35 (s, 3H), 3,18 - 3,26 (m, 2H), 3,49 is 3.57 (m, 2H), 4.75 V - 4,80 (m, 1,56 H), 4,85 - of 5.05 (m, 1H), 5,20 - and 5.30 (m, 0,44 H), 5,50 - 5,67 (m, 1H), 6,94 - 7,02 (m, 2H), 7.18 in - 7,24 (m, 2 H), 9,20 (s, 1H).

Elemental analysis for C20H22FN3(%):

Calculated: C 74,28; H 6,85; N 12,99;

Found: C 74,41; H 6,99; N 12,90.

Example 63

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

The target compound as pale yellow powdery crystals with access 72,7% was obtained by the method described in Example 62, using 7-[1-Chloro-3-(4-forfinal)-1-propenyl] -3-formyl-4,5 - dimethyl-1-(2-methylcyclopropyl)-pyrrole.

So pl.: 112-114oC.

Mass spectrum (Cl, m/z/): 338 (M++ 1).

The NMR spectrum (CDCl3(million days): 0,27 - 0,41 (m, 2H), 0,57 - of 0.79 (m, 2H), 0,97 (D. , J = 6 Hz, 3H), to 2.29 (s, 3H), 2,39 (s, 3H), 3,19 - of 3.25 (m, 2H), 3,57 - 3,63 (m, 2H), 4,20 (d, 06 Hz, 2H), 6,95 - 7,02 (m, 2H), 7,20 - 7,27 (m, 2H), 9,18 (s, 1H).

Elemental analysis for C22H24FN3(%):

Calculated: C 74,45; H 7,17; N 12,45

Found: C 74,63; H 7,27; N 12,42.

Example 64

1-Cyclopropylmethyl-7-(4-florfenicol)-2,3-dimethylpyrrole [2,3-d]pyridazin

The target compound as pale yellow powdery crystals with a yield of 53.4 per cent was obtained by the method described in Example 62 using 2-[1-x is="ptx2">

Mass spectrum (Cl, m/z): 324 (M++ 1).

The NMR spectrum (CDCl3(million days): 0,20 - 0,26 (m, 2 H), 0,52 is 0.59 (m, 2H), 1,02 - 1,10 (m, 1H), to 2.29 (s, 3H), 2,39 (s, 3H), 3,19 - of 3.25 (m, 2H), to 3.58 - to 3.64 (m, 2H), 4,20 (d, J = 6 Hz, 2H), 6,95 - 7,01 (m, 2H), 7,19 - 7,25 (m, 2H), 9,18 (s, 2H).

Elemental analysis for C20H22FN3(%):

Calculated: C 74,28; H 6,86; N 12,99;

Found: C 74,19; H 6,88; N 12,90.

Example 65

7-(4-forfinal)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d] pyridazin

The target compound as pale yellow powdery crystals with access to 55.8% was obtained by the method described in Example 62 using 2-[1-chloro-3-(4-forfinal)-1-propenyl] -3-formyl - 4,5-dimethyl-1-(2-propenyl)pyrrole.

So pl.: 123-124oC.

Mass spectrum (Cl, m/z/): 310 (M++ 1).

The NMR spectrum (CDCl3million days): 2,30 (s, 3H), of 2.34 (s, 3H), 3,19 - of 3.25 (m, 2H), 3,45 - 3,51 (m, 2H), 4,46 (d, J = 17 Hz, 1H), 4,81 - 4,84 (m, 2H), 5,16 (d, J = 10 Hz, 1H), 5,91 - 6,04 (m, 1H), 6,94 - 7,01 (m, 2H), 7.18 in - of 7.23 (m, 2H), 9,20 (s, 1H).

Elemental analysis for C19H20N3(%):

Calculated: C 73,76; H of 6.52; N OF 13.58

Found: C 73,72; H Is 6.61; N 13,45.

Example 66

1-(2-Butenyl)-2,3-dimethyl-7-generateerror[2,3-d]pyridazin

The target compound (CIS/TRANS = 14/86) as a dark yellow powder with a yield of 53.2% taught by the method described in Example 62, pl.: 98-106oC.

Mass spectrum (Cl, m/z): 306 (M++ +).

The NMR spectrum (CDCl3million days): 1,58 - of 1.65 (m, 3H), to 2.29 (s, 3H), of 2.34 (s, 3H), 3,19 - of 3.25 (m, 2H), 3,50 is 3.57 (m, 2H), 4,76 - 4,79 (m, 72H), 4,84 - 4,89 (m, 0,28 H), 4,94 - 5,02 (m, 1H), 5.56mm (Shir.D., 1H), 7,20 - to 7.35 (m, 5H), to 9.20 (s, 1H).

Elemental analysis for C20H23FN3(%):

Calculated: C 78,65; H to 7.59; N 13,76

Found: C 78,78; H To 7.61; N 13,76.

Example 67

2,3-Dimethyl-7-phenethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin

The target compound in the form of yellow crystals with a yield of 56.3 per cent instructed by the method described in Example 62 using 2-(1-chloro-3-phenyl-1-propenyl)-3-formyl - 4,5-dimethylpyrrole-1-(2-propenyl)pyrrole.

So pl.: 96-98oC.

Mass spectrum (Cl, m/z): 292 (M++ 1).

The NMR spectrum (CDCl3million days): 2,30 (s, 3H), of 2.34 (s, 3H), 3,20 - 3,26 (m, 2H), 3,48 - of 3.54 (m, 2H), 4,45 (d, J = 17 Hz, 1H), 4,82 - 4,85 (m, 2H), 5,16 (DD. , J = 10 Hz, 2 Hz, 1H), 5,98 (DDT, J = 17 Hz and 10 Hz, 4 Hz, 1H), 7,16 - 7,39 (m, 5H), of 9.21 (s, 1H).

Elemental analysis for C19H21N3(%):

Calculated: C 78,31; H 7,26; N 14,42

Found: C 78,28; H 7,42; N 14,20.

Example 68

2,3-Dimethyl-1-(methylcyclopropyl)-7-phenotypical[2,3-d] pyridazin

The target compound in the form of a cream-colored powder with a yield of 50.0% was obtained by the method described in Example 62, using the 103oC.

Mass spectrum (Cl, m/z): 320 (M++ 1).

The NMR spectrum (CDCl3million days): 0,26 - 0,41 (m, 2H), 0,57 is 0.67 (m, 1H), 0,73 - 0,80 (m, 1H), 0,97 (d, J = 6 Hz, 3H), of 2.28 (s, 3H), of 2.38 (s, 3H), 3,20 - 3,26 (m, 2H), 3,60 - 3,66 (m, 2H), 4,22 (d, J = 6 Hz, 2H), 7,14 - 7,38 (m, 5H), 9,18 (s, 1H).

Elemental analysis for C21H25N3(%):

Calculated: C 78,95; H 7,98; N 13,16.

Found: C 78,95; H Of 7.93; N 13,11.

Example 69

1-Cyclopropylmethyl-2,3-dimethyl-7-phenotypical[2,3-d]pyridazin

The target compound in the form of a cream-colored powder with access to 69.9% was obtained by the method described in Example 62 using 1-(1-chloro-3-phenyl-1-propenyl)-1-cyclopropylmethyl - 3-formyl-4,5-dimethylpyrrole.

So pl.: 133 - 135oC.

Mass spectrum (Cl, m/z): 306 (M++ 1).

The NMR spectrum (CDCl3million days): 0,20 - 0,26 (m, 2H), 0,51 is 0.58 (m, 2H), 1,02 by 1.12 (m, 1H), to 2.29 (s, 3H), 2,39 (s, 3H), 3,19 - of 3.25 (m, 2H), 3,60 - to 3.67 (m, 2H), 4,22 (d, J = 6 Hz, 2H), 7,16 and 7.36 (m, 5H), 9,19 (s, 1H).

Elemental analysis for C20H23FN3(%):

Calculated: C 78,65; H to 7.59; N 13,76

Found: C 78,42; H A 7.62; N 23,66.

Example 70

1-(2-Butenyl)-7-(2,4-divertenti)-2,3-dimethylpyrrole[2,3-d] pyridazin

The target compound (CIS/TRANS = 20/80) as pale yellow powdery crystals with access to 59.2% was obtained by the method, description of the P CLASS="ptx2">

So pl.: 114 - 118oC.

Mass spectrum (Cl, m/z): 342 (M++ 1).

The NMR spectrum (CDCl3million days): 1,58 - 1,71 (m, 3H), of 2.30 (s, 3H), of 2.35 (s, 3H), 3,17 - 3,26 (m, 2H), 3,45 - 3,55 (m, 2H), 4.80 to to 5.03 (m, 2,8 H), 5,19 is 5.28 (m, 0.2 H), 5,51 - to 5.66 (m, 1H), 6,77 - 6,84 (m, 2H), 7,22 - 7,32 (m, 1H), 9,19 (s, 1H).

Elemental analysis for C20H21F2N3(%):

Calculated: C 70,36; H 6,20; N 12,31

Found: C 70,52; H 6,23; N 12,27.

Example 71

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

The target compound as pale yellow powdery crystals with access 64,0% was obtained by the method described in Example 62 using 2-[1-chloro-3-(2,4-differenl)-1-propenyl]-3-formyl-4,5-dimethyl-1-(2-methylcyclopropyl)pyrrole.

So pl.: 105 - 106oC.

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

The NMR spectrum (CDCl3million days): 0,26 at 0.42 (m, 2H), 0,59 is 0.80 (m, 2H), 0,97 (d, J = 6 Hz, 3H), to 2.29 (s, 3H), 3,40 (s, 3H), 3,17 - 3,24 (m, 2H), 3,55 - 3,61 (m, 2H), 4,28 (d, J = 6 Hz, 2H), 6,78 - 6,85 (m, 2H), 7.23 percent - to 7.32 (m, 1H), 9,18 (s, 1H).

Elemental analysis for C21H23F2N3(%):

Calculated: C 70,97; H of 6.52; N 11,82

Found: C 71,11; H Is 6.54; N Up 11,86.

Example 72

1-Cyclopropylmethyl-7-(2,4-divertenti)-2,3-dimethylpyrrole [2,3-d] pyridazin

The target connection is Ecodom, described in Example 62 using 2-[1-chloro-3-(2,4-differenl)-1-propenyl]-1-cyclopropylmethyl - 3-formyl-4,5-dimethylpyrrole.

So pl.: 159 - 160oC.

Mass spectrum (Cl, m/z): 342 (M++ 1).

The NMR spectrum (CDCl3million days): 0,22 - 0,28 (m, 2H), 0,52 is 0.59 (m, 2H), 1,01 is 1.13 (m, 1H), to 2.29 (s, 3H), 2,41 (s, 3H), 3,17 - of 3.23 (m, 2H), 3,56 - 3,62 (m, 2H), 4,28 (d, J = 6 Hz, 2H), 6,78 - 6,85 (m, 2H), 7.23 percent - to 7.32 (m, 1H), 9,18 (s, 1H).

Elemental analysis for C20H21F2N31/5H2O (%):

Calculated: C 69,63; H 6,25; N 12,18

Found: C 69,71; H 6,22; N 12,12.

Example 73

7-(2,4-Divertenti)-2,3-dimethyl-1-(2-propenyl)pyrrolo [2,3-d]pyridazin

The target compound as pale yellow powdery crystals with a yield of 66.2 per cent, was obtained by the method described in Example 62 using 2-[1-chloro-3-(2,4-differenl)-1-propenyl] -3-formyl-4,5-dimethyl-1-(2-propenyl)pyrrole.

So pl.: 118 - 119oC.

Mass spectrum (Cl, m/z): 328 (M++ 1).

The NMR spectrum (CDCl3million days): 2,30 (s, 3H), of 2.35 (s, 3H), 3,17 - of 3.23 (m, 2H), 3.43 points - to 3.49 (m, 2H), 4,43 (d, J = 17 Hz, 1H), 4,90 - is 4.93 (m, 2H), 5,14 (d, J = 10 Hz, 1H), 5,94 - 6,05 (m, 1H), 6,76 - 6,84 (m, 2H), 7,22 - 7,31 (m, 1H), 9,20 (s, 1H).

Elemental analysis for C19H19F2N3(%):

Calculated: C 69,71; H of 5.85; N 12,84

Found: C 69,67; H 5,90; N 12,81.

the y containing 2.00 g (0,00615 mmol) 1-(2-butenyl)-7-(4-forbindelse)-2,3-dimethylpyrrole[2,3-d]pyridazine (CIS/TRANS = 1/99) in 160 ml of anhydrous diethyl ether under ice cooling was added dropwise 0.36 g (0.01 mol) of hydrogen chloride in 3.0 ml of ethanol, and then the mixture was stirred at the same temperature for 20 minutes. The resulting reaction mixture was concentrated at room temperature, after which the resulting residue was washed with a mixture containing 10 ml of ethanol and 120 ml of anhydrous diethyl ether. The thus obtained solid mass was collected by filtration, resulting in a received 1.88 g of target compound (TRANS isomer) as a white powder.

So pl.: 203 - 220oC.

Mass spectrum (Cl, m/z): 325 (M++ 1).

The NMR spectrum (CDCl3million days): of 1.62 (d, J = 9 Hz, 3H), 2,32 (s, 3H), of 2.46 (s, 3H), 5,00 (d, J = 5 Hz, 2H), 5,18 - 5,72 (m, 4H), 6,99 - 7,20 (m, 2H), was 7.36 - of 7.60 (m, 2H), 9,29 (s, 1H), 17,18 (s, 1H).

Elemental analysis for C19H20FN3O HCl (%):

Calculated: C 63,07; H of 5.85; N OF 11.61

Found: C 63,09; H 5,91; N Of 11.61.

Example 75

1-(2-Butenyl)-7-(4-forbindelse)-2,3-dimethylpyrrole [2,3-d] pyridazin-5-oxide

To a solution containing 0,72 g (0,0029 mmol) 1-(2-butenyl)-7-(4-forbindelse)-2,3-dimethylpyrrole[2,3-d] pyridazine war acid (purity = 70%) in 20 ml of dichloromethane, and the resulting mixture was stirred at the same temperature for 30 minutes; after completion of the reaction, the reaction mixture was three times washed with 40 ml (each time) of a saturated aqueous solution of sodium bicarbonate. Then the dichloromethane layer was dried with anhydrous sodium sulfate, and the solvent is kept at reduced pressure. The residue was purified by column chromatography on silica gel, using as eluent a mixture (100:1 - 100:4) of chloroform and methanol, resulting in the obtained crystals were washed with a mixture of ether and hexane. Thus was obtained 0,63 g of target compound (CIS/TRANS = 27/73) as a pale yellow powder.

So pl.: 138 - 148oC.

Mass spectrum (Cl, m/z): 342 (M++ 1).

The NMR spectrum (CDCl3million days): 1,42 by 1.68 (m, 3H), 2.13 and (s, 3H), of 2.30 (s, 3H), 4,69 of 4.83 (m, 1,46 H), 4,88 is equal to 4.97 (m, 0,54 H), 5,11 - to 5.66 (m, 4H), 6,98 - 7,13 (m, 2H), 7,39 - 7,52 (m, 2H), of 8.27 (s, 1H).

Elemental analysis for C19H20FN3O (%):

Calculated: C 66,85; H 5,91; N 12,31;

Found: C Up 66,78; H 5,88; N 12,29.

Example 76

1-(2-Butenyl)-7-(2,4-deferasirox)-2,3-dimethylpyrrole [2,3-d]pyridazin-5-oxide

The target compound (CIS/TRANS = 7/93) as a pale yellow powdery crystals with a yield of 87.0% had received the methods of the A.

So pl.: 166 - 168oC.

Mass spectrum (Cl, m/z): 360 (M++ 1).

The NMR spectrum (CDCl3million days): 1,58 - to 1.61 (m, 3H), and 2.14 (s, 3H), to 2.29 (s, 3H), 4,72 - of 4.75 (m, 1.86 H), 4,88 - 4,91 (m, 0,14 H), 5,15 - 5,31 (m, 1H), 5,38 - of 5.50 (m, 1H), 5,59 (s, 2H), 6,83 - 6,94 (m, 2H), 7,49 - 7,58 (m, 1H), 8,23 (s, 1H).

Elemental analysis for C19H19F2N3O (%):

Calculated: C 63,50; H 5,33; N OF 11.69

Found: C 63,49; H 5,28; N Of 11.69.

Example 77

1-(2-Butenyl)-7-(2,4-divertenti)-2,3-dimethylpyrrole [2,3-d]pyridazin-5-oxide and 1-(2-Butenyl)-7-(2,4-divertenti)-2,3-dimethylpyrrole [2,3-d] pyridazin-6-oxide

To a solution containing of 0.47 g (0,00138 mmol) 1-(2-butenyl)-7-(2,4-divertenti)-2,3-dimethylpyrrole [2,3-d] pyridazine in 10 ml of dichloromethane at room temperature for 30 minutes, one drop was added to the solution containing 0.35 gram (0,00142 mol) m-chloroperoxybenzoic acid (purity: 70%) in 5 ml of dichloromethane, and then the mixture was stirred at the same temperature for one hour. After completion of the reaction, the reaction mixture was three times washed with 30 ml (each time) of a saturated aqueous solution of sodium bicarbonate. Then the dichloromethane layer was washed with a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate, and the solvent is kept at pangenomic of chloroform and methanol (50: 1). The purified product was rubbed with a mixture of ether and hexane, resulting in received 0,058 g 5-oxide target compound (CIS/TRANS = 25/75) and 0,290 g 6-oxide target compound (CIS/TRANS = 25/75) as a pale yellow powder, respectively.

5-oxide

So pl. 104 - 112oC.

Mass spectrum (Cl, m/z): 358 (M++ 1).

The NMR spectrum (CDCl2(million days): 1,62 is 1.70 (m, 3H), of 2.25 (s, 3H), of 2.30 (s, 3H), is 3.08 - 3,18 (m, 2H), 3,41 - 3,51 (m, 2H), 4.63 to - 4,67 (m, 1.5 H), 4,74 - 4,78 (m, 0.5 H), equal to 4.97 is 5.07 (m, 0,75 H), 5,07 - 5,13 (m, 0,25 H), 5,50 - to 5.66 (m, 1H), 6,75 - 6,83 (m, 2H), 7,28 - 7,37 (m, 1H), charged 8.52 (s, 1H).

Elemental analysis for C20H21F2N3O 1,5 H2O (%):

Calculated: C 66,54; H 5,97; N 11,64

Found: C 66,64; H 5,88; N 11,55.

6-oxide

So pl. 135 - 141oC.

Mass spectrum (Cl, m/z): 358 (M++ 1).

The NMR spectrum (CDCl2(million days): 1,62 was 1.69 (m, 3H), 2,19 (s, 3H), of 2.33 (s, 3H), 3,12 - of 3.32 (m, 4H), 4,76 - 4,78 (m, 1.5 H), a 4.86 - to 4.87 (m, 0.5 H), 4,96 - 5,09 (m 0,75 H), 5,19 - a 5.25 (m, 0,25 H), 5,50 - 5,67 (m, 1H), 6,76 - 6,84 (m, 2H), 7,20 - 7,29 (m, 1H), 8,40 (s, 1H).

Elemental analysis for C20H21F2N3O (%):

Calculated: C 67,21; H of 5.92; N 11,76

Found: C 66,98; H Of 5.99; N Are 11.62.

Comparative example 1

Ethyl-1-(2-butenyl)-5-ethyl-4-methylpyrrole-2-carboxylate

(1) 3-Chloro-2-methyl-2-pentenal (mixture of CIS - and TRANS-isomere is a, cooling in this ice, and then the resulting mixture was stirred at the same temperature for 30 minutes, after which the mixture was stirred at room temperature for 20 minutes was added 21 ml (0.21 mol) of 3-pentanone, cooling while ice to maintain the reaction temperature below 40oC. This mixture was stirred for 10 minutes under ice cooling, and then for two hours at room temperature. The reaction mixture portions poured into about 300 ml of ice water, and then diluted the mixture was neutralized to pH 7-8 by adding sodium bicarbonate. The resulting mixture was extracted with diethyl ether (once with 200 milliliters three times 100 ml). The combined extracts were washed with saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. The solvent is kept on a rotary evaporator with a bath temperature below 30oC. the Residue was purified by distillation at 58-61oC/15 mm RT. Art. , resulting received 14.8 g of 3-chloro-2-methyl-2-pentenal in the form of a colorless transparent oily substance.

Mass spectrum (Cl, m/z): 133 (M++ 1), 135 (M++ 3).

The NMR spectrum (CDCl3(million days): of 1.23 (t, J = 8 Hz, H 3,4), of 1.30 (t, J = 8 Hz, H 9,4), of 1.84 (s, 3,4 H), 1.91 a (C, H 9,4), 2,65
To a solution containing 5.0 g (0.38 mol) of 3-chloro-2-methyl-2-pentenal in 10 ml of ethanol, with stirring, was added 3,74 g (0,024 mol) of ethyl N-(2-butenyl)glycinate, and then 6 ml (0,043 mol) of triethylamine and the resulting mixture was stirred at room temperature for 7 hours. After filtering off the precipitate to the filtrate portions was added 5.35 g (0,048 mol) of potassium tert-butylate and the mixture was stirred for 30 minutes. The reaction mixture is poured into about 150 ml of a saturated aqueous solution of ammonium chloride, and then extracted with ethyl acetate (once with 100 ml and twice with 50 milliliters). The combined extracts were washed with saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate, then the solvent drove away. The residue was purified by column chromatography on silica gel, using as eluent a mixture of ethyl acetate and hexane (3: 97), resulting in a received 1,53 g of ethyl 1-(2-butenyl)-5-ethyl-4-methylpyrrole-2-carboxylate (CIS/TRANS = 76/240 as an orange oily substance.

Mass spectrum (Cl, m/z): 236 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,10 (t, J = 8 Hz, 3/4H), 1,32 (t, J = 7 Hz, 3H), 1,61 - of 1.65 (m, 2,28 H), 1,74 - of 1.78 (m, 72H), 2,03 (s, 3H), 2,55 (sq , J = 8 Hz, 2H), 4,20 (sq, J = 7 Hz, 2H), 4,8 the propyl-4,5-dimethylpyrrole-2-carboxylate

The target compound as a yellow oily substance with a yield of 41.6% was obtained by the method described in comparative example 1, using 2-butanol and ethyl N-cyclopropylalanine.

Mass spectrum (Cl, m/z): 208 (M++ 1).

The NMR spectrum (CDCl3(million days): 0,79 - 0.87 (m, 2H), 1,08 is 1.16 (m, 2H), 1,35 (t, J = 8 Hz, 3H), of 1.98 (s, 3H), and 2.26 (s, 3H), 3,12 - 3,24 (m, 1H), 4,24 (sq, J = 8 Hz, 2H), of 6.71 (s, 1H).

Comparative example 3

Ethyl 1-cyclohexyl-4,5-dimethylpyrrole-2-carboxylate

The target compound as a yellow oily substance with a yield of 18.9% was obtained by the method described in comparative example 1, using 2-butanol and ethyl N-cyclopropylalanine.

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

The NMR spectrum (CDCl3(million days): to 1.32 (t, J = 8 Hz, 3H), 1,63 - of 1.94 (m, 6H), to 1.98 (s, 3H), 2,03 - of 2.24 (m, 4H), of 2.30 (s, 3H), 3,39 - 3,70 (m, 1H), 4,21 (sq, J = 8 Hz, 2H), 6.89 in (s, 1H).

Comparative example 4

Ethyl 4-ethyl-5-methyl-1-(2-propenyl)pyrrole-2-carboxylate

The target compound as a yellow oily substance with a yield of 25.6% was obtained by the method described in comparative example 1, using 2-pentanone and ethyl N-(2-propenyl)glycinate.

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

The NMR spectrum (CDCl3(million days): 1,17 (TM, 1H), 6,84 (s, 1H).

Comparative example 5

Ethyl 1-(2-butenyl)-5-ethyl-3-formyl-4-methylpyrrole-2-carboxylate

To a solution of ethyl 1-(2-butenyl-5-ethyl-4-methylpyrrole-2-carboxylate (1,38 g, 0,0059 mol) (TRANS/CIS = 76/24) in 3 ml of dimethylformamide was added 1.5 ml (0,0069 mol) of phosphorus oxychloride and the resulting mixture was stirred for two hours in an oil bath at a temperature of 100oC. the Cooled reaction mixture is poured dropwise in approximately 50 ml of ice water and then neutralized with a saturated aqueous solution of bicarbonate to pH 7 - 8. The aqueous mixture was extracted four times with 50 ml each time) ethyl acetate. The combined extracts were washed with saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate, then the solvent drove away. The residue was purified by column chromatography on siegele, using as eluent a mixture of ethyl acetate and hexane (1:10), resulting in received of 1.33 g of ethyl 1-(2-butenyl)-5-ethyl-3-formyl-4-methylpyrrole-2-carboxylate (TRANS/CIS = 77/23) in the form of orange-yellow oily substance).

Mass spectrum (Cl, m/z): 264 (M++ 1).

The NMR spectrum (CDCl3(million days): a 1.11 (t, J = 8 Hz, 3H), of 1.39 (t, J = 8 Hz, 3H), 1,65 was 1.69 (m, 2,31 H), 1,74 - to 1.79 (m, 0,69 H in), 2.25 (s, 3H), 2,6 is entrusted example 6

Ethyl 1-cyclopropyl-3-formyl-4,5-dimethylpyrrole-2-carboxylate

The target compound as a yellow oily substance with a yield of 37.7% was obtained by the method described in comparative example 5, using ethyl 1-cyclopropyl-4,5-dimethylpyrrole-2-carboxylate.

Mass spectrum (Cl, m/z): 236 (M++ 1).

The NMR spectrum (CDCl3(million days): 0,75 - 0,83 (m, 2H), 1,11 - 1,20 (m, 2H), 1,40 (t, J = 7 Hz, 3H), 2,24 (s, 3H), to 2.29 (s, 3H), 3,22 - to 3.33 (m, 1H), to 4.41 (sq, J = 7 Hz, 2H), 10,32 (s, 1H).

Comparative example 7

Ethyl 1-cyclohexyl-3-formyl-4,5-dimethylpyrrole-2-carboxylate

The target compound as a yellow oily substance with a yield of 47.1% was obtained by the method described in comparative example 5, using ethyl 1-cyclohexyl-4,5-dimethylpyrrole-2-carboxylate.

Mass spectrum (Cl, m/z): 278 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,17 - is 1.51 (m, 4H), of 1.40 (t, J = 8 Hz, 3H), 1,69 - of 2.15 (m, 6H), 2,22 (s, 3H), 2,31 (s, 3H), 4,381 (sq, J = 8 Hz, 2H), br4.61 - 4,82 (m, 1H), 10,29 (s, 1H).

Comparative example 8

Ethyl 4-ethyl-3-formyl-5-methyl-1-(2-propenyl)pyrrole-2-carboxylate

The target compound as a yellow-orange oily substance with a yield of 42.8% was obtained by the method described in comparative example 5, using ethyl 4-ethyl-5-methyl-1-(2-who, the LF.D.): of 1.10 (t, J = 7 Hz, 3H), of 1.37 (t, J = 7 Hz, 3H), of 2.18 (s, 3H), 2,74 (sq, J = 7 Hz, 2H), 4,37 (sq, J = 7 Hz, 2H), 4,79 (d, J = 17 Hz, 1H), 4.92 in - to 4.98 (m, 2H), 5,15 (d, J = 11 Hz, 1H), 5,88 - 6,04 (m, 1H), of 10.50 (s, 1H).

Comparative example 9

Methyl 1-(2-butenyl)-3-formyl-4,5-dimethylpyrrole-2-carboxylate

To a solution of methyl 3-formyl-4,5-dimethylpyrrole-2 - carboxylate (of 3.60 g, 0,0199 mol) and 18-crown-6 (0.36 g, 0,0014 mol) in 220 ml of tetrahydrofuran was added of 2.21 g (0,0199 mol) of potassium tert-butylate and the mixture was stirred at room temperature for 45 minutes. After addition of 3.60 g (0,0398 mol) 1-chloro-2-butene (mixture of CIS - and TRANS-isomers), the mixture was heated under reflux for 7 hours. After adding more of 1.80 g (0,0199 mol) 1-chloro-2-butene, the mixture was heated under reflux for 22 hours. The resulting reaction mixture was cooled to room temperature, added to ice water and was extracted with ethyl acetate. The extract was washed with water and dried with anhydrous sodium sulfate, then the solvent drove away. The residue was purified by column chromatography on silica gel, using as eluent a mixture of toluene and ethyl acetate (95:5), resulting in a received 4,50 g (0,0192 mol) of methyl 1-(2-butenyl)-3-formyl-4,5-dimethylpyrrole-2-carboxylate (CIS/TRANS = 24/76) in the form/SUB>(million days): 1,64 - to 1.70 (m, 2,3 H), 1,74 and 1.80 (m, 0,7 H) to 2.18 (s, 3H), and 2.27 (s, 3H), 3,90 (s, 3H), 4,82 - 4,91 (m, 1.5 H), equal to 4.97 - to 5.03 (m, 0.5 H), 5,27 - 5,70 (m, 2H), 10,45 (s, 1H).

Comparative example 10

Methyl 3-formyl-4,5-dimethyl-1-(3-methyl-2-butenyl)pyrrole-2-carboxylate

The target compound in the form of bright yellow-orange solid with a yield of 85.4% was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1-bromo-3-methyl-2-butene.

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

The NMR spectrum (CDCl3(million days): 1,71 (s, 3H), 1.77 in (s, 3H), of 2.16 (s, 3H), of 2.25 (s, 3H), 3,90 (s, 3H), to 4.92 (d, J = 6 Hz, 2H), 5,10 (t, J = 6 Hz, 1H), 10,44 (s, 1H).

Comparative example 11

Methyl 3-formyl-4,5-dimethyl-1-(2-propenyl)pyrrole-2-carboxylate

The target connection in the form of a yellow solid with a yield 95,1% was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-bromo-1-propene.

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

The NMR spectrum (CDCl3(million days): to 2.15 (s, 3H), and 2.26 (s, 3H), 3,88 (s, 3H), 4,78 (d, J = 16 Hz, 1H), equal to 4.97 (d, J = 5 Hz, 2H), 5,15 (d, J = 10 Hz, 1H), of 5.89 - of 6.02 (m, 1H), 10,47 (s, 1H).

Comparative example 12

Methyl 1-cyclopropylmethyl-3-formyl-4,5-dimethylpyrrole-2-carboxylate

Mass spectrum (Cl, m/z): 236 (M++ 1).

The NMR spectrum (CDCl3(million days): 0,32 is 0.60 (m, 4H), 1,08 of 1.28 (m, 1H), of 2.21 (s, 3H), of 2.25 (s, 3H), 3,90 (s, 3H), 4,16 (d, J = 8 Hz, 2H), 10,43 (s, 1H).

Comparative example 13

Methyl 3-formyl-4,5-dimethyl-1-(3-phenyl-2-propenyl)pyrrole-2-carboxylate

The target compound (TRANS) as a pale brown oily substance with a yield of 93.9 per cent was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-chloro-1-phenyl-1-propene (TRANS).

Mass spectrum (Cl, m/z): 298 (M++ 1).

The NMR spectrum (CDCl3(million days): 2,22 (s, 3H), and 2.27 (s, 3H), 3,90 (s, 3H), 5,12 (d, J = 4 Hz, 2H), 6,12 - 6,34 (m, 2H), 7,17 - the 7.43 (m, 5H), 10,48 (s, 1H).

Comparative example 14

Methyl 3-formyl-4,5-dimethyl-1-(2-pentenyl)pyrrole-2-carboxylate

The target compound (TRANS) as a yellow-orange oily substance with a yield of 85.1% was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1-bromo - 2-pentene (TRANS).

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

The NMR spectrum (CDCl3(million days): of 1.05 (t, J = 8 Hz, 3H), 2,09 - of 2.26 (bromacil)-3-formyl-4,5-dimethylpyrrole-2-carboxylate

The target compound in the form of dark yellow crystals with a yield of 9.4% was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1,2-dibromethane.

Mass spectrum (Cl, m/z): 288 (M++1), 290 (M++ 3).

The NMR spectrum (CDCl3(million days): of 2.27 (s, 6H), of 3.60 (t, J = 7 Hz, 2H), 3,92 (s, 3H), with 4.64 (t, J = 7 Hz, 2H), 10,48 (s, 1H).

Comparative example 16

Methyl 3-formyl-4,5-dimethyl-1-(2-methyl-2-propenyl)pyrrole-2 - carboxylate

The target compound as a pale yellow oily substance with a yield of 86.2 per cent was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-chloro-2-methyl-1-propene.

Mass spectrum (Cl, m/z): 236 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,78 (s, 3H), 2,12 (s, 3H), and 2.27 (s, 3H), 3,88 (s, 3H), 4,13 (s, 1H), 4,81 (s, 1H), a 4.86 (s, 2H), 10,48 (s, 1H).

Comparative primer

Methyl 3-formyl-4,5-dimethyl-1-(2,2,2-triptorelin)pyrrole-2-carboxylate

The target compound in the form of light brown crystals with a yield of 5.5% was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1,1,1-Cryptor-2-iodata.

Mass spectrum (Cl, m/z/): 264 (Manicely primer

Methyl 1-(2-foradil)-3-formyl-4,5-dimethylpyrrole-2-carboxylate

The target compound in the form of light brown crystals with access to 77.4% was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1-bromo-2-floridana.

Mass spectrum (Cl) m/z: 228 (M++ 1).

The NMR spectrum (CDCl3(million days): of 2.23 (s, 3H), and 2.27 (s, 3H), 3,90 (s, 3H), 4,46 - a 4.86 (m, 4H), 10,49 (s, 1H).

Comparative primer

Methyl 1-(2,2-dottorati)-3-formyl-4,5-dimethylpyrrole-2-carboxylate

The target compound in the form of flesh-colored crystals with a yield of 90.4 per cent was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 2-bromo-1,1-differetn.

Mass spectrum (Cl, m/z): 246 (M++ 1).

The NMR spectrum (CDCl3(million days): 2,24 (s, 3H), and 2.26 (s, 3H), 3,93 (s, 3H), of 4.66 (dt., J = 4 Hz, 14 Hz, 2H), 6,11 (TT, J = 4 Hz 54 Hz, 1H), 10,49 (s, 1H).

Comparative example 20

Methyl 1-(2-butenyl)-3-formyl-4,5-dimethylpyrrole-2-carboxylate

The target compound (CIS/TRANS = 93/7) as a pale brown oily substance with a yield of 33.4% was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylat (CDCl3(million days): 1,64 - to 1.70 (m, 0.2 H), 1,71 - to 1.82 (m, 2,8 H) 2,17 (s, 3H), of 2.25 (s, 3H), 3,90 (s, 3H), 4,85 - 4,91 (m, 0,1 H), 4,96 - of 5.06 (m, 1,9 H), 5,27 - 5,70 (m, 2H), 10,44 (s, 1H).

Comparative example 21

Methyl 1-(2-chloro-2-propenyl)-3-formyl-4,5-dimethylpyrrole-2-carboxylate

The target compound in the form of light yellow crystals with a yield of 77.5% was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 2,3-dichloro-1-propene.

Mass spectrum (Cl, m/z): 256 (M++ 1), 258 (M++ 3).

The NMR spectrum (CDCl3(million days): 2,19 (s, 3H), and 2.27 (s, 3H), 3,90 (s, 3H), 4,70 (s, 1H), 5,10 (c, 2H), from 5.29 (s, 1H), 10,49 (s, 1H).

Comparative example 22

Methyl 3-formyl-4,5-dimethyl-1-(4,4,4-Cryptor-2-butenyl)- pyrrole-2-carboxylate

The target compound (TRANS) as a pale yellow oily substance with access 60,0% was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 4,4,4-Cryptor-2-butylmalonate (TRANS).

Mass spectrum (Cl, m/z): 290 (M++ 1).

The NMR spectrum (CDCl3(million days): to 2.15 (s, 3H), and 2.27 (s, 3H), 3,90 (c, 3H), 5,09 - 5,13 (m, 2H), 5,22 - 5,31 (m, 1H), of 6.49 - to 6.57 (m, 1H), 10,48 (s, 1H).

Comparative example 23

Methyl 1-(3,3-debtor-2-propenyl)-3-formyl-4,5-dimethylpyrrole method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-bromo-3,3-debtor-1-propene.

Mass spectrum (Cl, m/z): 258 (M++ 1).

The NMR spectrum (CDCl3(million days): R $ 2.20 (s, 3H), of 2.25 (s, 3H), 3,91 (s, 3H), 4,50 - of 4.67 (m, 1H), 4,91 (d, J = 7 Hz, 2H), 10,46 (s, 1H).

Comparative example 24

Methyl 1-(3-forproper)-3-formyl-4,5-dimethylpyrrole-2-carboxylate

The target compound in the form of light yellow crystals with access 90,8% was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1-bromo-3-febraban.

Mass spectrum (Cl) m/z: 242 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,01 - of 2.30 (m, 2H), 2,22 (s, 3H), and 2.26 (s, 3H), 3,90 (c, 3H), 4,33 - 4,60 (m, 4H), 20,46 (c, 1H).

Comparative example 25

Methyl 3-formyl-4,5-dimethyl-1-(2-PROPYNYL)pyrrole-2-carboxylate

The target compound in the form of white crystals with a yield of 89.3 per cent was obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-bromo-1-propene.

Mass spectrum (Cl) m/z: 220 (M++ 1).

The NMR spectrum (CDCl3(million days): of 2.27 (s, 3H), to 2.29 (s, 3H), 3,93 (c, 3H), by 5.18 (s, 2H), 10,48 (s, 1H), 2,31 (s, 1H).

Comparative example 26

the smaller crystals with a yield of 87.1 percent were receiving method, described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 1,1,3-trichloro-1-propene.

Mass spectrum (Cl, m/z): 290 (M++ 1), 292 (M++ 3), 294 (M++ 5).

The NMR spectrum (CDCl3(million days): R $ 2.20 (s, 3H), of 2.25 (s, 3H), 3,91 (s, 3H), of 5.05 (d, J = 6 Hz, 2H), of 5.99 (t, J = 6 Hz, 1H), 10,46 (s, 1H).

Comparative example 27

Methyl 1-cyclohexylmethyl-3-formyl-4,5-dimethylpyrrole-2-carboxylate

The target compound as an orange oily substance with a yield of 79.6% obtained by the method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and cyclohexylethylamine.

Mass spectrum (Cl, m/z): 278 (M++ 1).

The NMR spectrum (CDCl3(million days): 0,83 - of 1.33 (m, 5H), 1,48 and 1.80 (m, 6H), 2,17 (s, 3H), and 2.26 (s, 3H), with 3.89 (s, 3H), 4,17 (D., J = 7 Hz, 2H), 10,42 (s, 1H).

Comparative example 28

1-(2-Butenyl)-2,3-dimethyl-6,7-dihydropyrrolo[2,2-d] pyridazin-7-he

1.10 g (0,0220 mmol) of hydrazine hydrate was added to the solution 4,50 g (0,0191 mol) of methyl 1-butenyl-3-formyl-4,5-dimethylpyrrole-2 - carboxylate (CIS/TRANS = 24/76) in 47 ml of acetic acid and the resulting mixture was stirred at 100oC for 2 hours. Then the reaction mixture was cooled to room temperature and poured into vocally was dissolved in 300 ml of dichloromethane and the solution was dried with anhydrous sodium sulfate. After removal of the solvent was received of 3.53 g (0,0163 mol) of 1-(2-butenyl)-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d] pyridazin-7-she (CIS/TRANS = 21/79) in the form of light brown crystals.

Mass spectrum (Cl, m/z): 218: (M++ 1).

The NMR spectrum (CDCl3million d): 1,59 was 1.69 (m, 2.4 H), 1,78 - of 1.85 (m, 0,6 H) of 2.20 (s, 3H), to 2.29 (s, 3H), 5,06 - 5,16 (m, 1,6 H), 5,24 - 5,31 (m, 0,4 H), 5,34 - of 5.68 (m, 2H), 8,07 (s, 1H), 10,29 (s, 1H).

Comparative example 29

1-Cyclopropyl-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-he

The target compound in the form of powder pale cream color with output 86,0% was obtained by the method described in comparative example 28, using Ethyl 1-cyclopropyl-3-formyl-4,5-dimethylpyrrole-2-carboxylate.

Mass spectrum (Cl, m/z): 204 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,05 - of 1.13 (m, 2H), of 1.23 to 1.31 (m, 2H), 2,19 (s, 3H), 3.27 to 3,37 (m, 1H), 8,00 (s, 1H), 9,88 (Shir.S., 1H).

Comparative example 30

1-Cyclohexyl-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyrazin-7-he

The target compound in the form of powder pale cream color with access to 95.3% was obtained by the method described in comparative example 28, using ethyl 1-cyclohexyl-3-formyl-4,5-dimethylpyrrole-2-carboxylate.

Mass spectrum (Cl, m/z): 246 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,R>
3-Ethyl-2-methyl-1-(2-propenyl)-6,7-dihydropyrrolo[2,3-d]pyridazin - 7-he

The target compound in the form of a white powder with access to 86.3% was obtained by the method described in comparative example 28, using ethyl 4-ethyl-3-formyl-5-methyl-1-2-propenyl)-pyrrole - 2-carboxylate.

Mass spectrum (Cl, m/z): 218 (M++1).

The NMR spectrum (CDCl3million days): 1,20 (t, J= 8 Hz, 3H), to 2.29 (s, 3H), 2,65 (kV, J= 8 Hz, 2H), 4,79 (d, J = 18 Hz, 1H), 5,15 (d, J = 9 Hz, 1H), 5,17-5,22 (m, 2H), 5,93-between 6.08 (m, 1H), 8,11 (s, 1H), 10,17 (Shir.S., 1H).

Comparative example 32

1-(2-Butenyl)-2-ethyl-3-methyl-6,7-dihydropyrrolo[2,3-d]pyridazin - 7-he

The target compound (CIS/TRANS = 15/85) as a white powder with a yield of 72,7% was obtained by the method described in comparative example 28, using ethyl 1-(2-butenyl)-5-ethyl-4-methylpyrrole-2-carboxylate (CIS/TRANS = 23/77).

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

The NMR spectrum (CDCL3million days): 1,20 (t, J= 8 Hz, 3H), of 1.66 (d,J=7 Hz, 2,55 H) to 1.82 (d, J= 7 Hz, 0,45 H) of 2.21 (s, 3H), 2,73 (sq, J = 8 Hz, 2H), 5,13 (d, J=7 Hz, 1,7 H), 5,28 (d, J=7 Hz, 0,3 H), 5,35-5,52 (m, 1H), 5,57-5,70 (m, 1H), 8,07 (s, 1H), 10,35 (Shir.S., 1H).

Comparative example 33

2,3-Dimethyl-1-(3-methyl-2-butenyl)-6,7-dihydropyrrolo[2,3-d] pyridazin-7-he

The target compound in the form of beige crystals with a yield of 90.3% was obtained by the method described in CLASS="ptx2">

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

The NMR spectrum (CDCl3million d): 1,70 (s, 3H), equal to 1.82 (s, 3H), of 2.20 (s, 3H), to 2.29 (s, 3H), 5,20 (s, 3H), 8,08 (s, 1H), 10, 20 (Shir.S., 1H).

Comparative example 34

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

The target compound in the form of a grayish-white solid with a yield of 99.5% was obtained by the method described in comparative example 28, using methyl 3-formyl-4,5-dimethyl-1-(2-propenyl)pyrrole-2-carboxylate.

Mass spectrum (Cl, m/z): 204 (M++1).

The NMR spectrum (CDCl3million d): 2,20 (s, 3H), of 2.28 (s, 3H), to 4.81 (d, J=16 Hz, 1H), 5,15 (d, J=10 Hz, 1H), total of 5.21 (d, J=6 Hz, 2H), 5,91-between 6.08 (m, 1H), 8,07 (s, 1H), to 10.09 (Shir. S., 1H).

Comparative example 35

1-Cyclopropylmethyl-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin - 7-he

The target compound as a white powder with a yield of 98.4 per cent was obtained by the method described in comparative example 28, using methyl 1-cyclopropylmethyl-3-formyl-4,5-dimethylpyrrole-2-carboxylate.

Mass spectrum (Cl, m/z): 218 (M++1).

The NMR spectrum (CDCl3million d): 0,46 is 0.55 (m, 4H), 1,14-of 1.29 (m, 1H), measuring 2.20 (s, 3H), of 2.36 (s, 3H), 4,43 (d, J = 8 Hz, 2H), 8,08 (s, 1H), of 10.05 (W, s, 1H).

Comparative example 36

2,3-Dimethyl-1-(3-phenyl-2-propenyl)-6,7-dihydropyrrolo[2,3-d] - pyridazin-7-he

Mass spectrum (Cl, m/z): 280 (M++1).

The NMR spectrum (CDCl3million days): of 2.21 (s, 3H), of 2.33 (s, 3H), 5,33-of 5.40 (m, 2H), 6,32 (s, 2H), 7,16-to 7.35 (m, 5H), 8,07 (s, 1H), 9,73 (s, 1H).

Comparative example 37

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

The target compound (TRANS) in the form of light brown crystals with a yield of 89.3 per cent was obtained by the method described in comparative example 28, using methyl 3-formyl-4,5-dimethyl-1-(2-pentene)pyrrole-2-carboxylate (TRANS).

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

The NMR spectrum (CDCl3million days): 1,04 (t, J=8 Hz, 3H), 2,15-of 2.30 (m, 8H), 5,22-the ceiling of 5.60 (m, 4H), of 8.06 (s, 1H), 10,23 (s, 1H).

Comparative example 38

2,3-Dimethyl-1-vinyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-he

The target compound as a pale yellow foamy substance with a yield of 92.6% was obtained by the method described in comparative example 28, using methyl 3-formyl-4,5-dimethyl-1-vinylpyrrole-2-carboxylate.

Mass spectrum (Cl, m/z): 190 (M++1).

The NMR spectrum (CDCl3million days): 2,22 (s, 3H), 2,43 (s, 3H), 5,23 (d, J= 9 Hz, 1H), 5,32 (d, J = 18 Hz, 1H), to 7.84 (DD, J = 18

Comparative example 39

2,3-Dimethyl-1-(2-methyl-6,7-length method described in comparative example 28, using methyl 3-formyl-4,5-dimethyl-1-(2-methyl-2-propenyl) pyrrole-2-carboxylate.

Mass spectrum (Cl, m/z): 218 (M++1).

The NMR spectrum (CDCl3million days): 1,72 (s, 3H), of 2.21 (s, 3H), of 2.25 (s, 3H), 4,30 (s, 1H), 4,82 (s, 1H), 5,12 (s, 2H), 5,12 (s, 2H), of 8.09 (s, 1H), 10.30 a.m. (s, 1H), 10.30 a.m. (lat., 1H).

Comparative example 40

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

The target compound in the form of light brown crystals with a yield of 70.0% of them were obtained by the method described in comparative example 28, using methyl 3-formyl-4,5-dimethyl-1- (2,2,2-triptorelin)pyrrole-2-carboxylate.

Mass spectrum (Cl, m/z): 246 (M++1).

The NMR spectrum (CDCl3+ DMSO-d6million days): 2,22 (s, 3H), of 2.35 (s, 3H), from 5.29 (sq, J = 9 Hz, 2H), 8,08 (s, 1H), 11,27 (s, 1H).

Comparative example 41

1-(2-foradil)-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-he

The target compound in the form of white crystals with a yield of 100% was obtained by the method described in comparative example 28, using methyl 1-(2-foradil)-3-formyl-4,5-dimethyl pyrrole-2-carboxylate.

Mass spectrum (Cl, m/z): 210 (M++1).

The NMR spectrum (CDCl3+ DMSO-d6million days ): of 2.21 (s, 3H), 2,32 (s, 3H), 4,62-4.89 (m, 4H), of 8.04 (s, 1H),

Crownie in the form of a grayish-white powder with a yield 91,0% was obtained by the method, described in comparative example 28, using methyl 1-(2,2-dottorati)-3-formyl-4,5-dimethylpyrrole - 2-carboxylate.

Mass spectrum (Cl) m/z: 228 (M++1).

The NMR spectrum (CDCl3+ DMSO-d6(million days): of 2.21 (s, 3H), of 2.35 (s, 3H), 4,85 (dt, J= 4 Hz, 2H), 6,20 (TT, J = 4 Hz 54 Hz, 1H), 8,07 (s, 1H), 12,10 (Shir. S., 1H).

Comparative example 43

1-(2-Butenyl)-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]-pyridazin - 7-he

The target compound (CIS/TRANS = 97/3) as light brown crystals with access 74,6% was obtained by the method described in comparative example 28, using methyl 1-(2-butenyl)-3-formyl-4,5-dimethylpyrrole-2-carboxylate (CIS/TRANS = 93/7).

The NMR spectrum (CDCl3(million days ): 1,62 by 1.68 (m, 0,09 H), a 1.75-of 1.85 (m, 2,91 H) of 2.20 (s, 3H), 2,29 (c, 3H), 5.08 to 5,14 (m 0,06 H), to 5.21-5,31 (m, 1,94 H), 5,34-5,70 (m, 2H), with 8.05 (s, 1H), of 9.89 (s, 1H).

Comparative example 44

1-(2-Chloro-2-propenyl)-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d] - pyridazin-7-he

The target compound in the form of pale yellow crystals with a yield of 100% was obtained by the method described in comparative example 28, using methyl 1-(2-chloro-2-propenyl)-3-formyl-4,5-dimethylpyrrole-2-carboxylate (TRANS).

Mass spectrum (Cl, m/z): 238 (M++1), 240 (M++3).

The NMR spectrum (CDCl3(million days): of 2.21 (s, 3H, 2,30 (s, 3H), 4 is-2-butenyl)-6,7-dihydropyrrolo [2,3-d]pyridazin-7-he

The target compound as a pale grayish-white powder (TRANS)output 40,0% was obtained by a method described in comparative example 28, using methyl 3-formyl-4,5-dimethyl-1-(4,4,4-Cryptor-2-butenyl) pyrrole-2-carboxylate (TRANS).

Mass spectrum (Cl, m/z): 272 (M++1).

The NMR spectrum (CDCl3+DMSO-d6(million days ): 2,22 (s, 3H), to 2.29 (s, 3H), 5.25-in of 5.40 (m, 3H), 6,55-6,63 (m, 1H), 8,08 (s, 1H), 11, 90 (lat., 1H).

Comparative example 46

1-(3,3-Debtor-2-propenyl)-2,3-dimethyl-7-dihydropyrrolo[2,3-d] pyridazin-7-he

The target compound in the form of a pale yellow powder with a yield of 83.0 per cent was obtained by a method described in comparative example 28, using methyl 1-(3,3-debtor-2-propenyl)-3-formyl-4.5-dimethylpyrrole-2-carboxylate.

Mass spectrum (Cl, m/z): 240 (M++1).

The NMR spectrum (CDCl3(million days): R $ 2.20 (s, 3H), 2,31 (s, 3H), 4,59-4,72 (m, 1H), 5,17 (d, J=8 Hz, 1H), 8,07 (s, 1H), 10,20 (width, 1H).

Comparative example 47

1-(3-Forproper)-2,3-dimethyl-6,7-dihydropyrrolo [2,3-d]pyridazin-7-he

The target compound in the form of white crystals with a yield 93,0% was obtained by a method described in comparative example 28, using methyl 1-(3-forproper)-3-formyl-4, 5-dimethylpyrrole-2-carboxylate.

Mass spectrum (Cl, m/z): 224 (M++ 1).

Comparative example 48

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

The target compound in the form of white crystals with a yield of 100% was obtained by a method described in comparative example 28, using methyl 3-formyl-4,5-dimethyl-1-(2-PROPYNYL)pyrrole-2 - carboxylate.

Mass spectrum (Cl, m/z): 202 (M++ 1).

The NMR spectrum (CDCl3+ DMSO-d6(million days): of 2.21 (s, 3H), 2,42 (s, 3H), 2,46 (s, 1H), 5,50 (s, 2H), with 8.05 (s, 1H), 11,49 (s, 1H).

Comparative example 49

1-(3,3-Dichloro-2-propenyl)-4,5-dimethyl-6,7-dihydropyrrolo [2,3-d] pyridazin-7-he

The target compound in the form of a grayish-white powder with a yield of 96.5% was obtained by a method described in comparative example 28, using methyl 1-(3,3-dichloro-2-propenyl)-3-formyl-4,5-dimethylpyrrole-2 - carboxylate.

Mass spectrum (Cl, m/z): 272 (M++ 1), 274 (M++ 3), 276 (M++ 5).

The NMR spectrum (CDCl3(million days): R $ 2.20 (s, 3H), 2,32 (m, 3H), 5,33 (d, J = 6 Hz, 2H), 6,09 (t, J = 6 Hz, 1H), 8,10 (s, 1H), 10,63 (width, 1H).

Comparative example 50

1-Cyclohexylmethyl-2,3-dimethyl-6,7-dihydropyrrolo [2,3-d]pyridazin-7-he

The target compound in the form of a white powder with a yield of 85.2% was obtained by a method described in comparative example 28, using the + 1).

The NMR spectrum (CDCl3(million days): 1,00 - of 1.29 (m, 5H), 1,47 - of 1.88 (m, 6H), of 2.20 (s, 3H), 2,31 (s, 3H), 4,33 (d, J = 7 Hz, 2H), 8,08 (s, 1H), 9,82 (Shir. S., 1H).

Comparative example 51

1-(2-Butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d]pyridazin

39 ml (0.43 mol) of phosphorus oxychloride was added to 3.53 grams (0,0163 mol) of 1-(2-butenyl)-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d] pyridazin-7-she (CIS/TRANS = 24/76) and the resulting mixture was stirred for 2.5 hours at a temperature of 97oC. the Reaction mixture was cooled to room temperature, and then, drop by drop was poured into water cooling with this ice. The resulting mixture was neutralized with 40% aqueous sodium hydroxide solution and was extracted with dichloromethane. The extract was washed with water and dried with anhydrous sodium sulfate, then the solvent drove away. The residue was purified by column chromatography on silica gel, using as eluent a mixture (1:1) toluene and ethyl acetate, resulting in a received 3,59 g (0,0152 mol) of 1-(2-butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d]pyridazine (CIS/TRANS = 21/79) in the form of light brown crystals.

Mass spectrum (Cl, m/z): 236 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,62 - 1,69 (2,4 (H, m), 1,79 - 1,85 (0,6 H, m) to 2.29 (3H, s), 2,39 (3H, s), 5,02 - 5,71 (4H, m), 9,17 (1H, s).

Comparative example 52
< / the output 67.2 per cent was obtained by way described in comparative example 51, using 2,3-dimethyl-1-(3-methyl-2-butenyl)-6,7 - dihydropyrrolo[2,3-d]pyridazin-7-it.

Mass spectrum (Cl) m/z: 250 (M++ 1), 252 (M++ 3).

The NMR spectrum (CDCl3(million days): 1,72 (s, 3H), equal to 1.82 (s, 3H), of 2.30 (s, 3H), 2.40 a (s, 3H), of 5.05 - 5,19 (m, 3H), 9,19 (s, 1H).

Comparative example 53

7-Chloro-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin

The target compound in the form of a pale yellow powder with a yield 94,0% was obtained by the method described in comparative example 51, using 2,3-dimethyl-1-(2-propenyl)-6,7-dihydropyrrolo [2,3-d]pyridazin-7-it.

Mass spectrum (Cl, m/z): 222 (M++ 1), 224 (M++ 3).

The NMR spectrum (CDCl3(million days): 2,30 (s, 3H), 2,39 (s, 3H), 4,63 (d, J = 16 Hz, 1H), 5,06 - to 5.21 (m, 3H), 5,93 - between 6.08 (m, 1H), 9,17 (s, 1H).

Comparative example 54

7-Chloro-1-cyclopropylmethyl-2,3-dimethylpyrrole[2,3-d]pyridazin

The target compound in the form of a pale yellow powder with a yield of 79.7 per cent was obtained by a method described in comparative example 51, using 1-cyclopropylmethyl-2,3-dimethyl-6,7-dihydropyrrolo [2,3-d]pyridazin-7-it.

Mass spectrum (Cl, m/z): 236 (M++ 1), 238 (M++ 3).

The NMR spectrum (CDCl3(million days): range 0.38 to 0.60 (m, 4H), 1,16 - 1,22 (m, 1H), 2,30 (s, 3H), of 2.44 (s, 3H), of 4.44 (d, J = 8 Hz, 2H), 9,16 (the e connection (TRANS) in the form of light brown crystals with a yield of 89.7% was obtained by way described in comparative example 51, using 2,3-dimethyl-1-(2-pentenyl)-6,7-dihydropyrrolo [2,3-d]pyridazin-7-it (trance)

Mass spectrum (Cl) m/z: 250 (M++ 1), 252 (M++ 3).

The NMR spectrum (CDCl3(million days): 1,09 (t, J = 8 Hz, 3H), 2,12 - 2,31 (m, 5H), 2.40 a (s, 3H), 5,19 (doctor J = 7 Hz, 2H), 5,24 - 5,62 (m, 2H), 9,16 (s, 1H).

Comparative example 56

7-Chloro-2,3-dimethyl-1-(3-phenyl-2-propenyl)pyrrolo[2,3-d]pyridazin

The target compound (TRANS) in the form of light brown crystals with a yield of 82.2 per cent was obtained by a method described in comparative example 51, using 2,3-dimethyl-1-(3-phenyl-2-propenyl)-6,7 - dihydropyrrolo[2,3-d]pyridazin-7-it (TRANS).

Mass spectrum (Cl, m/z): 298 (M++ 1), 300 (M++ 3).

The NMR spectrum (CDCl3(million days): 2,33 (s, 2H), 2,46 (s, 3H), 5.25 - in of 5.34 (m, 2H), 6,13 (d, J = 17 Hz, 1H), 6,32 (DD, J = 17 Hz, 5 Hz, 1H), 7.18 in - 7,40 (m, 5H), of 9.21 (s, 1H).

Comparative example 57

7-Chloro-2,3-dimethyl-1-vinylpyrrole[2,3-d]pyridazin

The target compound in the form of a white powder with a yield of 65.1% was obtained by a method described in comparative example 51, using 2,3-dimethyl-1-vinyl-6,7-dihydropyrrolo [2,3-d]pyridazin-7-it.

Mass spectrum (Cl, m/z): 208 (M++ 1), 210 (M++ 3).

The NMR spectrum (CDCl3(million days): 2,31 (s, 3H), 2,42 (s, 3H), lower than the 5.37 (d, J-1-(2-methyl-2-propenyl)pyrrolo[2,3-d]pyridazin

The target compound as a white powder with a yield of 91.2 per cent was obtained by a method described in comparative example 51, using 2,3-dimethyl-1-(2-methyl-2-propenyl)-6,7 - dihydropyrrolo[2,3-d]pyridazin-7-it.

Mass spectrum (Cl, m/z): 236 (M++ 1), 238 (M++ 3).

The NMR spectrum (CDCl3(million days): is 1.81 (s, 3H), of 2.30 (s, 3H), of 2.35 (s, 3H), 3,95 (s, 1H), around 4.85 (s, 1H), 4,99 (s, 2H), 9,18 (s, 1H).

Comparative example 59

7-Chloro-2,3-dimethyl-1-(2,2,2-triptorelin)pyrrolo[2,3-d]pyridazin

The target compound in the form of a white powder with a yield of 89.1% was obtained by a method described in comparative example 51, using 2,3-dimethyl-1-(2,2,2-triptorelin)-6,6 - dihydropyrrolo[2,3-d]pyridazin-7-it.

Mass spectrum (Cl, m/z): 264 (M++ 1).

The NMR spectrum (CDCl3(million days): 2,32 (s, 3H), 2,47 (s, 3H), 5,19 (kV, J = 9 Hz, 2H), which 9.22 (s, 1H).

Comparative example 60

7-Chloro-1-cyclopropyl-2,3-dimethylpyrrole[2,3-d]pyridazin

The target compound as a pale cream-colored powder with a yield of 95.5 percent was obtained by a method described in comparative example 51, using 1-cyclopropyl-2,3-dimethyl-6,7-dihydropyrrolo [2,3-d]pyridazin-7-it.

Mass spectrum (Cl, m/z): 222 (M++ 1), 224 (M++ 3).

The NMR spectrum (CDCl3(million days): 1,05 - 1,12 (m, 2H), 1,31 - 1,39 is almirola[2,3-d]pyridazin

The target compound in the form of a light brown powder with a yield of 56.2% was obtained by a method described in comparative example 51, using 1-(2-foradil)-2,3-dimethyl-6,7-dihydropyrrolo [2,3-d]pyridazin-7-it.

Mass spectrum (Cl) m/z: 228 (M++ 1), 230 (M++ 3).

The NMR spectrum (CDCl3(million days): 2,31 (s, 3H), of 2.46 (s, 3H), 4,67 - 4,82 (m, 2H), 4,88 (s, 2H), 9,19 (s, 1H).

Comparative example 62

7-Chloro-1-(2,2-dottorati)-2,3-dimethylpyrrole[2,3-d]pyridazin

The target compound in the form of light beige crystals with a yield of 75.0% was obtained by a method described in Comparative example 51, using 1-(2,2-triptorelin)-2,3-dimethyl-6,7-dihydropyrrolo [2,3-d]pyridazin-7-it.

Mass spectrum (Cl, m/z): 246 (M++1), 248 (M++3).

The NMR spectrum (CDCl3(million days): 2,30 (c, 3H), 2,45 (c, 3H), 4,87 (dt, J = 14 Hz, 4 Hz, 2H), 6,14 (TT, J = 54 Hz, 4 Hz, 1H), 9,20 (s, 1H).

Comparative example 63

7-Chloro-1-cyclohexyl-2,3-dimethylpyrrole[2,3-d]pyridazin

The target connection in the form of a cream powder with a yield of 84.8% was obtained by a method described in comparative example 51, using 1-cyclohexyl-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-it.

Mass spectrum (Cl, m/z): 264 (M++1), 266 (M++3).

The NMR spectrum (CDCl3

7-Chloro-3-ethyl-2-methyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin

The target compound in the form of a light brown powder with a yield of 68.8% was obtained by a method described in comparative example 51 using 3-ethyl-2-methyl-1-(2-propenyl) 6,7-dihydropyrrolo[2,3-d]pyridazin-7-it.

Mass spectrum (Cl, m/z): 236 (M++1), 238 (M++3).

The NMR spectrum (CDCl3(million days): 1,24 (t, J=8 Hz, 3H), 2.40 a (s, 3H), was 2.76 (q, J = 8 Hz, 2H), 4,63 (d, J = 17 Hz, 1H), 5,07-5,20 (m, 3H), 5,94 - 6,09 (m, 1H), of 9.21 (s, 1H).

Comparative example 65

1-(2-Butenyl)-7-chloro-2,3-dimethylpyrrole[2,3-d]pyridazin

The target compound (CIS/TRANS=98/2) as a pale yellow oily substance with access 84,9% was obtained by a method described in comparative example 51, using 1-(2-butenyl)-2,3 - dimethyl-6,7-dihydropyrrolo[2,3-d] -pyridazin-7-she (CIS/TRANS=97/3).

Mass spectrum (Cl, m/z): 236 (M++ 1), 238 (M++3).

The NMR spectrum (CDCl3) million days): 1,62 was 1.69 (m, 0.2 H), 1,78 - to 1.87 (m, 2,8 H) to 2.29 (s, 3H), 2,39 (s, 3H), 5,01-5,08 (m, 0,1 H), 5,15-5,23 (m, 1,9 H), and 5.30 - 5,73 (m, 2H), 9,14 (s, 1H).

Comparative example 66

7-Chloro-1-(2-chloro-2-propenyl)-2,3-dimethylpyrrole[2,3-d]pyridazin

The target compound in the form of grayish-white crystals with a yield of 94,4% was obtained by a method described in comparative example 51, the, /z): 256 (M++1), 258 (M++3), 260 (M++5).

The NMR spectrum (CDCl3(million days): 2,31 (s, 3H), 2.40 a (s, 3H), 4,50 - 4,55 (m, 1H), 5,18 - of 5.26 (m, 2H), 5,30 lower than the 5.37 (m, 1H), 9,20 (s, 1H).

Comparative example 67

1-(2-Butenyl)-7-chloro-2-ethyl-3-methylpyrrole[2,3-b]pyridazin

The target compound (CIS/TRANS= 4/96) in the form of a bright reddish-white powder with a yield of 63.4 per cent was obtained by a method described in comparative example 51, using 1-(2-butenyl)-2-ethyl-3-methyl-6,7-dihydropyrrolo[2,3-d] pyridazin-7-she (CIS/TRANS=15/85).

Mass spectrum (Cl) m/z: 250 (M++1), 252 (M++3).

The NMR spectrum (CDCl3(million days): of 1.23 (t, J = 8 Hz, 3H), 1,58 - to 1.67 (m, 2,88 H), 2.77 - to 2,84 (m, 0,12 H) of 2.30 (s, 3H), 2,82 (kV, J = 8 Hz, 2H), 5,00 - 5,09 (m, 2H), 5,16 - and 5.30 (m, 1H), of 5.53 - 5,69 (m, 1H), 9,14 (s, 1H).

Comparative example 68

7-chloro-2,3-dimethyl-1-(4,4,4-Cryptor-2-butenyl)pyrrolo[2,3-b] pyridazin

The target compound (TRANS) as a pale yellow solid with a yield 78,0% was obtained by a method described in comparative example 51, using 2,3-dimethyl-1-(4,4,4-Cryptor-2-butenyl)-6,7-dihydropyrrolo[2,3-d] pyridazin-7-it (TRANS).

Mass spectrum (Cl, m/z): 290 (M++ 1).

The NMR spectrum (CDCl3(million days): of 2.23 (s, 3H), 2,39 (s, 3H), 5.08 to to 5.17 (m, 1H), 5,24 - and 5.30 (m, 2H), 6,55 - 6,63 (m, 1H), which 9.22 (s, 1H).

Comparison is in the form of a white powder with output = 79,1% was obtained by way described in comparative example 51, using 1-(3,3-debtor-2-propenyl)-2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin - 7-it.

Mass spectrum (Cl, m/z): 258 (M++1), 260 (M++3).

The NMR spectrum (CDCl3(million days): 2,30 (s, 3H), 2,43 (s,3H), 4,50 - br4.61 (m, 1H), 5,11 - by 5.18 (m, 2H), 9,18 (s, 1H).

Comparative example 70

7-Chloro-1-(3-forproper)-2,3-dimethylpyrrole[2,3-d]pyridazin

The target compound in the form of white crystals with a yield of 86.9% was obtained by a method described in comparative example 51, using 1-(3-forproper)-2,2-dimethyl-6,7-dihydropyrrolo[2,3-d] pyridazin-7-it.

Mass spectrum (Cl) m/z: 242 (M++1), 244(M++3).

The NMR spectrum (CDCl3(million days): 2,08 - of 2.36 (m, 2H), 2,30 (s, 3H), of 2.44 (s, 3H), of 4.49 (dt, J = 54 Hz, 6 Hz, 2 H), with 4.64 (t, J=8 Hz, 2H), 9,17 (s, 1H).

Comparative example 71

7-Chloro-2,3-dimethyl-1-(2-PROPYNYL)pyrrolo[2,3-d]-pyridazin

The target compound as a white powder with a yield of 67.2 per cent was obtained by a method described in comparative example 51, using 2,3-dimethyl-1-(2-PROPYNYL)-6,7-dihydropyrrolo [2,3-d]pyridazin-7-it.

Mass spectrum (Cl) m/z: 220 (M++1), 222 (M++3).

The NMR spectrum (CDCl3(million days): 2,30 (s, 3H), 2,39 (s, 1H), 2,50 (s, 3H), 5,31 (s, 2H), 9,19 (s, 1H).

Comparative example 72

Mass spectrum (Cl, m/z): 290 (M++ 1), 292 (M++ 3), 294 (M++ 5).

The NMR spectrum (CDCl3(million days): 2,30 (s, 3H), 2,42 (s, 3H), 5,27 (d, J = 6 Hz, 2H), 5,96 (t, J = 6 Hz, 1H), 9,17 (s, 1H).

Comparative example 73

7-Chloro-1-(3,3-dichloro-2-propenyl)-2,3-dimethylpyrrole [2,3-d]pyridazin

The target compound as a white powder with a yield of 95.5 percent was obtained by a method described in comparative example 51, using 1-cyclohexylmethyl-2,3-dimethyl-6,7-dihydropyrrolo [2,3-d]pyridazin-7-it.

Mass spectrum (Cl, m/z): 278 (M++ 1), 280 (M++3).

The NMR spectrum (CDCl3(million days): 0,95 - of 1.30 (m, 5H), 1,45 - 1,90 (m, 6H), of 2.28 (s, 3H), 2.40 a (s, 3H), 4,29 (d, J = 8 Hz, 2H), 9,14 (s, 1H).

Comparative example 74

Methyl 4,5-dimethylpyrrole-2-carboxylate

(1) 2-Methyl-3-oxobutanoate salt

To a mixture of 20.5 g (0, 891 mol) of sodium and 720 ml of anhydrous diethyl ether under stirring for 2 hours was added a solution consisting of 67,6 g (of 0.93 mol) of 2-butanone and 71.7 g (of 0.93 mol) of ethylformate, cooling with this ice, and then the resulting mixture was stirred at the same temperature for 6.5 hours. Osujdennymi-3-oxobutanoate salt in the form of a dark yellow solid.

(2) Methyl 4,5-dimethylpyrrole-2-carboxylate

To a solution containing 61,5 g (of 0.53 mol) of methylacetoacetate in 208 ml of acetic acid under ice cooling for 3 hours at the drop of a solution was added containing 40,7 g (0.59 mol) of sodium nitrate in 68 ml of water, and the resulting mixture was stirred at the same temperature for three hours and then left overnight at room temperature. To the reaction mixture for two hours was added to the solution containing 104 g (0,852 mol) of the above 2-methyl-3-oxobutanoate salt (1) in 200 ml of water, and then 90 g (1.38 mol) of zinc powder at 60-64oC and the resulting mixture was heated under reflux for 30 minutes. Thus obtained hot reaction mixture was poured into 1 kg of ice water and the precipitated dark yellow solid was collected by filtration, and then washed with water. These solids were dissolved in 800 ml of ethyl acetate, and any insoluble substances containing zinc was filtered. The filtrate was dried with anhydrous sodium sulfate, and the solvent drove away. Thus obtained concentrate was left overnight at room temperature, after which the precipitated crystals were collected by filtration and washed twice with 25 ml (each of roxelana in the form of dark yellow powdery crystals.

Mass spectrum (Cl, m/z): 154 (M++1).

The NMR spectrum (CDCl3(million days): 2,00 (s, 3H), of 2.21 (s, 3H), 3,81 (s, 3H), of 6.68 (s, 2H), 9,20 (Shir. S., 1H).

Comparative example 75

Methyl-3-formid-4,5-dimethylpyrrole-2-carboxylate

To a solution of methyl 4,5-dimethylpyrrole-2-carboxylate (13,7 g, 0,0898 mol) in 13 ml of 0.17 mol) of dimethylformamide in a period of 1.3 hours under ice cooling for one drop was added 15.0 g (0,0979 mol) of phosphorus oxychloride and the resulting mixture was stirred for half an hour at room temperature, and then within half an hour at a temperature of 90 - 100oC. the thus Obtained hot reaction mixture was poured into ice water, and then dissolved. The solution was brought to pH 5 to 6 by adding 10% aqueous sodium hydroxide solution. Precipitated solids were collected by filterChain and was dissolved in 600 ml of ethyl acetate. The filtrate was extracted with twice 200 ml (each time) of ethyl acetate. The combined extracts were washed with water, dried with anhydrous sodium sulfate, and the solvent drove away. The residue was washed with a mixture of hexane and ethyl acetate, and then collected by filtration, which was obtained 10.6 g (0,0583 mol) of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate as a brown powder.

MA,54 (s, 1H).

Comparative example 76

Methyl 3-acetyl-4,5-dimethylpyrrole-2-carboxylate

To a solution of methyl 4,5-dimethylpyrrole-2-carboxylate (1.50 g, 0,0098 mol) in 15 ml dichloromethane at room temperature was added 5.0 ml of acetic anhydride, and then within 10 minutes, one drop was added a mixture consisting of 1.5 ml (0,013 mol) of tin tetrachloride (2) and 4 ml of dichloromethane. The resulting mixture was stirred for 30 minutes, poured into ice water, neutralized with an aqueous solution of sodium bicarbonate to pH 7 to 8 and was extracted with dichloromethane. After drying of the extract with anhydrous sodium sulfate, the solvent is kept at reduced pressure. The residue was purified by column chromatography on silica gel, using as eluent a mixture (1:2) etelaat and hexane, resulting in received of 1.61 g of methyl 3-acetyl-4,5-dimethylpyrrole-2-carboxylate in the form of a grayish white solid.

Mass spectrum (Cl, m/z): 196 (M++ 1).

The NMR spectrum (CDCl3(million days): 2,02 (s, 3H), of 2.20 (s, 3H), 2.57 m (s, 3H), 3,85 (s, 3H), 8,95 (Shir.s, 1H).

Comparative example 77

2,3-Dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-he

To a solution of methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate (of 4.00 g of 0.022 mol) in 80 ml of acetic acid Nero was stirred for 2 hours at a temperature of 110oC. After completion of the reaction, the reaction mixture was poured into ice water. The precipitate was collected by filtration and thoroughly washed with water. Then the residue was dissolved in dichloromethane and this solution was dried with anhydrous sodium sulfate. After removal of the solvent under reduced pressure received 3,40 g of 2,3-dimethyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-it is in the form of grayish-white powder.

Mass spectrum (Cl, m/z): 164 (M++ 1).

The NMR spectrum (CDCl3+ DMSO-d6(million days): to 2.18 (s, 3H), 2,31 (s, 3H), 8,03 (s, 1H), 12,04 (Shir.s, 2H).

Comparative example 78

7-Chloro-2,3-dimethylpyrrole[2,3-d]pyridazin

45 ml of phosphorus oxychloride was added to the 3.35 g (0,021 mol) of 2,3-dimethyl-6,7-dihydropyrrolo[2,3-d] pyridazin-7-she and the resulting mixture was heated under reflux for 2 hours. After completion of the reaction, the reaction mixture was slowly poured into ice water and the aqueous mixture was neutralized by adding an aqueous solution of sodium hydroxide. The precipitated yellow solid was collected by filtration and thoroughly washed with water. Then the solid residues were dissolved in dichloromethane and dried with anhydrous sodium sulfate, then the solvent is kept at reduced pressure. The residue was purified is La, resulting received 2,39 g of 7-chloro-2,3-dimethylpyrrole[2,3-d]pyridazine in the form of a pale yellow powder.

Mass spectrum (Cl, m/z): 182 (M++ 1), 184 (M++ 3).

The NMR spectrum (CDCl3+ DMSO-d6(million days): to 2.29 (s, 3H), of 2.46 (s, 3H), 9,14 (s, 1H), 11,70 (Shir.s, 1H).

Comparative example 79

7-Benzyloxy-2,3-dimethylpyrrole[2,3-d]pyridazin

To a solution obtained by adding 0.26 g (to 0.011 mol) of sodium in 25 ml of benzyl alcohol at room temperature was added 1.35 g (0,0074 mol) of 7-chloro-2,3-dimethyl-pyrrolo[2,3-d] pyridazine and the resulting mixture was heated at a temperature of 115oC, and then heating this mixture was added 10 ml of benzyl alcohol. Heating was continued for 30 hours with stirring. After completion of the reaction, the reaction mixture was poured into ice water and was extracted with dichloromethane; after drying of the extract with anhydrous sodium sulfate the solvent was removed under reduced pressure, and benzyl alcohol drove away under reduced pressure. The residue was purified by column chromatography on silica gel, using as eluent a mixture (20: 1) of chloroform and methanol, resulting in a received 1,15 g of 7-benzyloxy-2,3-dimethylpyrrole[2,3-d]pyridazine in the form of pale yellow is.D.): of 2.23 (s, 3H), of 2.38 (s, 3H), 5,69 (s, 2H), 7,30 - of 7.60 (m, 5H), 8,99 (s, 1H), 10,65 (Shir.s, 1H).

Comparative example 80

7-(4-Forbindelse)-2,3-dimethylpyrrole[2,3-d]pyridazin

The target compound in the form of pale yellow crystals with a yield of 29.8 per cent was obtained by a method described in comparative example 79, using 7-chloro-2,3-dimethylpyrrole[2,3-d]pyridazine and 4-fermentelos alcohol.

Mass spectrum (Cl, m/z): 272 (M++ 1).

The NMR spectrum (CDCl3+ DMSO-d6(million days): of 2.23 (s, 3H), 2,39 (s, 3H), to 5.66 (s, 2H), 7,06 for 7.12 (m, 2H), 7,52 - to 7.61 (m, 2H), of 8.92 (s, 1H), 11,40 (Shir. s, 1H).

Comparative example 81

Methyl 3-formyl-4,5-dimethyl-1-vinylpyrrole-2-carboxylate

A solution containing 0.15 g (0,00052 mol) of methyl 1-(2-bromacil)-3-formyl-4,5-dimethylpyrrole-2-carboxylate and 0.08 g (0,00052 mol) of 1,8-diazabicyclo[5.4.0] undec-7-ene dissolved in 2 ml of tetrahydrofuran was heated under reflux for 6 hours; the reaction mixture was left to cool to room temperature, and then was purified by column chromatography on silica gel, using as eluent a mixture (9: 1) toluene and ethyl acetate, resulting received 0,080 g (yield 74%) of methyl 3-formyl-4,5-dimethyl-1-vinylpyrrole-2-carboxylate as pale yellow crystals.

Comparative example 82

Ethyl 1-(2-butenyl)-4-ethyl-5-methylpyrrole-2-carboxylate

The target compound (CIS/TRANS = 25/75) as a pale yellow oily substance with access to 30.1% was obtained by a method described in comparative example 1, using 2-pentene and ethyl N-(2-butenyl)glycinate.

Mass spectrum (Cl, m/z): 236 (M++ 1).

The NMR spectrum (CDCl3(million days): of 1.13 (t, J = 7 Hz, 3H), 1,32 (t, J = 7 Hz, 3H), of 1.62 (d, J = 7 Hz, 2,25 H) of 1.75 (d, J = 7 Hz, 0,75 H) of 2.16 (s, 3H), 2.40 a (sq , J = 7 Hz, 2H), 4,24 (sq, J = 7 Hz, 2H), 4,87 (d, J = 7 Hz, 1,5 H), 5,00 (d, J = 7 Hz, 0.5 H), a 5.25 - 5,41 (m, 1H), 5,49 - to 5.66 (m, 1H), 6,83 (s, 1H).

Comparative example 83

Ethyl 1-(2-butenyl)-5-methyl-4-pentylindol-2-carboxylate

The target compound (CIS/TRANS = 21/79) as a red oily substance with a yield of 26.1% was obtained by a method described in comparative example 1, using 2-octanone and ethyl N-(2-butenyl)glycinate.

Mass spectrum (Cl, m/z): 278 (M++ 1).

The NMR spectrum (CDCl3(million days): from 0.90 (t, J = 7 Hz, 3H), 1.18 to the 1.44 (m, 7H), 1,44 is 1.60 (m, 2H), 1,65 (d, J = 7 Hz, 2,37 H) of 1.73 (d, J = 7 Hz, 0,63 H) of 2.15 (s, 3H), is 2.37 (t, J = 7 Hz, 2H), 4,22 (sq, J = 7 Hz, 2H), 4,84 - 4,89 (m, 1,58 H), free 5.01 (d, J = 7 Hz, 0,42 H), 5,23 - 5,42 (m, 1H), 5,48 - 5,63 (m, 1H), 6,79 (s, 1H).

Comparative note the yellow oily substance with a yield of 44.1% was obtained by way described in comparative example 1, using Propionaldehyde and ethyl N-(2-butenyl)glycinate.

Mass spectrum (Cl, m/z): 208 (M++ 1).

The NMR spectrum (CDCl3(million days): to 1.32 (t, J = 7 Hz, 3H), 1,68 (d, J = 8 Hz, H 2,1), 1,74 (d, J = 8 Hz, H 0,9), to 2.06 (s, 3H), 4.26 deaths (sq, J = 7 Hz, 2H), 4,79 (d, J = 7 Hz, 1,4 H), is 4.93 (d, J = 6 Hz, 0.6 a (H), 5,49 - of 5.68 (m, 2H), 6,62 (s, 1H), 6,77 (s, 1H).

Comparative example 85

Ethyl 1-(2-butenyl)-4-ethyl-3-formyl-5-methylpyrrole-2-carboxylate

The target compound (CIS/TRANS = 27/73) as an orange oily substance with a yield of 26.5% was obtained by a method described in comparative example 5, using 1-(2-butenyl)-4-ethyl-5-methylpyrrole-2-carboxylate (CIS/TRANS = 25/75).

Mass spectrum (Cl, m/z): 264 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,08 (t, J = 8 Hz, 3H), of 1.38 (t, J = 8 Hz, 3H), 1,67 (d, J = 6 Hz, 2,19 H) of 1.75 (d, J = 6 Hz, 0,81 H), are 2.19 (s, 3H), 2,72 (sq , J = 8 Hz, 2H), 4,37 (sq, J = 8 Hz, 2H), 4,87 (d, J = 6 Hz, 1,46 H), at 4.99 (d, J = 6 Hz, 0,54 H), and 5.30 - 5,49 (m, 1H), 5,52 - of 5.68 (m, 1H), 10,48 (s, 1H).

Comparative example 86

Methyl 3-formyl-4,5-dimethyl-1-(2-methylcyclopropyl) pyrrole-2-carboxylate

The target compound in the form of yellow crystals with access 92,0% was obtained by a method described in comparative example 9, using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate B>(million days): 0,22 - 0,31 (m, 1H), 0,46 - of 0.53 (m, 1H), up 0.70 to 0.92 (m, 2H), 1.00 m (doctor J = 6 Hz, 3H), of 2.21 (s, 3H), of 2.28 (s, 3H), 3,90 (s, 3H), 4,25 (doctor J = 6 Hz, 2H), 10,43 (s, 1H).

Comparative example 87

Ethyl 1-(2-butenyl)-3-formyl-5-methyl-4-pentylindol-2-carboxylate

The target compound (CIS/TRANS = 22/78) as an orange oily substance with a yield of 41.4 per cent was obtained by a method described in comparative example 5, using ethyl 1-(2-butenyl)-5-methyl-4-pentylindol-2-carboxylate (CIS/TRANS = 21/79).

Mass spectrum (Cl, m/z): 306 (m++ 1).

The NMR spectrum (CDCl3(million days): 0,88 (t, J = 7 Hz, 3H), 1,21 - of 1.53 (m, 9H), 1,68 (doctor J = 8 Hz, 2,34 H) to 1.79 (d, J = 8 Hz, 0,66 H) of 2.20 (s, 3H), 2,70 (so J = 7 Hz, 2H), 4,36 (sq J = 7 Hz, 2H), around 4.85 (d, J = 6 Hz, 1,56 H), 4,99 (doctor J = 7 Hz, 0,44 H), and 5.30 - vs. 5.47 (m, 1H), 5,49 - to 5.66 (m, 1H), 10,47 (s, 1H).

Comparative example 88

1-(2-Butenyl)-3-ethyl-2-methyl-6,7-dihydropyrrolo[2,3-d] pyridazin-7-he

The target compound (CIS/TRANS = 23/77) in the form of a pale yellow powder with a yield rate of 99.0% was obtained by a method described in comparative example 28, using ethyl 1-(2-butenyl)-4-ethyl-3-formyl-5-methylpyrrole-2-carboxylate (CIS/TRANS = 25/75).

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

The NMR spectrum (CDCl3(million days): 1,20 (t, J = 8 Hz, 3H), 1,67 (d, J = 8 Hz, 2,31 H), 1,80 (doctor J = 8 Hz, 0,69 H) of 2.30 (s, 3H), 2,65 (kV, J = 8 Hz, 2H), 5,13 (doctor J = 7 Hz,3-Dimethyl-1-(2-methylcyclopropyl)-6,7-dihydropyrrolo[2,3-d] pyridazin-7-he

The target compound as white helplearn crystals with a yield of 88.7 per cent was obtained by a method described in comparative example 28, using ethyl 3-formyl-4,5-dimethyl-1-(2 - methylcyclopropyl)pyrrole-2-carboxylate.

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

The NMR spectrum (CDCl3(million days): for 0,19 0,26 (m, 1H), and 0.61 to 0.70 (m, 1H), 0,84 - of 1.02 (m, 5H), of 2.23 (s, 3H), of 2.38 (s, 3H), of 4.44 (d, J = 6 Hz, 2H), 8,08 (s, 1H), 10,13 (Shir. s, 1H).

Comparative example 90

1-(2-Butenyl)-2-methyl-3-pentyl-6,7-dihydropyrrolo[2,3-d] pyridazin-7-he

The target compound (CIS/TRANS = 20/80) in the form of a brownish-white powder with a yield of 80.1% was obtained by a method described in comparative example 28, using ethyl 1-(2-butenyl)-3-formyl-5-methyl-4-pentylindol-2-carboxylate (CIS/TRANS = 22/78).

Mass spectrum (Cl, m/z): 274 (M++ 1).

The NMR spectrum (CDCl3(million days): from 0.90 (t, J = 7 Hz, 3H), 1,21 - of 1.42 (m, 4H), 1,48 - to 1.63 (m, 2H), 1.69 in (d, J = 7 Hz, H 2,4), of 1.80 (d, J = 8 Hz, 0.6 a (H), of 2.28 (s, 3H), 2,61 (t, J = 7 Hz, 2H), 5,07 - of 5.15 (m, 1,6 H), 5,28 (d, J = 8 Hz, 0,4 H), 5,34 - 5,52 (m, 1H), 5,54 - 5,69 (m, 1H), of 8.06 (s, 1H), 9,82 (Shir.S., 1H).

Comparative example 91

1-(2-Butenyl)-7-chloro-3-ethyl-2-methylpyrrole[2,3-d]pyridazin

The target compound (CIS/TRANS = 26/74) as a dark yellow powder with access to 80.8% was obtained by a method described in the CIS/TRANS = 23/77).

Mass spectrum (Cl) m/z: 250 (M++ 1), 252 (M++ 3).

The NMR spectrum (CDCl3(million days): of 1.23 (t, J = 8 Hz, 3H), 1,66 (doctor J = 8 Hz, 2,22 H), is 1.81 (d, J = 8 Hz, 0,78 H) to 2.40 (s, 3H), was 2.76 (sq, J = 8 Hz, 2H), 5,03 - 5,10 (m, 1,48 H), 5,20 (doctor J = 8 Hz, 0,52 H), 5,24 - 5,41 (m, 1H), 5,55 - 5,69 (m, 1H), 9,20 (s, 1H).

Comparative example 92

7-Chloro-2,3-dimethyl-1-(2-methylcyclopropyl)pyrrolo [2,3-d]pyridazin

The target compound in the form of white crystals with a yield of 98.3% was obtained by a method described in comparative example 51, using ethyl 2,3-dimethyl-1-(2-methylcyclopropyl)- 6,7-dihydropyrrolo[2,3-d]pyridazin-7-it.

Mass spectrum (Cl, m/z): 350 (M++ 1), 352 (M++ 3).

The NMR spectrum (CDCl3(million days): 0,26 - 0,34 (m, 1H), 0,50 - 0,59 (m, 1H), from 0.76 to 1.03 (m, 5H), is 2.30 (s, 3H), of 2.46 (s, 3H), 4,46 (doctor J = 7 Hz, 2H), 9,04 (s, 1H).

Comparative example 93

1-(2-Butenyl)-7-chloro-2-methyl-3-Pantelleria[2,3-d]pyridazin

The target compound (CIS/TRANS = 20/80) as an orange oily substance with a yield of 88.5 percent was obtained by a method described in comparative example 51, using 1-(2-butenyl)-2-methyl-3-pentyl-6,7-dihydropyrrolo[2,3-d]pyridazin-7-she (CIS/TRANS = 20/80).

Mass spectrum (Cl, m/z): 292 (M++ 1), 294 (M++ 3).

The NMR spectrum (CDCl3(million days): 0,88 (t, J = 8 Hz, 3H), 1,23 - of 1.40 (m, 4H), 1.55V is anicely example 94

5-[3-(4-forfinal)propionyl]-2,3-dimethylpyrrole

To a solution of bromide of etermine in 17 ml of anhydrous tetrahydrofuran was obtained from 0,83 g (0,0341 mol) magnesium turnings and £ 4.02 g (0,0361 mol) of ethylbromide at room temperature for 10 minutes, one drop of solution was added 2,3-dimethylpyrrole (2.50 g, to 0.263 mol) in 10 ml of anhydrous tetrahydrofuran. Then boiling the mixture was left for 30 minutes for cooling to room temperature, resulting in a received bromide 4,5-dimethyl-2-pyrroline. To a solution of 3-(4-forfinal)propionitrile in 25 ml of anhydrous tetrahydrofuran was obtained from 9,50 g (0,0565 mol) 3-(4-forfinal)propionic acid and 6.0 ml of thionyl chloride, for approximately 35 minutes at a temperature of -78oC in a stream of nitrogen drop was added to the above tertrahydrofuran ring bromide solution of 4,5-dimethyl-2-pyrroline, and then the reaction mixture was heated to room temperature for approximately 2 hours. To the mixture was added 15 ml of a saturated aqueous solution of ammonium chloride and 5% ml of water, after which the aqueous layer was separated and was extracted with ether. The combined ether extract (250 ml), washed twice with 100 ml each time) about 10% aqueous sodium hydroxide solution, and zation solvent under reduced pressure the residue was purified by column chromatography on silica gel, using as eluent a mixture (1:10) of ethyl acetate and hexane, resulting in received of 3.42 g of the target compound as a pale brown solid.

Mass spectrum (Cl, m/z): 264 (M++ 1).

The NMR spectrum (CDCl3(million days): a 2.01 (s, 3H), 2,22 (s, 3H), 2,98 (Shir.s, 4H), 6,66 (doctor J = 2 Hz, 1H), 6,92 - of 6.99 (m, 2H), 7,15 - 7,20 (m, 2H), 9,31 (Shir.S., 1H).

Comparative example 95

5-(3-Phenylpropionyl)-2,3-dimethylpyrrole

The target compound as a pale purple solid with a yield 51,4% was obtained by a method described in comparative example 94, using 3-phenylpropionic acid.

Mass spectrum (Cl) m/z: 228 (M++ 1).

The NMR spectrum (CDCl3(million days): 2,00 (s, 3H), 2,22 (s, 3H), 3.00 and (Shir. s, 4H), of 6.66 (d, J = 2 Hz, 1H), 7,17 - to 7.32 (m, 5H), 9,41 (Shir.s, 1H).

Comparative example 96

5-[3-(2,4-Differenl)propionyl]-2,3-dimethylpyrrole

The target compound in the form of a brownish-yellow solid with a yield 48,0% was obtained by a method described in comparative example 94, using 3-(2,4-differenl-propionic acid.

Mass spectrum (Cl, m/z): 264 (M++ 1).

The NMR spectrum (CDCl3(million days): 2,00 (s, 3H), 2,22 (s, 3H), 2,94 was 3.05 (m, 4H), of 6.66 (d, J = 3 Hz, 1H), 6,67-for 6.81 (m, 2H), 7,14-7,22 (m, 1H), 9,44 (Shir.s, 1H).

Senil)propionyl] -2,3-dimethylpyrrole (1.39 g, 0,00567 mol) and 18-crown-6 (0,19 g, 0,00074 mol) in 40 ml of tetrahydrofuran was added 0,82 (0,00731 mol) of potassium tert-butylate and the mixture was stirred for 20 minutes at room temperature. After addition of 1.80 g (0,0115 mol) 1-bromo-2-butene (mixture of CIS - and TRANS-isomers), and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was poured into ice water and the aqueous mixture was extracted twice with 80 ml (each time) of ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and was dried with anhydrous sodium sulfate. After removal of the solvent under reduced pressure the residue was purified by column chromatography on silica gel, using as eluent a mixture (1:10) of ethyl acetate and hexane, resulting received from 0.90 g of target compound (CIS/TRANS = 22/78) as a pale yellow oily substance.

Mass spectrum (Cl, m/z): 300 (M++ 1).

ESR-spectrum (CDCl3(million days ): 1,58-of 1.65 (m, 2,34 H), 1,71-to 1.77 (m, 0,66 H), a 2.01 (s, 3H), and 2.14 (s, 3H), 2,90 totaling 3.04 (m, 4H), 4,89-4,94 (m, 1,56 H), 5,03-5,08 (m, 0,44 H), 5,28-5,41 (m, 1H), 5,49-the ceiling of 5.60 (m, 1H), 6,76 (s, 1H), 6,92-7,00 (m, 2H), 7,13-7,21 (m, 2H).

Comparative example 98

5-[3-(4-Forfinal)propionyl] -2,3-dimethyl-1-(2 - methylcyclopropyl)pyrrol

Mass spectrum (Cl, m/z): 314 (M++ 1).

The NMR spectrum (CDCl3(million days ): of 0.14-0.21 (m, 1H), 0,41-of 0.48 (m, 1H), 0.67 and-of 0.90 (m, 2H), 0,97 (d, J = 6 Hz, 3H), a 2.01 (s, 3H), 2,17 (s, 3H), 2.91 in-of 3.07 (m, 4H), 4,25-to 4.28 (m, 2H), 6,77 (s, 1H), 6,91-6,98 (m, 2H), 7,16-7,22 (m, 2H).

Comparative example 99

1-Cyclopropylmethyl-5-[3-(4-forfinal)propionyl]-2,3-dimethylpyrrole

The target compound as a pale yellow oily substance with access to 64.8% was obtained by a method described in comparative example 97 using 5-[3-(4-forfinal)propionyl] -2,3-dimethylpyrrole and cyclopropanemethylamine.

Mass spectrum (Cl, m/z): 300 (M++ 1).

The NMR spectrum (CDCl3(million days ): of 0.29 to 0.36 (m, 2H), 0.39 to-0,49 (m, 2H), 1,07-to 1.21 (m, 1H), 2,02 (s, 3H), of 2.18 (s, 3H), 2.93 which is a 3.06 (m, 4H), 4,27 (d, J = 7 Hz, 2H), 6,78 (s, 1H), 6,91-of 6.99 (m, 2H), 7,14-7,22 (m, 2H).

Comparative example 100

5-[3-(4-Forfinal)propionyl]-2,3-dimethyl-1-(2-propenyl)pyrrol

The target compound as a pale yellow oily substance with a yield of 60.3% was obtained by a method described in comparative example 97 using 5-[3-(4-forfinal)propionyl]-2,3-dimethylpyrrole and 3-bromo-1-propene.

Mass spectrum (Cl, m/z): 286 (M++ 1).

I have 7 (C, 1H), 6.90 to-6,99 (m, 2H), 7,13-7,21 (m, 2H).

Comparative example 101

1-(2-Butenyl)-2,3-dimethyl-5-(3-phenylpropionyl)pyrrol

The target compound (CIS/TRANS = 23/77) as a yellow oily substance with access to 75.7% was obtained by a method described in comparative example 97 using 2,3-dimethyl-5-(3-phenylpropionyl)of pyrrole and 1-bromo-2-butene.

Mass spectrum (Cl, m/z): 282 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,64 (d, J = 8 Hz, 2,31 H), or 1.77 (d, J = 8 Hz, 0,69 H), a 2.01 (s, 3H), 2,17 (s, 3H), 3,02 (Shir.s, 4H), 4,89-5,96 (m, 1,54 H) 5,08 (d, J = 7 Hz, 0,46 H), 5,28-5,42 (m, 1H), 5,49-5,61 (m, 1H), 6,77 (s, 1H), 7,15-to 7.32 (m, 5H).

Comparative example 102

2,3-Dimethyl-5-(3-phenylpropionyl)-1-(2-propenyl)pyrrol

The target compound as a yellow oily substance with the release of 86,6% was obtained by a method described in comparative example 97 using 2,3-dimethyl-5-(3-phenylpropionyl)pyrrole and 3-methyl bromide-1-propene.

Mass spectrum (Cl, m/a): 268 (M++ 1).

The NMR spectrum (CDCl3(million days): 2,02 (s, 3H), 2.13 and (s, 3H), 2,94-3,10 (m, 4H), 4,70-of 4.77 (m, 1H), 4,99-5,09 (m, 3H), 5,94 (DDT, J = 17 Hz, 11 Hz, 7 Hz, 1H), 6,79 (s, 1H), 7,12-7,33 (m, 5H).

Comparative example 103

2,3-Dimethyl-1-(2-methylcyclopropyl)-5-(3-phenylpropionyl)pyrrol

The target compound as a yellow oily wellprepared)of pyrrole and 1-methyl bromide-2-methylcyclopropane.

Mass spectrum (Cl, m/z): 296 (M++ 1).

The NMR spectrum (CDCl3(million days ): of 0.14-0.21 (m, 1H), 0,42-0,49 (m, 1H), 0,68 with 0.93 (m, 2H), 0,97 (d, J = 6 Hz, 3H), a 2.01 (s, 3H), 2,17 (s, 3H), 3,05 (Shir.S., 4H), 4,25-4,34 (m, 2H), 6,78 (s, 1H), 7,12-7,33 (m, 5H).

Comparative example 104

1-Cyclopropylmethyl-2,3-dimethyl-5-(3-phenylpropionyl)pyrrol

The target compound as an orange oily substance with access 93,0% was obtained by a method described in comparative example 97 using 2,3-dimethyl-5-(3-phenylpropionyl)of pyrrole and bromelicola.

Mass spectrum (Cl, m/z): 282 (M++ 1).

The NMR spectrum (CDCl3(million days): 0,30-0,49 (m, 4H), 1,10-1,25 (m, 1H), 2,02 (s, 3H), 2,17 (s, 3H), 3,03 (Shir.s, 4H), 4,28 (d, J = 7 Hz, 2H), 6,800 (s, 1H), 7,14-7,31 (m, 5H).

Comparative example 105

1-(2-Butenyl)-5-[3-(2,4-differenl)propionyl]-2,3-dimethylpyrrole

The target compound (CIS/TRANS = 23/77) as a yellow oily substance with a yield of 55.4% was obtained by a method described in comparative example 97 using 5-[3-(2,4-differenl)propionyl]-2,3-dimethylpyrrole and 1-bromo-2-butene.

Mass spectrum (Cl, m/z): 318 (M++ 1).

The NMR spectrum (CDCl3(million days ): 1,62-of 1.64 (m, 2,31 H) of 1.74-1.77 in (m, 0,69 H) a 2.00 (s, 3H), and 2.14 (s, 3H), 2,99 (dir.s, 4H), 4,89 to 4.92 (m, 1,54 H) 5,04 is 5.07 (m, 0,46 H), 5,28-of 5.40 (m, 1H), 5,51-the ceiling of 5.60 (m, 1H), 6.73 x-to 6.80 (m, 3H), 7 is permitil)pyrrol

The target compound as a yellow oily substance with the release of an 80.2% was obtained by a method described in comparative example 97 using 5-[3-(2,4-differenl)propionyl]-2,3-dimethylpyrrole and 2-methylcyclopentanone.

Mass spectrum (Cl, m/z): 332 (M++ 1).

The NMR spectrum (CDCl3(million days ): 0,14-0,20 (m, 1H), 0,41-of 0.48 (m, 1H), 1,67-of 1.92 (m, 2H), 0,97 (d, J = 6 Hz, 3H), a 2.01 (s, 3H), 2,17 (s, 3H), 3.00 and (Shir.s, 4H), 4,20-4,32 (m, 2H), 6.73 x-to 6.80 (m, 3H), 7,15-of 7.23 (m, 1H).

Comparative example 107

1-Cyclopropylmethyl-5-[3-(2,4-differenl)propionyl]-2,3-dimethylpyrrole

The target compound as a yellow oily substance with a yield of 85.1% was obtained by a method described in comparative example 97 using 5-[3-(2,4-differenl)propionyl] -2,3-dimethylpyrrole of cyclopropanemethylamine.

Mass spectrum (Cl, m/z): 318 (M++ 1).

The NMR spectrum (CDCl3(million days): 0,30-0,50 (m, 4H), 1.06 a-1,12 (m, 1H), 2,02 (s, 3H), of 2.18 (s, 3H), 3.00 and (Shir.s, 4H), 4,27 (d, J = 7 Hz, 2H), 6,72-for 6.81 (m, 3H), 7,14-7,22 (m, 1H).

Comparative example 108

5-[3-(2,4-Differenl)propionyl]-2,3-dimethyl-1-(2-propenyl)pyrrol

The target compound as pale yellow oily substance with a yield of 81.7% was obtained by a method described in comparative example 97 using 5-[3-(2,4-di">

The NMR spectrum (CDCl3(million days): a 2.01 (s, 3H), 2.13 and (s, 3H), 2,99 (Shir.s, 4H), 4.72 in (d, J = 17 Hz, 1H), 4,98-free 5.01 (m, 2H), is 5.06 (d, J = 10 Hz, 1H), 5,86-6,00 (m, 1H), 6.73 x-to 6.80 (m, 3H), 7,13-7,21 (m, 1H).

Comparative example 109

1-(2-Butenyl)-2-[1-chloro-3-(4-forfinal)-1-propenyl] -3-formyl - 4,5-dimethylpyrrole

of 0.38 ml (0,00408 mol) of phosphorus oxychloride was added to 0,29 g (0,00397 mol) of anhydrous dimethylformamide and the resulting mixture was stirred for 30 minutes at room temperature. After adding one drop of a solution containing 0,89 g (0,00297 mol) of 1-(2-butenyl)-5-[3-(4-forfinal)propionyl] -2,3-dimethylpyrrole in 4 ml of dichloromethane, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water and then neutralized with an aqueous solution of sodium hydroxide. Water the mixture three times was extracted with 50 milliliters (every time) dichloromethane. The extract is successively washed with 30 ml of saturated aqueous sodium bicarbonate solution and 30 ml of a saturated aqueous solution of sodium chloride, and then dried with anhydrous sulfate into three. After purification of the solvent under reduced pressure the residue was purified by column chromatography on silica gel, using as eluent a mixture (1:12 - 1:9 ethyl acetate and hexane CLASS="ptx2">

Mass spectrum (Cl, m/z): 346 (M++ 1).

The NMR spectrum (CDCl3(million days): 1,55-of 1.74 (m, 3H), 2,10 (s, 3H), of 2.23 (s, 3H), and 3.72 (d, J = 7 Hz, 2H), 4,39-4,43 (m, 1,56 H), 4,51-4,55 (m, 0,44 H), 5,27-to 5.66 (m, 2H), between 6.08 (t, J = 7 Hz, 1H), 6,97? 7.04 baby mortality (m, 2H), 7,16-7,24 (m, 2H), 9,77 (s, 1H).

Comparative example 110

2-[1-Chloro-3-(4-forfinal)-1-propenyl] -3-formyl-4,5-dimethyl-1-(2 - methylcyclopropyl)pyrrol

The target compound as a pale brown oily substance with a yield of 71.2 percent was obtained by a method described in comparative example 109, using 5-[3-(4-forfinal)propionyl] -2,3 - dimethyl-1-(2-methylcyclopropyl) pyrrole.

Mass spectrum (Cl, m/z): 360 (M++ 1).

The NMR spectrum (CDCl3(million days ): 0,22-0,28 (m, 1H), 0,34-0,41 (m, 1H), 0,59-0,78 (m, 2H), were 0.94 (d, J = 6 Hz, 3H), 2,17 (s, 3H), 2,24 (s, 3H), 3,68-of 3.78 (m, 4H), 6,12 (t, J = 7 Hz, 1H), 6,98? 7.04 baby mortality (m, 2H), 7,19-7,26 (m, 2H), 9,76 (s, 1H).

Comparative example 111

2-[1-Chloro-3-(4-forfinal)-1-propenyl] -1-cyclopropylmethyl-3 - formyl-4,5-dimethylpyrrole

The target compound as pale yellow oily substance with a yield of 72.3% was obtained by a method described in comparative example 109, using 1-cyclopropylmethyl-5-[3-(4 - forfinal)propionyl]-2,3-dimethylpyrrole.

Mass spectrum (Cl, m/z): 346 (M++ 1).

The NMR spectrum (CDCl3(million days )25 (m, 2H), made up 9.77 (s, 1H).

Comparative example 112

2-[1-Chloro-3-(4-forfinal)-1-propenyl] -3-formyl-4,5-dimethyl - 1-(2-propenyl)pyrrol

The target compound as a yellow oily substance with a yield of 70.8% was obtained by a method described in comparative example 109, using 5-[3-(4-forfinal)propionyl]-2,3-dimethyl-1-(2-propenyl)pyrrole.

Mass spectrum (Cl, m/z): 332 (M++ 1).

The NMR spectrum (CDCl3(million days): 2,09 (s, 3H), 2,24 (s, 3H), and 3.72 (d, J = 7 Hz, 2H), 4,46-4,51 (m, 2H), a 4.83 (d, J = 17 Hz, 1H), 5,14 (d, J = 10 Hz, 1H), 5,78-of 5.92 (m, 1H), 6,09 (t, J = 7 Hz, 1H), of 6.96? 7.04 baby mortality (m, 2H), 7,15-7,34 (m, 2H), 9,78 (s, 1H).

Comparative example 113

1-(2-Butenyl)-1-(1-chloro-3-phenyl-1-propenyl)-3-formyl-4,5-dimethylpyrrole

The target compound (CIS/TRANS = 23/77) Orangevale yellow oily substance with a yield of 61.6% was obtained by a method described in comparative example 109, using 1-(2-butenyl)-2,3-dimethyl-5-(3-phenylpropionyl)pyrrole (CIS/TRANS = 23/77).

Mass spectrum (Cl, m/z): 328 (M++ 1), 330 (M++ 3).

The NMR spectrum (CDCl3(million days): 1,61-of 1.73 (m, 3H), 2,10 (s, 3H), of 2.23 (s, 3H), 3,76 (d, J = 7 Hz, 2H), 4,40-4,43 (m, 1,54 H), 4,50-4,55 (m, 0,46 H), and 5.30-of 5.45 (m, 2H), 5,12 (t, J = 7 Hz, 1H), 7,22-to 7.35 (m, 5H), 9,79 (s, 1H).

Comparative example 114

2-(1-Chloro-3-phenyl-1-propenyl)-3-formyl-4,5-dimethyl-1-(2-PR is Ali way, described in comparative example 109, using 2,3-dimethyl-5-(3-phenylpropionyl)-1-(2-propenyl)pyrrole.

Mass spectrum (Cl, m/z): 314 (M++ 1), 316 (M++ 3).

The NMR spectrum (CDCl3(million days): 2,09 (s, 3H), 2,24 (s, 3H), of 3.75 (d, J = 7 Hz, 2H), 4,47-to 4.52 (m, 2H), a 4.83 (d, J = 17 Hz, 1H), 5,14 (d, J = 9 Hz, 1H), to 5.85 (DDT, J = 17 Hz, 9 Hz, 7 Hz, 1H), 6,16 (t, J = 7 Hz, 1H), 7,14-7,41 (m, 5H), 9,80 (s, 1H).

Comparative example 115

2-(1-Chloro-3-phenyl-1-propenyl)-3-formyl-4,5-dimethyl-1-(2 - methylcyclopropyl)pyrrol

The target compound as a yellow-orange oily substance with access 65,9% was obtained by a method described in comparative example 109, using 2,3-dimethyl-1-(2-methylcyclopropyl)- 5-(3-phenylpropionyl)pyrrole.

Mass spectrum (Cl, m/z): 342 (M++ 1), 344 (M++ 3).

The NMR spectrum (CDCl3(million days ): of 0.21 to 0.28 (m, 1H), 0,34-0,40 (m, 1H), 0,62-to 0.73 (m, 2H), 0,93 (d, J = 6 Hz, 3H), of 2.16 (s, 3H), 2,24 (s, 3H), 3,68-a-3.84 (m, 4H), x 6.15 (t, J = 7 Hz, 1H), 7,15-7,40 (m, 5H), 9,78 (s, 1H).

Comparative example 116

2-(1-Chloro-2-phenyl-1-propenyl)-1-cyclopropylmethyl-3-formyl-4,5 - dimethylpyrrole

The target compound as a yellow-orange oily substance with a yield of 75.5% was obtained by a method described in comparative example 109, using 1-cyclopropylmethyl-2,3-dimethyl-5 (CDCl3(million days ): 0,21 is 0.27 (m, 2H), 0,47-of 0.54 (m, 2H), 0,99-1,08 (m, 1H), 2,18 (s, 3H), 2,24 (s, 3H), 2,70-2,84 (m, 4H), 6,17 (t, J = 7 Hz, 1H), 7,16-7,40 (m, 5H), 9,78 (s, 1H).

Comparative example 117

1-(2-Butenyl)-2-[1-chloro-3-(2,4-differenl)-1-propenyl] -3 - formyl-4,5-dimethylpyrrole

The target compound (CIS/TRANS=23/77) as a pale yellow oily substance with a yield of 85.7% was obtained by a method described in comparative example 109 using 1-(2-butenyl)-5-[3-( 2,4-differenl)propionyl] -2,3-dimethylpyrrole.

Mass spectrum (Cl, m/z): 364 (M++1).

The NMR spectrum (CDCl3(million days): 1,59-1,71 (m, 3H), 2,10 (s, 3H), 2,22 (s, 3H), and 3.72 (d, J = 7 Hz, 2H), 4,39-to 4.41 (m, 1,54 H), 4,51-a 4.53 (m, 0,46 H), 5,27-5,67 (m, 2H), equal to 6.05 (t, J = 7 Hz, 1H), 6,77-6,87 (m, 2H), 7.18 in-7,27 (m, 1H), of 9.75 (s, 1H).

Comparative example 118

2-[1-Chloro-3-(2,4-differenl))-1-propenyl] -3-formyl-4,5-dimethyl - 1-(2-methylcyclopropyl)pyrrol

The target compound as a pale brown oily substance with a yield of 70.8% was obtained by a method described in comparative example 109, using 5-[3-(2,4-deformity)propionyl] -2,3-dimethyl-1-(2 - methylcyclopropyl)pyrrol

Mass spectrum (Cl, m/z): 378 (M++ 1).

The NMR spectrum (CDCl3(million days ): of 0.21 to 0.28 (m, 1H), 0,33-0,40 (m, 1H), 1.56 to of 1.80 (m, 2H), 0,93 (d, J = 6 Hz, 3H), of 2.16 (s, 3H), 2,24 (s, 3H), 3,70-of 3.77 (m, 4H), 6,09 (t, J = 7 HL] -1-cyclopropylmethyl-3 - formyl-4,5-dimethylpyrrole

The target compound as a pale brown oily substance with access 67,8% was obtained by a method described in comparative example 109, using 5-[3-(2,4-differenl)propionyl]-2,3 - dimethylpyrrole.

Mass spectrum (Cl, m/z): 364 (M++ 1).

The NMR spectrum (CDCl3(million days ): 0,20-0,26 (m, 2H), 0,47-of 0.54 (m, 2H), 0,98-1,11 (m, 1H), 2,18 (s, 3H), 2,24 (s, 3H), 3,70-with 3.79 (m, 4H), 6,10 (t, J = 7 Hz, 1H), 6,78-to 6.88 (m, 2H), 7,21-7,29 (m, 1H), 9,75 (s, 1H).

Comparative example 120

2-[1-Chloro-3-(2,4-differenl)-1-propenyl] -3-formyl-4,5-dimethyl - 1-(2-propenyl)pyrrol

The target compound in the form of a pale brownish-yellow oily substance from the output of an 80.2% was obtained by a method described in comparative example 109, using 5-[3-(2,4-differenl)propionyl]-2,3-dimethyl-1-(2-propenyl)pyrrole.

Mass spectrum (Cl, m/z): 350 (M++ 1).

The NMR spectrum (CDCl3(million days): 2,09 (s, 3H), of 2.23 (s, 3H), and 3.72 (d, J = 7 Hz, 2H), 4,46 figure-4.49 (m, 2H), to 4.81 (d, J = 17 Hz, 1H), 5,14 (d, J = 10 Hz, 1H), 5,77-5,91 (m, 1H), 6,06 (t, J = 7 Hz, 1H), 6,77-6,86 (m, 2H), 7.18 in-of 7.23 (m, 1H), 9,76 (s, 1H).

Experimental example 1

Test the activation of the proton, potassium-adenosinetriphosphatase (H+, K+-ATPase)

In accordance with the method described Sachs and others (J. Biol. Chem., 251, 7690 (1976)), where the H+, K+-adenosil membrane of the stomach of the pig by ultracentrifugation in a density gradient, 10 μl solution of the test compound in dimethyl sulfoxide was added to 0.75 ml of 70 mm Tris-HCl buffer solution (5 mm sodium chloride, 20 mm potassium chloride, pH 6,85) containing from 30 to 80 μg/ml (based on protein concentration) of the enzyme preparation, and the mixture was incubated for 45 minutes at 37oC and with shaking at 200 times per minute. The enzymatic reaction was initiated by adding 0.25 ml of 8 mm solution of districtdistrict. 20 minutes after start of the reaction the reaction was stopped by adding 1 ml of 10% trichloroacetic acid and activated charcoal (100 mg). Then the reaction solution was centrifuged (4oC, 3000 rpm, 15 minutes) and the amount of inorganic phosphate in the supernatant obtained after hydrolysis of ATP was measured using the colorimetric method Yoda Hokin (Biochem. Res. Commun., 40, 880 (1970)). Likewise determined the amount of inorganic phosphate in the reaction solution in the absence of potassium chloride. H+, K+-adenosinetriphosphatase activity was calculated based on the difference in the amounts of phosphate obtained in the presence and in the absence of potassium chloride. Based on the activity values obtained for the control and test compounds becuause 50% inhibition of the activity of H+, K+-adenosinetriphosphatase (IC50). Especially high activity was found connection examples 1, 4, 7, 9, 17, 21, 22, 35, 44, 48, 49, 57, 58, 74, 75 and 76.

Experimental example 2

Test for the activity of the secretion of gastric juice with the use of ligatures in the region of the pylorus of the stomach of rats (method Shay rats)

The imposition of ligatures on the area of the pylorus of the stomach was performed according to the method of shay and other (Gastroenterology, 5, 43 (1945)). For this purpose, rats-males line SD kept on starvation diet for 24 hours, after which the abdominal cavity of the rats under ether anesthesia, were opened. Then, the exposed region of the duodenum and the pylorus of the stomach and the region of the pylorus was ligated. The solution of the test compounds (10 mg/ml), obtained using a 1.5% parts of dimethylacetamide, 68.5% of frequent. polyethylene glycol (PEG-400) and 30% frequent. saline, were injected with in the region of the duodenum at a dose of 20 mg/kg using a 1-ml syringe with a needle for injection (26G). After injection of the test compounds, the abdominal cavity was sutured. Animals kept for 4 hours without eating and drinking, and then were killed using carbon dioxide. The stomach was dissected and collected gastric Sogo juice was determined by the amount of the supernatant liquid. The acidity of the gastric juice was determined by the amount (ml) of 0.01 n sodium hydroxide solution required for the titration of 0.1 ml of the supernatant liquid to obtain a pH of 7.0 using the apparatus for automatic titration. The amount of secretion in the stomach was calculated using values of secretion of gastric juice and gastric juice acidity. The degree of inhibition was determined based on the values of the secretion of gastric acid, obtained for the control group and the treated group. Especially high activity was found connection examples 1, 3, 5, 7, 9, 11, 12, 14, 16, 17, 22, 26, 32, 33, 35, 37, 40, 41, 42, 44, 48, 57, 58, 62 and 68.

Experimental example 3

Antibacterial activity against Helicobacter pylori

Antibacterial activity of the compounds of the present invention was evaluated by measuring the minimum inhibitory concentration (MIC) of these compounds, when growth strains 9470, 9472 and 9474 Helicobacter pylori.

These strains of Helicobacter pyroli incubated for 4 days in the medium for culturing the bacterial cups. This environment was obtained by dissolving agar with cardio-cerebral extract (product of DIFCO) in a given volume of distilled water; autoclave sterilization; Wed environment was 7%; and curing.

The bacteria Helicobacter pylori, cultured for 4 days in a slightly aerobic conditions at 37oC, suspended in saline solution to obtain a supernatant with a population density of about 108CFU/ml (CFU - colony forming unit). The suspension was subjected to 100-fold dilution and about 10 μl of the diluted suspension was inoculable on Wednesday to determine the MIC.

The medium used to determine the MIC, contained the same compounds that were used for pre-cultivation. Environment to determine the MIC was prepared by mixing one part of 2-fold diluted in sterilized distilled water solutions of compounds dissolved in dimethyl sulfoxide, and 99 parts of the environment, followed by curing the mixture in cups.

As in the case of pre-cultivation, Helicobacter pylori was cultured in a slightly aerobic conditions at 37oC for 3 days. After completion of culturing, the bacterial growth in each inoculated Cup was observed by the naked eye. Minimum inhibitory concentration (MIC) of the compounds of the present invention was determined as the minimum concentration at which no observed bacter, 48 - 52, 56 - 58, 75 and 76.

Prescription example 1.

Tablet:

The compound of example 57, mg - 30

Lactose, mg - 144

Starch, mg - 25

Magnesium stearate, mg - 1

All mg - 200

Listed in the recipe ingredients are mixed and formed into tablets using a tabletting machine to obtain tablets of 250 mg each. The tablet may be sugar coated if necessary.

1. Derivatives pyrrolopyridine having a General formula I

< / BR>
where R1represents a C2- C6-alkenylphenol group, halogen-C2- C6-alkenylphenol group, phenyl-C2- C6-alkenylphenol group, C2- C6-alkylamino group, C3- C7-cycloalkyl group, (C3- C7-cycloalkyl)-C1- C6-alkyl groups, where the specified cycloalkyl group can be unsubstituted or substituted C1- C6is an alkyl group, or halogen-C1- C6is an alkyl group;

R2and R3may be the same or different, and each represents a C1- C6is an alkyl group;

R4is a hydrogen atom;

R5represents a phenyl group which may be unsubstituted or substituted and halogen-C1- C6-alkoxygroup, or 5 - or 6-membered heteroaryl group containing heteroatoms selected from nitrogen atoms, oxygen and sulfur;

A represents A C1- C3-alkylenes group;

X represents aminogroup, oxygen atom, sulfur atom or methylene group;

m = 0 or 1;

n = 0 or 1, and m and n cannot both be 1,

or their pharmacologically acceptable salts.

2. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R1represents a C2- C5-alkenylphenol group; C3- C4-alkenylphenol group substituted by fluorine or chlorine; phenyl-C3- C5-alkenylphenol group; C3- C4-alkylamino group; cyclopropyl group; C3- C6-cycloalkylation group where the specified cycloalkyl group can be unsubstituted or substituted alkyl group, or halogen-C1- C4is an alkyl group.

3. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R1represents a C2- C5-alkenylphenol group; C3- C4-alkenylphenol group substituted by fluorine or chlorine; 3-phenyl-2-propenyloxy group; 2-propenylidene group.

4. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R1is a 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 2-methyl-2-propenyloxy, propane-1,2-dianilino, 3-phenyl-2-propenyloxy, 2-propenyloxy, cyclopropylmethyl, 2-methylcyclopropyl, 2,2,2-triptorelin or 3-forproperty group.

5. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R1is a 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 2-methyl-2-propenyloxy, 3-phenyl-2-propenyloxy, cyclopropylmethyl or 2-methylcyclopropyl group.

6. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R2and R3are the same or different and each represents a C1- C4is an alkyl group.

7. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R2and R3are the same or different and each represents a C1- C3is an alkyl group.

8. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R2and R32">

9. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R2and R3are the same and each represents methyl group.

10. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R5represents a phenyl group, optionally substituted by at least one Deputy, selected from halogen atoms, halogen-C1- C4-alkyl and halogen-(C1- C4-alkoxy, or follow, thienyl or pyridyloxy group.

11. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R5represents a phenyl group, optionally substituted by at least one Deputy, selected from the group of fluorine, chlorine, triptorelin group or dipterocarp, or follow group, thienyl group or pyridyloxy group.

12. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R5represents a phenyl group, optionally substituted by fluorine, chlorine, triptorelin group or dipterocarps.

13. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1. proizvodnye pyrrolopyridine or their pharmacologically acceptable salts under item 1, where A represents a methylene group.

15. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where X represents an oxygen atom, a sulfur atom or methylene group.

16. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where X represents an oxygen atom or methylene group.

17. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where X represents the oxygen atom.

18. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where m = 0.

19. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where n = 0.

20. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R1represents a C2- C5-alkenylphenol group; C3- C4-alkenylphenol group substituted by fluorine or chlorine; phenyl-C3- C5-alkenylphenol group; C3- C4-alkylamino group; cyclopropyl group; C3- C6-cycloalkylation group where the specified cycloalkyl ginou group; R2and R3are the same or different and each represents a C1- C4is an alkyl group or a C6-aryl group; R4represents a hydrogen atom; R5represents a phenyl group, optionally substituted by at least one Deputy, selected from halogen atoms, halogen-C1- C4is an alkyl group or halogen-C1- C4-alkoxygroup, follow group, thienyl group or pyridyloxy group; A represents a methylene group; X represents an oxygen atom, a sulfur atom or methylene group and n = 0 or 1, m = 0.

21. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R1represents a C2- C5-alkenylphenol group; C3- C4-alkenylphenol group substituted by fluorine or chlorine; 3-phenyl-2-propenyloxy group; 2-propenyloxy group; cyclopropyl group; cyclopropylmethyl group; 2-methylcyclopropyl group or fluorine-C2- C3is an alkyl group; R2and R3are the same or different and each represents a C1- C3is an alkyl group; R4represents a hydrogen atom; R5represents the FEA, triptorelin group or dipterocarp; follow group; thienyl group or pyridyloxy group; A represents a methylene group; X represents an oxygen atom, a sulfur atom or methylene group, m = 0 and n = 0.

22. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R1is a 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyloxy, 2-methyl-2-propenyloxy, propane-1,2-dianilino, 3-phenyl-2-propenyloxy, 2-propenyloxy, cyclopropylmethyl, 2-methylcyclopropyl, 2,2,2-triptorelin or 3-forproperty group; R2and R3are the same or different and each represents a C1- C2is an alkyl group; R4is a hydrogen atom; R5represents a phenyl group, optionally substituted by at least one Deputy, selected from fluorine, chlorine, triptorelin group or dipterocarp; A represents a methylene group; X is an oxygen atom or a methylene group; m = 0 and n = 0.

23. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where R1is a 1-propenyloxy, 2-propenyloxy, 1-butenyloxy, 2-butenyl the u; R2and R3are the same and each represents a methyl group; R4is a hydrogen atom; R5represents a phenyl group, optionally substituted by fluorine or chlorine; A is a methylene group; X is an oxygen atom, m = 0 and n = 0.

24. Derivatives pyrrolopyridine or their pharmacologically acceptable salts under item 1, where these derivatives pyrrolopyridine choose from the following connections:

1-(2-butenyl)-7-benzyloxy-2,3-dimethylpyrrole[2,3-d]pyridazin;

7-benzyloxy-2,3-dimethyl-1-(2-methyl-2-propenyl)pyrrolo[2,3-d]pyridazin;

7-benzyloxy-2,3-dimethyl-1-(2-PROPYNYL)pyrrolo[2,3-d]pyridazin;

7-benzyloxy-1-cyclopropylmethyl-2,3-dimethylpyrrole[2,3-d]pyridazin;

7-(4-forbindelse)-2,3-dimethyl-1-(1-propenyl)pyrrolo[2,3-d]pyridazin;

7-(4-forbindelse)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

1-(2-butenyl)-7-(4-forbindelse)-2,3-dimethylpyrrole[2,3-d]pyridazin;

1-cyclopropylmethyl-7-(4-forbindelse)-2,3-dimethylpyrrole[2,3-d] pyridazin;

7-(2,4-deferasirox)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d] pyridazin;

1-(2-butenyl)-7-(2,4-deferasirox)-2,3-dimethylpyrrole[2,3-d]pyridazin;

7-(4-chlorobenzoyloxy)-2,3-dimethyl-1-(2-propenyl)Pirro is 2,4-dichloraniline)-2,3-dimethylpyrrole[2,3-d]pyridazin;

7-(2-forbindelse)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

1-(2-butenyl)-3-ethyl-7-(4-forbindelse)-2-methylpyrrole[2,3-d] pyridazin;

7-(4-forbesii)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

1-(2-butenyl)-7-(4-forbesii)-2,3-dimethylpyrrole[2,3-d]pyridazin;

1-(2-butenyl)-7-(2,4-diferentially)-2,3-dimethylpyrrole[2,3-d] pyridazin;

1-(2-butenyl)-7-(2-chloro-6-forbindelse)-2,3-dimethylpyrrole[2,3-d]pyridazin;

1-(2-butenyl)-7-(4-chloro-2-forbindelse)-2,3-dimethylpyrrole[2,3-d]pyridazin;

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

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

2,3-dimethyl-7-phenethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

1-(2-butenyl)-2,3-dimethyl-7-phenotypical[2,3-d]pyridazin;

7-(4-florfenicol)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

1-(2-butenyl)-7-(4-florfenicol)-2,3-dimethylpyrrole[2,3-d]pyridazin;

1-cyclopropylmethyl-7-(4-florfenicol)-2,3-dimethylpyrrole[2,3-d]pyridazin;

7-(2,4-divertenti)-2,3-dimethyl-1-(2-propenyl)pyrrolo[2,3-d]pyridazin;

1-(2-butenyl)-7-(2,4-divertenti)-2,3-dimethylpyrrole[2,3-d]pyridazin;

1-cyclopropylmethyl-7-(2,4-divertenti)-2,3-dimethylpyrrole[2,3-d] feast is Teal)-2,3-dimethyl-1-(2-methylcyclopropyl)pyrrolo[2,3-d]pyridazin;

2,3-dimethyl-1-(2-methylcyclopropyl)-7-phenotypical[2,3-d] pyridazin;

1-(2-butenyl)-7-(4-forbindelse)-2,3-dimethylpyrrole[2,3-d] pyridazin-5-oxide;

1-(2-butenyl)-7-(2,4-deferasirox)-2,3-dimethylpyrrole[2,3-d] pyridazin-5-oxide;

1-(2-butenyl)-7-(2,4-divertenti)-2,3-dimethylpyrrole[2,3-d] pyridazin-5-oxide, and

1-(2-butenyl)-7-(2,4-divertenti)-2,3-dimethylpyrrole[2,3-d] pyridazin-6-oxide.

25. Antiulcer agent, wherein the active ingredient contains an effective amount of a derivative pyrrolopyridine or its pharmacologically acceptable salt according to any one of paragraphs.1 - 24.

26. The method of obtaining derivatives pyrrolopyridine having the General formula

< / BR>
where R1, R2, R3, R4, R5, A, m and n are defined in paragraph (1; Xadefined below,

or their pharmacologically acceptable salts, characterized in that carry out the reaction of compounds of General formula (II)

< / BR>
where R1, R2, R3and R4have the values listed in paragraph 1,

Y is halogen atom,

with a compound of General formula (III)

R5- A - Xa- H,

where R5and A have the meanings specified in paragraph 1,

Xais aminogroup, ATO the hydrated product.

27. The method of obtaining derivatives pyrrolopyridine having the General formula

< / BR>
where R1- R5and A is defined in paragraph 1;

m = 0;

n = 0,

or their pharmacologically acceptable salts, characterized in that carry out the reaction of compounds of General formula

< / BR>
where R1- R5and A have the meanings specified in paragraph 1;

Y is halogen atom,

with hydrazine or its hydrate and, if necessary, with subsequent oxidation of the resulting product.

 

Same patents:

The invention relates to nitroglicerine General formula A-X1-NR2or their salts, where a and X1have the meanings indicated in the claims, as well as to pharmaceutical compositions based on them

The invention relates to new heterocyclic compounds with biological activity, more specifically, to the derivatives of benzothiophene, benzofuran, indoltiazepinone, oxazepines and diazepinone, the pharmaceutical composition having inhibitory cell adhesion or HIV activity, method of inhibition of leukocyte adhesion to endothelial cells in the treatment of diseases caused by it and the method of treating mammals infected with HIV

Substituted pyrrole // 2141960

The invention relates to new imidazolidinedione intended for use in the pharmaceutical industry as active ingredients in the manufacture of medicines

The invention relates to new nitrogen-containing heterocyclic compounds possessing biological activity, and more particularly to derivatives of 1,2,4-triazolo[1,5-a]pyrimidines, their pharmaceutically acceptable salts and stereoisomers, pharmaceutical compositions containing them, and method of inhibiting seizures

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

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: medicine; veterinary science.

SUBSTANCE: invention refers to application of compounds with common structural formula

R1=-H, -NH2, -Br, -Cl, -ОН, -СООН,

B=-N=, -CH=, Z=-CH=, -N=,

A=-CH- at B=-N=, Z=-CH-,

A=-CH- at В=-СН=, Z=-CH=,

A=-N= at B=-N=, Z=-CH-,

A=-CH- at B=-N=, Z=-N=,

A=-CH= at В=-СН=, Z=-N=.

Structures of specified formula are active for nitrergic and dopaminergic systems of mammal body including human body. These compounds can be applied as neuroprotectors, to improve cognitive function and to normalise psychophysiologic state, to treat consequences of substance abuse, as well as to treat wide range of diseases including neuropsychic, cardiovascular, immune, inflammatory and gastro-intestinal disorders.

EFFECT: application of new and well-known compound to effect nitrergic and dopaminergic systems for treatment purposes.

4 ex, 3 tbl, 8 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to medicinal agents containing combined inhibitor of dipeptidylpeptidase IV (DPPIV) and biguanide agent. Offered application of pharmaceutical agent implies production of preventive and therapeutic agent and method of intensified effects of active circulating GLP-1 and/or active circulating GLP-2. Besides, invention concerns method of prevention or treatment of disease connected with active circulating GLP-1 and/or active circulating GLP-2, specifically diabetes, obesity, hyperlipidemia, gastrointestinal diseases. Combined inhibitor DPPIV of formula (I) and biguanide agent, specifically phenformine, methformin or buformine stimulates action of active circulating glucagon-like peptide-1 (GLP-1) and/or active circulating glucagon-like peptide -2 (GLP-2) and, therefore inhibits destruction of GLP-1 and GLP-2, with their levels raised up with biguanide agent.

EFFECT: agent has improved efficiency.

17 cl, 12 tbl, 425 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the novel inhibitor of phosphodiesterase (PDE) IV and/or to the tumor necrosis factor (TNF) production inhibitor, which corresponds to the compound with formula (I), where R1 is: (1) mono- or di(inferior)alkylamino, (2) phenyl, (3) saturated or unsaturated 5-or 6-membered heteromonocyclic group, selected from a group which includes pyrrolidinyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl and piridinyl, or (4) inferior alkyl not necessarily substituted with (i) inferior alkoxi or (ii) saturated 5- or 6-membered heteromonocyclic group, selected from the group, consisting of piperazinyl and morpholinyl, where the inferior alkoxi is not necessarily substituted with cyclo(inferior)alkyl or piridinyl, R2 corresponds to R7 or - A2R7 , where A2 is -(CH2)n- or -(CH=CH)m- [where n is an even number within 2 to 6, and m is an even number 1 or 2], and R7 is a hydrogen, inferior alkylsulfonyl, carboxy, etherificated carboxy or piridinyl; R3 is: (1) phenyl, not necessarily substituted with inferior alkyl, cyclo(inferior)alkyl, inferior alkoxi, halogen, cyano or carbamoyl; or (2) quinolinyl; or piridinyl, substituted with inferior alkyl, cyclo(inferior)alkyl, inferior alkoxi, carbamoyl or halogen, and R4 corresponds to the inferior alkyl, or its pharmaceutically acceptable salt. The application of the compound with formula is invented, for producing the therapeutic agent with the PDE IV and/or TNF production inhibiting activity and the pharmaceutical composition containing the effective amount of compounds with formula (I) mixed with the pharmaceutically acceptable carriers. The method for prevention and treatment of the diseases where the application of the PDE IV and/or TNF production inhibitor is considered to be reasonable, including the administration of the therapeutically effective amount of the compound with formula (I). The method for prevention and treatment of asthma, chronic obstructive pulmonary disease, fibrous disorders, acute and fulminant hepatitis, hepatic steatosis, chronic hepatitis, cirrhosis, autoimmune hepatitis, autoimmune inflammatory intestine disease, atopic dermatitis, Alzheimer's disease or viral infection, including the administration of the therapeutically or preventively effective amount of the compound with formula (I).

EFFECT: compound with the PDE IV and/or TNF production inhibiting activity.

11 cl, 2 tbl, 672 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diazaindoledicarbonylpiperazinyl compounds of formula I, including its pharmaceutically acceptable salts, which possess antiviral activity and can be used for HIV-infection treatment. In compounds of formula I Q represents , T represents -C(O)- or -CH(CN)-; R1 represents hydrogen; R3 represents hydrogen; R5 is independently selected from group including halogen, cyano, XR9 and B; R2 and R4 are absent; R6 represents hydrogen; -- represents carbon-carbon bond; -Y- is selected from group including , each of R10, R11, R12, R13, R14, R15, R16 and R17 represents H; R18 is selected from group including C(O)-phenyl, isoquinolyl, quinazolyl; D is selected from group including cyano, 5-member heteroaryl containing 3 heteroatoms selected from nitrogen and oxygen; A is selected from group including phenyl, pyridinyl; B is selected from group including -C(O)CH3; piperazinyl; 5-, 6-member heteroaryl containing 1-3 N atoms and possibly O atom; where said heteroaryl optionally is substituted with from one to three similar or different substituents selected from F; F is selected from group including (C1-6)alkyl, phenyl, pyridinyl, COOR26, -COR21, and -CONR24R25; where phenyl is optionally substituted with (C1-6)alkoxy, CF3, or halogen atom; R9, R24, R25 and R26 each is independently selected from group including hydrogen and (C1-6)alkyl; X represents O; R27 represents piperazinyl, N-methylpiperazinyl, or 3-pirazolyl. Invention also relates to pharmaceutical composition.

EFFECT: obtaining compounds and pharmaceutically acceptable salts, which possess antiviral activity and can be used for treatment of HIV infection.

19 cl, 50 dwg, 4 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a cyclic bioisostere of purine system derivatives, with general structural formula given below , where R = , Li, Na or K, R1 = -H, -NH2, -Br, -Cl, -OH, -COOH; A = -N- for B=-N=, Z = -CH-; A = -CH= for B = -N=, Z = -CH-; A = -CH= for B = -N=, Z = -N=; A = -CH= for B = -CH=, Z - -CH=; A = -CH= for B = -CH=, Z = -N=, except compounds in which A = -CH= for B = -CH=, Z = -CH=, R= Li, Na or K and R1= -NH2 in the 5th position of the benzo[d]-3H-pyridazine-1,4-dione nucleus, and its pharmacologically acceptable salts, with normalising effect on intracellular processes.

EFFECT: obtaining compounds which can be used for normalising intracellular processes in therapy of disorders, caused by intracellular acidosis and/or oxygen deficiency and/or excess formation of free radicals and/or excess formation of free radical forms of oxygen and/or high thrombocyte aggregation and/or erythrocytes and/or adverse effects and/or nitrergic cell mechanism disorder.

17 cl, 14 tbl, 15 dwg

FIELD: medicine.

SUBSTANCE: present invention concerns medical products, particularly pharmaceutical combination for development inhibition or treatment of proliferative disease which contains in therapeutically effective amounts (a) compound PTK787 and (b) epothilone derivative of formula , where A means O or NRN, where RN means hydrogen or lower alkyl, R means hydrogen or lower alkyl, and Z means oxygen or chain, for simultaneous, separate or consecutive application. Besides the invention concerns a pharmaceutical composition, application and commercial package thereof.

EFFECT: specified combination of active components ensures synergetic effect in treatment of proliferative diseases.

7 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of modulating expression of a target gene induced by β-catenin using an agent which increases linkage of p300 with β-catenin and reduces linkage of CBP with β-catenin, involving bringing a composition containing β-catenin, CBP and p300, where β-catenin is more likely linked to CBP than p300, into contact with an agent in an amount which is effective for changing the probability of linking β-catenin to CBP compared to p300, where the said agent is a compound with a structure selected from formula (I), or its stereoisomers: where A represents -(C=O)-, B represents -(CHR4)-, D represents -(C=O)-, E represents -(ZR6)-, G represents -(XR7)n-> W represents (C=O)NH-, X represents nitrogen or CH, Z represents CH, n = 0 or 1. Values of substitutes R1 and R2 are indicated in the formula of invention. The invention also relates to a composition for modulating expression of a target gene induced by β-catenin.

EFFECT: novel compounds have useful biological properties.

9 cl, 7 tbl, 30 dwg, 7 ex

FIELD: medicine.

SUBSTANCE: method involves introducing endoscope, clearing injured surface and applying gel produced on Tisol substance base (aqua-complex of titanium glycerosolvate) as medicinal composition via the endoscope. Tisol is administered as aqueous solution of concentration not less than 60% after Tisol. The composition is applied to injured surface in the amount of 2 to 8 ml for one session. The number of treatment sessions is equal to 1 to 7 with 3-5 days long pauses. The composition is prepared by mechanically mixing medicinal microadditives with Tisol substance. The medicinal microadditives are introduced in total amount of 7.26% of composition mass. The ingredients are selected depending on disease. The medicinal composition is applied as 1-2 mm thick layer. When treating the cases of erosion or gastritis, sea-buckthorn oil and/or propolis solution are of preference to be introduced into Thysol as the medicinal microadditives. When treating the cases of gastric or duodenal peptic ulcer, methyluracyl, hydrocortisone, cycloferon or aecol are preferentially introduced into Tisol as the medicinal microadditives. The composition formula is adjusted from session to session on the basis of treatment results visual control and analysis data. Taking meals and drinks is restricted for a patient for half an hour or longer.

EFFECT: enhanced effectiveness in administering drugs into mucous membrane and soft tissues without using needle injectors.

5 cl,4 tbl

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