The inhibitor of expression of integrin

 

The invention relates to chemical-pharmacological industry and relates to an inhibitor of the expression of integrin, comprising as active ingredient a compound sulfonamida formula IaIbthat means, containing an inhibitor of the expression of integrin formula IaIbfor the treatment of arteriosclerosis, psoriasis, osteoporosis, angiogenesis, retinal angiogenesis, diabetic retinopathy, inflammatory diseases, and how to prevent, treat or alleviate disease associated with increased expression of integrin. The inhibitor of expression of integrin has reduced toxicity, the tool is highly effective and has a high bioavailability. 4 C. and 15 C.p. f-crystals, 4 Il.

The technical field

The present invention relates to an inhibitor of the expression of integrin, in particular the inhibitor of expression of integrin21,31,51,63 orv5. In addition, it is intended to be used for angiogenesis, the anticoagulation agent, anti-cancer agent, the suppressor of metastasis of the cancer and the treatment for retinal angiogenesis, diabetic retinopathy, inflammatory diseases, arteriosclerosis, psoriasis and osteoporosis on the basis of the inhibitory effect in relation to the expression of integrin.

Prior art

Integrin structurally consists of heterodimer, two types of subunits which, namely integrinand the integrinconnected to each other by non-covalent bond. It was found that at least 16 typescircuits and 8 typescircuits. A number of molecular groups, which differ in the specificity of the ligand is formed by a combination of theseandcircuits, and already know of 22 types of integrins. Integrin functions as a protein receptor found on the cell membrane for adhesion molecules of animal cells, is expressed on the cell membrane and is involved in adhesion between what Agronom, begins to operate the system signal transmission in the cell and, as a result, comes into effect not only cell adhesion, but also the evolution of cells, cell proliferation, apoptosis, differentiation, orientation of the cytoskeleton, cell migration, histogenesis, infiltration and metastasis of cancer, wound healing, blood coagulation, etc., it is Known that among these integrins integrin21, adhesive molecules which are collagen and laminin, is involved in platelet aggregation, infiltration and metastasis of cancer (Masao HAYASHI & MIYAMOTO Yasunori, PROTEIN, NUCLEIC ACID, ENZYME, Vol 44, pp.l30-135, (1999)) and angiogenesis (Donald R. Senger et al, Proc. Natl. Acad. Sci. USA, 94, 13612-13617, (1997)). This led to the realization that on the basis of these characteristics, proliferation of cancer is closely associated with angiogenesis. In recent years, in clinical studies it has been experimentally shown that an anti-angiogenesis may inhibit further reduce proliferative cancer and that no sustainable cancer is not generated in the model transplant, cancer, and was the correlation between angiogenesis and exacerbations of many solid malignancies, such as breast cancer, prostate cancer, lung cancer src="https://img.russianpatents.com/chr/946.gif" border="0">1, adhesive molecules which are fibronectin and vitronectin, participates in the adhesion of cancer cells to the substrate, andv3, adhesive molecules which are vitronectin and thrombospondin, andv5, an adhesive molecule which is vitronectin, are involved in angiogenesis, cancer metastasis and bone regeneration (Shattil, S. J., Thromb. Haemost., 74, 149-155, (1995), Friedlander M, et al., Sceience, 270, 1500-1502, (1995)). In addition, it is known that31, adhesive molecules which are fibronectin, collagen, laminin, laminin 5, etc.,51, the adhesive molecule is fibronectin, and61, adhesive molecules which are laminin and laminin 5, are involved in the infiltration and metastasis of cancer (MATSUURA Nariaki et al., JAPAN CLINIC, Vol 53, PP.1643-1647, (1995), Ichiro OTA et al., CLINICAL PATHOLOGY, Vol 45, 528-533, (1997)).

WO 9950249 reveals antagonist integrinv3, however, there are no assumptions about its Yves JP-A 7-165708 and JP-A 8-231505, opens the connection sulfonamida similar connection sulfonamida used in the present invention; however, there is no description, no mention of the relative inhibitory effect disclosed in these publications compounds sulfonamida on the expression of integrin. WO 9301182 reveals antineoplastic agents, using an inhibitory effect on the specific tyrosinekinase compounds having the structure of indole. These funds represent connections indolylmethane-2-indolinone, which differ from the compounds of the present invention. WO 964016 also reveals antineoplastic agents, using an inhibitory effect against specific tyrosine kinase compounds having the structure of indole. However, these funds are derived from 2-indoline-3-methylene, which differ from the compounds of the present invention.

Still were not known remedy against angiogenesis, anti-cancer agent, a suppressor of metastasis of a cancer, an anticoagulant and a tool for the treatment of arteriosclerosis, psoriasis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases based on the inhibitory effect in relation to the expression of integrin.

The present image is integrin is effective. In particular, the present invention is to develop protivoallergennogo tools, anti-cancer tools, suppressor of metastasis of cancer, anticoagulant and means for the treatment of arteriosclerosis, psoriasis, osteoporosis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, which comprises as an active ingredient the compounds having inhibitory activity against the expression of integrin. Another purpose of this invention is the provision of an inhibitor of expression of integrin, including a connection sulfonamida.

Disclosure of inventions

The inventors have conducted serious studies and it was found that the connection sulfonamida with the bicyclic heterocycle, has inhibitory activity against the expression of integrin. Thus, they created the present invention.

In accordance with this present invention relates to:

1. 1) the remedy for the treatment of arteriosclerosis, psoriasis, cancer, osteoporosis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, 2) the anticoagulant, 3) the suppressor of metastasis of a cancer or 4) protivognilostnomu means on the basis of which riaza, cancer, osteoporosis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, 2) the anticoagulant, 3) the suppressor of metastasis of a cancer or 4) protivognilostnomu means on the basis of the inhibitory effect in relation to the expression of integrin as described in 1., where integrin is integrin2,3,5,6,v,1,3,4,5,21,31,51,61,v1,v3 orv5.

3. the inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida represented by the formula (I), its pharmacologically acceptable salt 6-10-membered heteroaryl ring, which may have a substituent and in which part of the ring may be saturated; It represents a single bond, -CH=CH - or - (CR4bR5b)bm- (where R4band R5bare the same or different from each other and each represents a hydrogen atom or a C1-C4 alkyl group; and mbmeans an integer of 1 or 2); R1represents a hydrogen atom or C1-C6 alkyl group; Z represents a single bond or-CO-NH-; R represents a C6-C10 aryl ring or 6-10-membered heteroaryl ring which may have a substituent and in which part of the ring may be saturated, respectively.

4. the inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida described in 3, its pharmacologically acceptable salt or hydrate, where R represents indole, quinoline or isoquinoline.

5. the inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida represented by the formula (Ia), its pharmacologically acceptable salt or hydrate:

In the formula, ring Aarepresents a monocyclic or bicyclic aromatic ring which may have Samanid or unsaturated 6-membered heterocycle, containing one nitrogen atom as heteroatom; ringarepresents an optionally substituted 5-membered heterocycle containing 1 or 2 nitrogen atom; R1arepresents a hydrogen atom or C1-C6 alkyl group; Warepresents a single bond or-CH=CH-; Yarepresents a carbon atom or a nitrogen atom; Zarepresents-N(R2a)- (where R2ameans a hydrogen atom or a lower alkyl group) or a nitrogen atom, respectively.

6. the inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida described in 5, its pharmacologically acceptable salt or hydrate, where Warepresents a single bond.

7. the inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida presented in 5, its pharmacologically acceptable salt or hydrate, where Warepresents a single bond; Zais-NH-; and Yarepresents a carbon atom.

8. the inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida presented in any of paragraphs.5, 6 and 7, its pharmacologically acceptable salt or hydrate, where the ring Inais pownage component connection sulfonamida, presented in any of paragraphs.5-8, its pharmacologically acceptable salt or hydrate, where the ring Withais optionally substituted pyrrole.

10. the inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida presented in 5, its pharmacologically acceptable salt or hydrate, where the ring Andarepresents a benzene or pyridine which may have a Deputy; ringarepresents benzene which may have a Deputy, a ring Withais pyrrole which may have a Deputy; Warepresents a single bond; Zais-NH-.

11. the inhibitor of expression of integrin containing as an active ingredient sulfonamides heterocyclic compound represented by formula (Ib), its pharmacologically acceptable salt or hydrate:

In the formula abrepresents a hydrogen atom, halogen atom, hydroxyl group, C1-C4 alkyl or alkoxy group which may be substituted by halogen atom, cyano group, -(CO)bkNR2bR3b(where R2band R3bare the same or different from each other and each is o or 1), C2-C4 alkenylphenol or alkenylphenol group which may have a Deputy, or phenyl or phenoxy group which may have a Deputy, selected from the following group A; Bbmeans aryl group or monocyclic heteroaryl group which may have a Deputy, selected from the following group a, or the following formula:

where the ring Qbmeans an aromatic ring which may have one or two nitrogen atom; and the ring Mbmeans C5-C12 unsaturated monocycle or a heterocycle having a double bond, in common with the ring Qbthe ring may have from 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, the ring Onband the ring Mbmay have a common nitrogen atom, and the ring Qband the ring Mbmay have a Deputy, selected from the following group a); Kbmeans a single bond or -(CR4bR5b)mb- (where R4band R5bare the same or different from each other and each means hydrogen atom or a C1-C4 alkyl group; mbmeans an integer of 1 or 2); Tb, WbXband Ybare the same or different from each other is 1-C4 alkyl or alkoxy group, which may be substituted by halogen atom, cyano group, -(CO)bnNR6bR7b(where R6band R7bare the same or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted by a halogen atom; nb0 or 1) or C2-C4 alkenylphenol or alkenylphenol group which may have a Deputy, respectively) or a nitrogen atom; Uband Vbare the same or different from each other and each means=C(Db)- (where Dbhas the same meaning as described above), a nitrogen atom, -CH2-, an oxygen atom or-CO-; Zbmeans a single bond or-CO-NH-; R1bmeans a hydrogen atom or a C1-C4 alkyl group; andmeans a single or double bond.

Group a: a halogen atom, hydroxyl group, C1-C4 alkyl or alkoxy group which may be substituted by halogen atom, cyano group, -R8bR9bN (NH)bp- (where R8band R9bare the same or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted by a halogen atom; pbis 0 or 1, or R8band R9bcan obrasocial the nitrogen atom, an oxygen atom or a sulfur atom and, in addition, may have a Deputy), aminosulfonyl group which may be substituted mono - or di-C1-C4 alkyl group, C1-C8 acyl group which may have a Deputy, C1-C4 alkyl-S(O)bs-C1-C4 Allenova group (where sbmeans the integer 0, 1 or 2), phenylcarbonylamino group which may have a C1-C4 alkyl or Deputy, -(CO)bqNR10bR11b(where R10band R11bare the same or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted amino group which may be substituted by halogen atom or C1-C4 alkyl group; and qb0 or 1), or aryl group or heteroaryl group which may have a Deputy).

12. the inhibitor of expression of integrin containing, as an active ingredient sulfonamides heterocyclic compound represented at 11, its pharmacologically acceptable salt or hydrate, where Uband Vbpresent =C(Db)- (where Dbhas the same meaning as above) or a nitrogen atom.

13. the inhibitor of expression of integrin containing as the active component self the eh or their hydrate, where Zbrepresents a single bond.

14. the inhibitor of expression of integrin containing as an active ingredient sulfonamides heterocyclic compound represented by any of 11-13, its pharmacologically acceptable salt or hydrate, where at least one of the TbUb, Vb, WbXband Ybrepresents a nitrogen atom.

15. the inhibitor of expression of integrin containing as an active ingredient sulfonamides heterocyclic compound represented by any of 11-14, its pharmacologically acceptable salt or hydrate, where abrepresents a halogen atom, C1-C4 alkyl group or alkoxy group which may be substituted by halogen atom, cyano group, -(CO)brNR12bR13b(where R12band R13bare the same or different from each other and each represents a hydrogen atom or a C1-C4 alkyl group which may be substituted by a halogen atom; and rb0 or 1) or C2-C4 alkenylphenol or alkenylphenol group which may have a Deputy.

16. the inhibitor of expression of integrin containing as an active ingredient sulfonamides heterocyclic compounds b Ub, Vb, WbXband Ybrepresents a nitrogen atom.

17. the inhibitor of expression of integrin containing as an active ingredient sulfonamides heterocyclic compound represented by any of 11-16, its pharmacologically acceptable salt or hydrate, where only one of the Tb, Wband Ybrepresents a nitrogen atom.

18. the inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida presented in any of 5-17, its pharmacologically acceptable salt or hydrate, where the integrin is2,3,5,6,v,1,3,4 or5 integrin.

19. the inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida presented in any of 5-17, its pharmacologically acceptable salt or hydrate, where the integrin is21,361,v1,v3 orv5 integrin.

20. 1) the remedy for the treatment of arteriosclerosis, psoriasis, cancer, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, 2) the anticoagulant, 3) the suppressor of metastasis of a cancer or 4) protivognilostnomu means on the basis of the inhibitory effect in relation to the expression of integrin, which contains as an active ingredient the compound sulfonamida presented in any of 5-17, its pharmacologically acceptable salt or hydrate.

21. 1) the remedy for the treatment of arteriosclerosis, psoriasis, or osteoporosis, or 2) to anticoagulant-based inhibitory effect in relation to the expression of integrin, which contains as an active ingredient, a compound sulfonamida presented in any of 5-17, its pharmacologically acceptable salt or hydrate.

The present invention provides a method of preventing, treating or alleviating disease, which effectively inhibits the expression of integrin, by introducing the patient gabrieleno salt or hydrate.

In addition, the present invention provides the use of compounds represented by any of formulas (I), (Ia) and (Ib), its pharmacologically acceptable salt or hydrate to obtain the means to prevent, treat or alleviate disease, which effectively inhibits the expression of integrin.

In the present invention the disease, which makes efficient inhibition expresii integrin include arteriosclerosis, psoriasis, cancer, osteoporosis, retinal angiogenesis, diabetic retinopathy and inflammatory diseases.

In addition, in the present invention the means for prevention, cure or relief of disease, which effectively inhibits the expression of integrin, includes a tool for the treatment of arteriosclerosis, psoriasis, cancer, osteoporosis, retinal angiogenesis, diabetic retinopathy or inflammatory diseases, anticoagulant, suppressor of metastasis of a cancer and anti-angiogenesis.

Hereinafter the present invention will be described in more detail.

For R and C6-C10 aryl ring or 6-10-membered heteroaryl ring which may have a substituent and in which a part of a cyclic structure may be saturated, means the arc is l, containing as the heteroatom, at least one atom selected from nitrogen atoms, oxygen and sulfur, and may have one or more substituents in the ring and the part of the said ring may be saturated. Specific examples include benzene, pyridine, pyrimidine, pyrazin, pyridazine, naphthalene, quinoline, isoquinoline, phthalazine, naphthiridine, cinoxacin, hinzelin, cinnolin, indole, isoindole, indolizine, indazole, benzofuran, benzothiophene, benzoxazole, benzimidazole, benzopinacol, benzothiazole, 4,5,6,7-tetrahydroindole, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihydrobenzofuran, indan, tetralone, indolin, isoindoline, chroman, tetralin. The above-mentioned aromatic ring may have 1 to 3 substituents. In the case when there are multiple substituents, these substituents may be the same or different. Examples of the substituent may include an amino group which may be substituted by a lower alkyl group or lower cycloalkyl group, a lower alkyl group, lower alkoxy group, hydroxyl group, nitro group, mercapto group, cyano group, lower alkylthio group, group, halogen, a group represented by formula-aa-ba(where aameans a single bond, -(CH2)athe e kameans an integer from 1 to 5; and R3ameans a hydrogen atom or a lower alkyl group); and bameans-CH2-da(where dameans an amino group which may be substituted by a lower alkyl group, halogen atom, hydroxyl group, lower alkylthio group, cyano group or lower alkoxy group)), a group represented by formula-aa-ea-fa(where aahas the same meaning as above; eameans-S(O)- or-S(O)2-; and fameans an amino group which may be substituted by a lower alkyl group or lower alkoxy group, lower alkyl group, triptorelin group, -(CH2)am-baor-N(R4a)-(CH2)am-ba(where bahas the same meaning as above; R4ameans a hydrogen atom or a lower alkyl group; and mameans an integer from 1 to 5)), the group represented by formula-aa-qa-ha(where aahas the same meaning as above; gameans-C(O)- or-C(S)-; and hameans an amino group which may be substituted by a lower alkyl group, hydroxyl group, lower alkyl group, lower alkoxy group, a -(With same value as above; R5ameans a hydrogen atom or a lower alkyl group; and nameans an integer from 1 to 5)), the group represented by formula-aa-N(R6a)-ga-ia(where aaand gahave the same meanings as above; R6ameans a hydrogen atom or a lower alkyl group; iameans a hydrogen atom, a lower alkoxy group, or fa(fahas the same meaning as above)), a group represented by formula-aa-N(R7a)-ea-fa(where aaeaand fahave the same meanings as above; R7ameans a hydrogen atom or a lower alkyl group), the formula -(CH2)ap-ja-(CH2)aq-ba(where jameans an oxygen atom or a sulfur atom; bahas the same meaning as above; and Raand qaare the same or different from each other and each indicates an integer from 1 to 5), the formula -(CH2)au-AGa(where AGameans phenyl group or heteroaryl group which may be substituted by a lower alkyl group, lower alkoxy group or halogen atom; and uameans 0 or an integer from 1 to 5), Fe) or group represented by the formula-SO2-(CH2)au-Ara(where Araand uahave the same meanings as described above).

Compounds represented by formula (I) in which R represents an indole, quinoline or isoquinoline, are preferred.

In the formula (Ia), "monocyclic or bicyclic aromatic ring which may have a Deputy," represented by ring Andarepresents an aromatic hydrocarbon or aromatic heterocycle containing at least one atom selected from nitrogen atoms, oxygen and sulphur, the ring which may contain from 1 to 3 substituents. Examples of key aromatic rings, representing the ring Andainclude pyrrole, pyrazole, imidazole, thiophene, furan, thiazole, oxazole, benzene, pyridine, pyrimidine, pyrazin, pyridazine, naphthalene, quinoline, isoquinoline, phthalazine, naphthiridine, cinoxacin, hinzelin, cinnolin, indole, isoindole, indolizine, indaial, benzofuran, benzothiophene, benzoxazole, benzimidazole, benzopinacol and benzothiazole. The above-mentioned aromatic ring may have 1 to 3 substituents. When there are multiple substituents, these substituents may be the same or different. Examples samesign group, lower alkyl group, lower alkoxy group, hydroxyl group, nitro group, mercapto group, cyano group, lower alkylthio group, group, halogen, a group represented by formula-aa-ba(where aameans a single bond, -(CH2)ak-, -O-(CH2)ak-, -S-(CH2)ak- or-N(R3a)-(CH2)ak-; kameans an integer from 1 to 5; R3ameans a hydrogen atom or a lower alkyl group; and barepresents-CH2-da(where dameans an amino group which may be substituted by a lower alkyl group, halogen atom, hydroxyl group, lower alkylthio group, cyano group or lower alkoxy group)), a group represented by formula-aa-ea-fa(where aahas the same meaning as above; eameans-S(O)- or-S(O)2-; fameans an amino group which may be substituted by a lower alkyl group or lower alkoxy group, lower alkyl group, triptorelin group, -(CH2)am-baor-N(R4a)-(CH2)am-ba(where bahas the same meaning as above; R4ameans atom bodoro>a-ga-ha(where aahas the same meaning as above; gameans-C(O)- or-C(S)-; hameans an amino group which may be substituted by a lower alkyl group, hydroxyl group, lower alkyl group, lower alkoxy group, -(CH2)an-baor-N(R5a)-(CH2)an-ba(where bahas the same meaning as above; R5adenotes a hydrogen atom or a lower alkyl group; and nameans an integer from 1 to 5)), the group represented by formula-aa-N(R6a)-ga-ia(where aaand gahave the same meanings as above; R6ameans a hydrogen atom or a lower alkyl group; and iameans a hydrogen atom, a lower alkoxy group, or fa(fahas the same meaning as above)), a group represented by formula-aa-N(R7a)-ea-fa(where aaeaand fahave the same meanings as above; and R7ameans a hydrogen atom or a lower alkyl group), the formula -(CH2)ap-ja-(CH2)aq-ba(where jameans an oxygen atom or a sulfur atom; bahas the same mean an integer from 1 to 5), the formula -(CH2)au-Ara(where AGameans phenyl group or heteroaryl group which may be substituted by a lower alkyl group, lower alkoxy group or halogen atom; uameans 0 or an integer from 1 to 5), the formula N-(CH2)au-AGa(where AGaand uahave the same meanings as above) or a group represented by the formula-SO2-(CH2)au-AGa(where AGaand uahave the same meanings as described above).

In the above examples, the Deputy, when the amino group is substituted by two alkyl groups, these alkyl groups can be linked together with the formation of 5-6-membered rings. In addition, in the case when the ring Andarepresents a nitrogen-containing heterocycle having a hydroxyl group or mercapto group, ring Andamay be the above-mentioned substituents in the form oxo group or thio group because of the possible formation of resonant structures.

"6-membered cyclic unsaturated hydrocarbon or unsaturated six-membered heterocycle which contains one nitrogen atom as a heteroatom, which may have a substitute, represented by the ring is the" in the ring. In the case where there are two substituent, these substituents may be the same or different.

"The five-membered heterocycle, which may have a substituent and contains one or two nitrogen atom" represented by ringais pyrrole, pyrazole or imidazole, part of which can be gidrirovannah and may have one or two substituent in the ring. In the case where there are two substituent, these substituents may be the same or different.

Examples of substituents which may have a ring Inaand the ring Camay include the group of halogen, cyano group, lower alkyl group, lower alkoxy group, hydroxyl group, oxo group, a group of the formula-C(O)-ra(where rameans a hydrogen atom, an amino group which may be substituted by a lower alkyl group, a lower alkyl group, lower alkoxy group or hydroxyl group), amino group which may be substituted by a lower alkyl group, and triptorelin group.

Examples of the lower alkyl groups in the definition of the substituent, which may have R1a, R2aand rings AndaInaandain the above formula (Ia), means a straight or branched iruppu, ISO-propyl group, n-boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, n-pentelow (amylou group), isopentyl group, neopentyl group, tert-pentelow, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl group, n-hexoloy group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group and 1-ethyl-2-methylpropyloxy. As preferred groups among the above groups may be offered a methyl group, ethyl group, n-sawn group, isopropyl group, n-bucilina group and isobutylene group. Among these preferred groups is most preferred methyl group, ethyl group, n-sawn group and isopropyl group.

Examples of the lower cycloalkyl group in the definition of the substituent which may have a ring AA include cyclopropyl group, cyclopentyl also Andaring Inaand a ring Withathat means a lower alkoxy group derived from the above lower alkyl groups, such as methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group and tert-butoxy group. Among the above groups, methoxy group, ethoxy group can be presented as preferable examples. In addition, examples of the halogen atom include fluorine atom, chlorine atom and bromine atom.

Among these substituents, particularly preferred examples include 1) N-(3-cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonyl; 2) N-(3-cyano-4-methyl-1H-indol-7-yl)-6-chloro-3-pyridinesulfonamide; 3) N-(3-bromo-5-methyl-1H-indol-7-yl)-4-sulfamoylanthranilic; 4) N-(5-bromo-3-chloro-1H-indol-7-yl)-6-amino-3-pyridinesulfonamide; 5) N-(3-bromo-5-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonyl; 6) N-(4-bromo-1H-indol-7-yl)-4-cyanobenzenesulfonyl; 7) N-(4-chloro-1H-indol-7-yl)-6-amino-3-pyridinesulfonamide; 8) N-(3-bromo-4-chloro-1H-indol-7-yl)-6-amino-Z-pyridinesulfonamide; 9) N-(3-bromo-5-methyl-1H-indol-7-yl)-5-cyano-2-thiophenesulfonyl; 10) N-(4-bromo-3-chloro-1H-indol-7-yl)-2-amino-5-pyrimidinemethanol; 11) N-(3-chloro-1H-indol-7-yl)-4-sulfamoylanthranilic.

The case when prooi or base. The present invention also provides salts of the compounds (Ia). Examples of the salt of the acid include inorganic salts such as hydrochloride, hydrobromide and sulfate, salts of organic acids such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonate and p-toluensulfonate. Examples of the salt of the base may include an inorganic salt such as sodium salt, potassium salts and calcium salts, and salts of organic bases such as triethylamine, arginine and lysine.

In the present invention, the term "aromatic ring which may have one or two nitrogen atom" represented by ring Qbmeans an aromatic hydrocarbon or 6-membered aromatic heterocycle containing one or two nitrogen atom. Examples of key aromatic ring represented by ring Qbinclude benzene, pyridine, pyrimidine, pyrazin and pyridazin. In addition, the ring M, represented by the term "means C5-C12 unsaturated monocycle or politics, which may have from 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom" means a monocycle or politicl having a double bond together with to the e hydrocarbons, such as cyclopentene, cyclohexene, cycloheptene, cyclooctene, cyclopentadiene, cycloheptadiene and cyclooctadiene, and unsaturated heterocycles, such as tetrahydropyridine, pyrrole, furan, thiophene, oxazole, isoxazol, thiazole, isothiazol, pyrazole, imidazole, triazole, pyridine, pyrimidine, pyrazin, pyridazine, triazine, indole, isoindole, quinoline, isoquinoline, indazole, naphthiridine, benzofuran, Benaojan, benzothiophene, benzimidazole, benzoxazole, benzothiazole, pyrrolopyridine, pyridopyrimidines and imidazopyridine. In addition, the term "ring Qbhas one nitrogen atom together with ring Mb" this is when a nitrogen atom is present at the position where both rings are condensed. Examples of the cyclic structure formed thereby include indazolin, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine and pyrazolo[1,5-a] pyrimidine.

In the present invention, C1-C4 alkyl group, R1b, R4band R5bor in the expression "C1-C4 alkyl group which may be substituted by a halogen atom" AndbDb, R1b, R2b, R3b, R6b, R7b, R8b, R9b, R10b, R11b, R12b, R13b, R14b, R15b, G1b, G2band the " group means a straight or RAPP, ethyl group, n-sawn group, isopropyl group, n-bucilina group, isobutylene group, sec-bucilina group and tert-bucilina group. The term "may be substituted by a halogen atom" means that the alkyl group may be substituted by a halogen atom selected from fluorine atom, chlorine atom, bromine atom and iodine atom. For example, can be offered mooftormetilnoy, monochloromethyl group, deformational group, triptorelin group, 1 - or 2-mooftormetilnoy group, 1 - or 2-monochloroethylene group, 1 - or 2-monobromodiphenyl group, 1,2-deperately group, 1,2-dichloroethylene group, 1,1,2,2,2-panafcortelone group and 3,3,3-cryptosporella group. Preferred examples of these groups include monitoramento group, deformational group, triptorelin group, 1 - or 2-monitoramento group, 1,2-deperately group and 1,1,2,2,2-panafcortelone group.

In the present invention, C1-C4 alkoxy group, the term "C1-C4 alkoxy group which may be substituted by a halogen atom" in AaDband the " group means a straight or branched alkoxy group having from 1 to 4 carbon atoms. May be offered, for example, methoxy group, ethoxy group, p-p is butylochki group. The term "may be substituted by a halogen atom" means that the alkoxy group may be substituted by a halogen atom selected from fluorine atom, chlorine atom, bromine atom and iodine atom. May be offered, for example, monitorless group, deformedarse group, triptoreline group, 1 - or 2-monitorate group, 1 - or 2-monochloracetic group, 1-or 2-monobromide group, 1,2-diflorasone group, 1,1,2,2,2-pentaborate group and 3,3,3-cryptocracy group. Among these groups, preferred examples include monitorless group, deformedarse group, triptoreline group, 1 - or 2-monitorate group, 1,2-diflorasone group and 1,1,2,2,2-pentaborate group.

In the present invention, C2-C4 Alchemilla or Alchemilla group, represented in Aband Dbmeans alkenylphenol or alkenylphenol group having from 2 to 4 carbon atoms. May be offered, for example, vinyl group, allyl group, 2-or 3-bucinellina, 1,3-butadienyl group, etinilnoy group, 2-proponila group, 2-methyladenine group and 2 - or 3-Butyrina group.

In the present invention aryl group, appearing inband the group means an aromatic hydrocarbon, and illustrative is Nozick or politics, having one or two or more atoms selected from nitrogen, oxygen and sulfur. For example, can be offered pyrrolidine group, imidazolidinyl group, pyrazolidine group, thiazolidine group, furilla group, thienyl group, oxazoline group, isoxazolyl group, thiazolidine group, isothiazolinone group, thiadiazolyl group, Peregrina group, piramidalnaya group, perazella group, indayla group, indolizinyl group, benzoimidazolyl group, benzothiazolyl group, benzoxazolyl group, hyalinella group, sochineniia group, chinadaily group and phthalazinone group.

In the present invention, the term "R8band R9bmay form a 5 - or 6-membered ring together with the nitrogen atom to which they relate, and the ring may optionally contain a nitrogen atom, an oxygen atom or a sulfur atom" in the definition of R8band R9bmeans that R8band R9bform pyrrolidinyloxy group, piperidinyl group, morpholino group, thiomorpholine group, piperazinilnom group, etc. together with the nitrogen atom to which they relate.

In the present invention in terms of aminosulfonyl group which may be substituted mono - ia, which may have a C1-C4 alkyl group or a Deputy, and C1-C4 alkyl group which may be substituted by C1-C4 alkyl group, in the group definition And meaning the same alkyl group as mentioned above, and examples alkalinous group may include methylene group, ethylene group, propylene group, butylene group, metilbutilovy group, 1 - or 2-methylethanol group, 1-, 2 - or 3-methylpropanoyl group and dimethylmethylene group.

In addition, C1-C8 alcoolica group means, for example, formyl group, acetyl group, propionyl group, butyryloxy group, isobutyryloxy group, valerino group and benzoyloxy group.

Protective group in the term "amino group which may have a protective group" appearing in the Jbthe present invention may be any group which is known as a protective group in organic synthesis, and there are no special restrictions regarding the use of specific protective group. May be offered, for example, benzyloxycarbonyl group, t-butoxycarbonyl group, formyl group, acetyl group, chlorocichla group, 2,2,2-trichlorethylene group, benzylidene group, benzhydryl group, and the protective group of the carboxy group in R16bcan be any group which is known as a protective group in organic synthesis and there are no particular restrictions regarding the use of protective groups. May be offered, for example, methyl group, ethyl group, through the group, isopropyl group, t-bucilina group, methoxymethyl group, 2,2,2-trichlorethylene group, pivaloyloxymethyl group and benzyl group.

In the present invention, the substituent in the term "may have a Deputy" means the above-mentioned halogen atom, C1-C4 alkyl group or alkoxy group which may be substituted by halogen atom, hydroxyl group, hydroxy C1-C4 alkyl group, amino group which may be substituted mono - or di-C1-C4 alkyl group, C2-C4 alkenylphenol or alkenylphenol group, cyano group, C1-C8 acyl group, aminosulfonyl group which may be substituted mono-or di-C1-C4 alkyl group, a carboxy group, C1-C4 alkoxycarbonyl group and karbamoilnuyu group which may be substituted mono - or di-C1-C4 alkyl group.

Sulfonamides heterocyclic compound represented by the above formulalocal salt of compound (Ib). Examples of the salt of the acid include inorganic salts such as hydrochloride, hydrobromide and sulfate, salts of organic acids such as acetic acid, lactic acid, succinic acid, fumaric acid, maleic acid, citric acid, benzoic acid, methanesulfonate and p-toluensulfonate. In addition, as the salt of the base can be represented by inorganic salts such as salts of sodium, potassium salts and calcium salts, and salts of organic bases such as triethylamine, arginine and lysine.

In addition, it goes without saying that the present invention also includes hydrates of these compounds, optical isomers, if these isomers exist. In addition, the present invention includes compounds exhibiting activity against angiogenesis, and compounds derived from this connection due to metabolism in vivo, namely, oxidation, recovery, hydrolysis and conjugation. In addition, the present invention further includes compounds producing the compound of the present invention due to metabolism in vivo, such as oxidation, recovery and hydrolysis.

The compound (Iain accordance with the present invention can poluchi.

As mentioned above, the compound (Ia) of the present invention can be obtained by using different methods. Among these methods are typically of the following.

1) the Above compound can be obtained by the interaction of the sulfonic acid represented by the formula (IIa):

(where the ring Aaarepresents a monocyclic or bicyclic aromatic ring which may have a protected or unprotected Deputy; and Wahas the same meaning as above) or its reactive derivative with the compound represented by formula (IIIa):

where the ring VAarepresents a 6-membered unsaturated hydrocarbon or unsaturated 6-membered heterocycle which contains one nitrogen atom as a heteroatom, which may be protected or unprotected Deputy; the ring of CAarepresents a 5-membered ring which may have a protected or unprotected substituent and contains one or two nitrogen atom; and Xa, Yaand Zahave the same meanings as above.

Examples of the reactive derivative of sulfonic acid (IIagericy sulfonic acid and N-sulfanilimide. Particularly preferred examples are sulphonylchloride. Although there is no specific restrictions used in the reaction solvent, it is desirable to use a solvent which dissolves the initial substance and which does not react easily with those of the original substances. For example, can be used pyridine, tetrahydrofuran, dioxane, benzene, ethyl ether, dichloromethane and dimethylformamide or a mixed solvent using two or more solvents selected from the above solvents. In addition, in the reaction, in the case where as the reaction you receive the free acid, as shown in the case of sulphonylchloride, the reaction is preferably carried out in the presence of an appropriate reducing agent. Therefore, the use of a basic solvent such as pyridine, is particularly preferable. If you use a neutral solvent, possibly adding a basic substance, such as a carbonate of an alkali metal or an organic tertiary amine. Needless to say, suitable for use in this reaction, the solvents are not limited to the illustrated examples rastvoriteleyj be cooled or heated. The reaction time is usually in the range from 10 minutes to 20 hours and, as a rule, is selected depending on the type of the source materials and the reaction temperature.

In the case where the resulting product of the amino group or hydroxyl group is protected, derived sulfonamida or sulphonate derivative (Ia) having a free hydroxyl group, or amino group, can be obtained by using, if required, the usual method of removing protection, such as acid treatment, alkali treatment and catalytic reduction.

2) the Above compound can be obtained by the interaction of the compounds represented by formula (IVa):

(where the ring Aaaring BAa, WaXaand Zahave the same meanings as above) with a halogenation agent. As halogenation means may be proposed N-chlorosuccinimide, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, N-bromoacetamide, chlorine and bromine. Although there is no specific restrictions used in the reaction solvent, typically use the connection alkylchloride, such as dichloromethane, chloroform, tetrachloride and in the range of the solvent, such as dimethylformamide, dioxane, pyridine and acetonitrile. Although the reaction temperature varies depending on the types of halogenation means and the substrate, usually the reaction is carried out at a temperature in the range from -50 to 100°C.

In the case where the resulting product of the amino group or hydroxyl group is protected, derived sulfonamida or sulphonate derivative (Ia) having a free hydroxyl group, or amino group, can be obtained by using, if necessary, a conventional method of removing protection, such as acid treatment, alkali treatment and catalytic reduction.

3) the Above compound can be obtained by the interaction of the compounds represented by formula (Va):

(where the ring AAaring BAa, WaXaand Zahave the same meanings as above, and Earepresented by the Deputy, which was transformed into a cyano dehydration) with a dehydrating agent. As a substitute, turn to the cyano dehydration, can be used (hydroxyimino) methyl group and carnemolla group.

In addition, you can first of the aldehyde and the fact that not distinguishing, to expose them to interact with the dehydrating agent. As examples of the dehydrating agent can be represented dehydrating, used in the conventional method for the synthesis of nitrile, for example acetic anhydride, thionyl chloride, phosphorus oxychloride (III), selenium dioxide and 1,3-dicyclohexylcarbodiimide. Although there are no particular restrictions on the solvent to be used in this reaction, the desired those solvents that do not interact easily with these substances, for example pyridine, ethyl ether, benzene, dimethylformamide, carbon tetrachloride, acetonitrile and tetrahydrofuran, or you can use a mixed solvent of two or more solvents selected from the above solvents. Although the reaction temperature varies depending on the types of dehydrating and substrate, usually the reaction is carried out at a temperature of from -50°C to 150°C.

In the case where the resulting product of the amino group or hydroxyl group is protected, derived sulfonamida or sulphonate derivative (Ia) having a free hydroxyl group, or amino group, can be obtained ispolzuyuschie recovery.

4) the Above compound can be obtained by the interaction of the compounds represented by formula (VIa):

(where the ring ABarepresents a monocyclic or bicyclic aromatic ring which has a Deputy, which was transformed into the amino group of the restoration, and, in addition, may be protected or unprotected Deputy; ring BAaring of CAa, WaXa, Yaand Zahave the same meanings as mentioned above) with a reducing agent. As a substitute, turn in the amino recovery, can be cited as examples of the nitrogroup, nitrosolobus, hydroxyamino and isogroup.

The way nitrogroup reduction, which is a typical example of the method of recovery may be represented by catalytic regeneration using as a catalyst of palladium on carbon and platinum oxide, and the recovery of zinc, iron or tin with acid. Catalytic reduction is usually carried out under normal pressure or under pressure in an organic solvent, such as methanol, tetrahydrofuran or dimethylformamide.

In the case Conetoe derivative (Ia) having a free hydroxyl group can be obtained by using, if required, the usual method of removing protection, such as acid treatment, alkali treatment and catalytic reduction.

5) the Above compound can be obtained by the interaction of the compounds represented by formula (VIIa):

(where the ring AUarepresents a monocyclic or bicyclic aromatic ring which has dissotsiiruut group on the ring or Deputy, and, in addition, may be protected or unprotected Deputy; and ring BAaring of CAa, WaXa, Yaand Zahave the same meanings as above) with a nucleophilic agent. Examples tsepliaeva group may include halogen, methanesulfonate group and p-toluensulfonate group. Examples of the nucleophilic agent may include amines, alcohols and thiols. In the case of alcohols and thiols of the above compounds after the reaction can take the form of a salt of an alkali metal or etc., Although there is no particular restrictions on the solvent to be used in this reaction, the desired solvent to tetrahydrofuran, dioxane, dimethylformamide or water. Although the reaction temperature varies depending on the type of substrate, the reaction is usually carried out at a temperature of from -50 to 150°C.

In the case where the resulting product of the amino group or hydroxyl group is protected, derived sulfonamida or sulphonate derivative (Ia) having a free hydroxyl group, or amino group, can be obtained by using, if necessary, a conventional method of removing protection, such as acid treatment, alkali treatment and catalytic reduction.

The following are ways to obtain the compound (IIa), the original substance and its reactive derivative and the compound (IIIa) used in the present invention.

The original compound (IIa) and its reactive derivative include known compounds and new compounds. As for these new compounds can be obtained using the method of synthesis known connection that has already been set forth, or using a combination of these known methods. For example, the new sulphonylchloride can be obtained by the method developed by the use of synthetic methods described in Chem. Ber.,1948), J. Am. Chem. Soc., 78, 2171 (1956), and so on

Starting material, the compound (IIIa), include known compounds and new compounds. In the case when N-Xa- represents the amino group of H2N - in the original substance, the compound (IIIa), H2N-containing agent (IIIa) can be obtained by reduction of compound containing the nitro-group, using the method of nitrogroup reduction, which is usually used. Preferred examples of recovery methods include catalytic reduction using a catalyst of palladium-carbon and recovery using powder zinc-hydrochloric acid. Catalytic reduction can be carried out at normal pressure or under pressure in an organic solvent, such as methanol, tetrahydrofuran and dimethylformamide.

In the case when N-Xarepresents a hydroxyl group, (BUT) in the original substance, the compound (IIIa), BUT containing the compound (IIIa) can be obtained by diazotization of the above-mentioned amino compounds and the subsequent hydrolysis of the resulting product.

In the case when the source compounds are new compounds can be obtained using the method of synthesis known compound can be obtained, using the methods described in Can. J. Chem., 42, 1235 (1964), Chem. Abst., 59, 8855f (1963), Tetrahedron Lett., 30, 2129 (1989), and so on, through, for example, the following path.

Scheme 1a

In the formula Qamean identical or different substituents; Gameans the group of halogen; and tarepresents an integer from 0 to 2.

Scheme 2a

In the formula Qaand tahave the same meanings as above.

Scheme 3a

In the formula Qa, Gaand tahave the same meanings as above; DFFA (DPPA) means diphenylphosphinite.

Scheme 4a

In the formula Qa, Gaand tahave the same meanings as above; DH (DDQ) means 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.

Further, the compound (Ib) of the present invention can be obtained in various ways. Among them, the typical methods are as follows.

1) When Zbrepresents a single bond

In the formula abInbTbUb, VbWb), or its reactive derivative with the compound represented by formula (VIb).

As examples of the reactive derivative of sulfonic acid (Vb), can usually offered frequently used reactive derivatives, such as sulphonylchloride, anhydrides, sulfonic acids and N-sulfanilimide. Especially preferred example is sulfonylmethane. Although there is no specific limitation on the solvent to be used in this reaction, the desired ones, which dissolve the starting material and does not react easily with the original substance. For example, you can use pyridine, tetrahydrofuran, dioxane, benzene, ethyl ether, dichloromethane and dimethylformamide or a mixed solvent of two or more solvents selected from the above. Furthermore, in this reaction, in the case where at least it appears the free acid, as shown in the case of sulphonylchloride, the reaction is preferably carried out in the presence of an appropriate reducing agent. Therefore, the use of a basic solvent such as pyridine, the aqueous substance, such as a carbonate of an alkali metal or an organic tertiary amine. Needless to say, usable solvents are not limited to illustrated here by examples of solvents. Although the reaction generally proceeds at room temperature, the starting materials, if required, can be subjected to cooling or heating. The reaction time is usually in the range from 10 minutes to 20 hours, but it is not necessarily selected in accordance with the type of the original substance and the reaction temperature.

In the case where the resulting product of the amino group or hydroxyl group is protected, derived sulfonamida (VIIb) having a free hydroxyl group, or amino group, can be obtained by using, if necessary, a conventional method of removing protection, such as acid treatment, alkali treatment and catalytic reduction

2) When Zbrepresents-CO-NH-

In the formula Lbmeans a chlorine atom or a bromine atom; R17brepresents C1-C4 alkyl group or benzyl group; AndbInbTbUb, Vb, WbXband Tbhave the same values, cacciata formula (VIIIb), with sulfonamidnuyu compound represented by the formula (IXb).

The reaction is carried out in water or miscible with water directionspanel a solvent such as tetrahydrofuran, and acetone, in the presence of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide and sodium hydride. The reaction is carried out at a temperature of from 0 up to 100°C and preferably at a temperature of approximately 20 to 30°C.

Another preferred reaction is carried out according to the method in which the amine represented by the formula (XIb), is subjected to the interaction with the carbamate represented by the formula (XIIbthe interaction sulfonamida represented by the formula (IXb), with halogenerator represented by the formula (XIIIb).

The reaction between the sulfonamide represented by the formula (IXb), and halogenerator represented by the formula (XIIIb), is carried out in directionspanel a solvent such as acetone, tetrahydrofuran and methyl ethyl ketone, in the presence of an acid acceptor such as potassium carbonate, sodium carbonate, potassium hydroxide and sodium hydroxide. The reaction is carried out at a temperature of from about 30°C to the boiling point openim formula (XIb), is carried out in inert high-boiling solvent, such as dioxane, toluene, diglyme, when heated at a temperature of from about 50°C to the boiling temperature under reflux.

Aminobenzamide compound represented by the formula (VIbor (XIb), as the original substance of the sulfonamide or sulfonilmocevinnah heterocyclic compounds of the present invention can be obtained by using a combination of known methods.

For example, derivatives of quinoline and isoquinoline can be obtained through the following stages of receipt.

In the formula, where abE2b, G2band R16bhave the same meanings as above, R18bmeans C1-C4 alkyl or benzyl group.

In the formula aband G2bhave the same meanings as above.

In the formula, R18bhas the same meaning as above; R19bmeans C1-C4 alkyl group.

In the formula, R18band E2bhave the same meanings as above; R20band R21brespectively denote the atom of water which may have a Deputy, the cyano or amino group which may be substituted mono - or di-C1-C4 alkyl group; E3brepresents a hydrogen atom, halogen atom, C1-C4 alkoxygroup, fenoxaprop or phenyl group which may have a Deputy, cyano or amino group which may be substituted mono - or di-C1-C4 alkyl group.

When the compound of the present invention are used as medicines, it is administered orally or parenterally. The dose of the compound varies depending on the extent of symptoms (evidence of pathology), age, sex, weight, and differences in sensitivity to the drug in patients, the method of administration, time of administration, interval of administration, characteristics of drugs, formulations and types of drugs, types of active components and so on, and there is no specific limitation regarding the dose. However, the dose usually ranges from 10 to 6000 mg, preferably from about 50 to 4000 mg, and more preferably from 100 to 3000 mg per day for an adult and the drug is usually taken in a certain amount in installments from one to three times a day.

Upon receipt of solid medicines DL the Xia, binder, disintegrator, lubricant, coloring and flavoring and then mix and prepare medicines in the form of tablets, coated tablets, granules, fine granules, powders or capsules.

The filler used, for example, lactose, corn starch, sucrose, glucose, sorbitol, crystalline cellulose or silica; binders, for example polyvinyl alcohol, ethylcellulose, methylcellulose, Arabian gum, hydroxypropylcellulose or hypromellose; as lubricants, for example magnesium stearate, talc or silica; as a dye those that are permitted as additives to medicines; as a flavouring cocoa powder, menthol, aromatic acid, essential oil of peppermint, camphor, the cinnamon powder and so on These tablets and granules may be provided with a sugar coating or a coating of gelatin and, in addition, if required, can be covered properly.

In the case of obtaining injectable drugs to the main drug type, if required, a pH regulator, a buffer, suspendisse tool, solubilizer, stabilizer, istoricheskoi intramuscular injection. Currently, these injectable drugs are sometimes prepared in the form of food, dried by freezing (freeze-dried foods).

Examples of the suspending means may include methylcellulose, Polysorbate 80, hydroxyethyl cellulose, Arabic gum, powder tragakant, sodium carboxymethyl cellulose and polyoxyethylene sorbitan monolaurate.

Examples of the solubilizer may include polyoxyethylene gidrirovannoe castor oil, Polysorbate 80, nicotinic acid amide, polyoxyethylene sorbitan monolaurate, macrogol ethyl ester of fatty acids of castor oil.

In addition, examples of stabilizers may include sodium sulfite and metasulfite sodium; examples of the preservative may include methylparahydroxybenzoate, metilparagidroksibenzoat, ascorbic acid, phenol, cresol and chlorocresol.

Brief description of drawings

Fig.1 represents, in the upper part, the results of quantitative measurements of the expression of integrin after 48 hours using the connection (unhandled case and 0.05 μg/ml) for endothelial cells of the umbilical vein of a person and, at the bottom, the ratio T/S, expressed in %, as a result of the activity of a compound As compared to the untreated case.

Fig.2 to depict the line of the colon (or colorectal) cancer man (NST-C9) after 48 hours: the effect of the compounds As compared with the untreated case is expressed as the ratio of T/C (%).

Fig.3 shows the inhibitory activity of the compounds And in relation to the expression of integrin at high concentration (0.5 μg/ml and 5 μg/ml) in normal cell line (WI38) in human fibroblasts after 48 hours: the effect of the compounds As compared with the untreated case is expressed as the ratio of T/C (%).

Fig.4 shows the inhibitory activity of each compound (0.5 μg/ml) on the expression of integrin2 on endothelial cells of the umbilical cord human (HUVEC) after 48 hours: the ratio of the number downregulation of integrin2 (treated case) compared to the untreated case is expressed as (%). (The name of each connection is represented by a number of synthetic example).

The action of the compounds of the present invention is illustrated below by means of examples of pharmacological tests.

It should be borne in mind that the connection And in the examples, pharmacological test indicates the compound obtained in synthetic example 1.

Example 1.

Inhibition of expression of integrin on endothelial cells of the umbilical vein of a person (HUVEC)

Endothelial cells of the umbilical vein of a person (HUVEC) in an amount of 5×105b>2-incubator. Then, 3 hours later, EGM medium replaced with the same medium containing the compound a, and continue culturing for a further 48 hours. The cells are then harvested and washed with phosphate buffer containing bovine serum albumin, and the cells added the above buffer solution containing various mouse antibodies against human integrins, and the solution containing the cells, allow to stand at 4°C for 30 minutes. After washing, the cell type associated with FITZ (FITC) antibody against mouse IgG, and then the content allow to stand for 30 minutes and washed again. The cells are then fixed and using the flow cytometer, determine the number of antibodies bound per cell, as the number of FITZ.

As shown in Fig.1, compound a inhibits the expression of integrins2,3,5,6,v,1,3 and5 on the surface of the cells at a concentration of 0.05 mg/ml

Example 2

Inhibition of expression of integrin in cancer cell l is ressie integrin on the above cells was investigated in the same way, as in example 1.

As shown in Fig.2, compound a inhibits the expression of integrins2,3,5,6,1 and4 at a concentration of 0.05 mg/ml and at a concentration of 0.5 μg/ml

Example 3

Inhibitory activity against the expression of integrin in normal cell line (WI38) human fibroblasts (WI38)

The inhibitory activity of the compounds And in relation to the expression of integrin on the above cells was investigated in the same manner as in example 1.

As shown in Fig.3, the connection And having a higher concentration than in examples 1 and 2, slightly inhibits the expression of integrins2,3 and4, but has no effect on the expression of integrins1,5,6 and1.

As mentioned above, it is evident that compound a inhibits the expression of integrin in endothelial cells and cancer cells, but almost has no inhibitory effect on The degree of inhibition of angiogenesis, which is observed when the slices of rat aorta were incubated in collagen was determined as protivokariesnoe action. That is, the aorta, isecheno from rat male line Sprague-Dawley (aged 10-12 weeks), washed with Hanks' solution in order thoroughly to remove fatty tissue around it. The aorta was cut off, getting pieces with an area of 2 mm, and these pieces were given the opportunity to stand in a 24-hole tablet, holding endothelial cells up. Then on top of each well was filled with 500 μl of neutralized collagen Type I (Type I-A (supra)the cell matrix (Cell Matrix Type I-A)); produced by Nitta Gelatin) and allowed to stand at room temperature for about 20 minutes on a clean bench for curing gel. After confirmation of the fact that the gel overiden, to this is added 500 μl of medium MCDB 131 (produced by Chlorella Kogyo), followed by incubation in CO2-incubator (5% CO2) at 37°C. the next day the culture medium replaced with 500 μl of medium MCDB 131 containing the test compound, and the incubation continued. After three days Wednesday again replaced with 500 µl medium MCDB 131 containing the test compound, and at the stage of the 7th day from the start of addition of the test compounds conducting the test compound, in a system with three breeding, in which a solution with a concentration of 10 μg/ml was the solution with the highest concentration.

The degree of inhibition was calculated from the following formula, and for each connection defined concentration of 50% inhibition (IC50IC50).

The degree of inhibition (%)=(s-T)/S×100

where C is the number of capillaries in the case when not being added to the Union;

T - the number of capillaries when the connection has been added.

Connection in accordance with the invention demonstrated the value MC50(IC50) from 0.05 to 3 mg/ml

Example 5

Protivokariesnoe action 2

0.4 ml of collagen Type I were added to 24-well plate and subjected to curing. Endothelial cells of the umbilical vein of a person (HUVEC) in the amount of 8×104sown on collagen and cultured over night, using a culture solution of endothelial cells (Gibco BRL) containing 10 ng/ml EGF (EGF) and 20 ng/ml bfrf (bFGF). Then the supernatant is removed and then the top place a layer of 0.4 ml of the same collagen. In addition, add the culture solution containing 1.5 ml of compound A, and the cells cultured for 4 days. Then using image analysis (image analysis) kolichestve.podrobnee, what antibody2 has the same effect, but this effect was not observed in the case of antibodies5.

Example 6

Protivokariesnoe step 3 (in vivo)

The above activity was evaluated using the method derived by partial improvement method based on the use of air capsules mouse (Sakamoto et al., Cancer Res., 1, 55-57, 1986). In this case, using a 0.22 μm membrane filter (HAWPO, Nippon Millipore), seal milleporidae ring (Nippon Millipore), while receiving the camera. Lines colitis (colic) cancerous human cells (WiDr)) in quantities of 1×107that were suspended in the buffer solution on the basis of phosphoric acid, sealed inside the chamber. Then form an air capsule subcutaneously on the back of a black mouse-female line S, aged 6-8 weeks and this air capsule transplanted in the above-mentioned camera. After approximately 6 hours after transplantation orally administered compound a and subsequently injected sequentially once a day for three days. Erythrocytes mouse that was in the state of51SG, is injected via the tail vein of mice, after 4 days after it was transpla with the camera. After the skin will freeze, strictly isolate just the part that was in contact with camera, to measure the amount of blood using-counter. Then the value obtained by subtracting the amount of blood, measured in the case of cameras that do not contain cancer cells, of the above-mentioned quantity of blood is defined as a measure of angiogenesis. In the test group consisted of 10 mice per group, the group that was administered the compound consisted of 5 mice per group.

If the results are to be assessed by the T/C (%): ratio of angiogenesis in groups, which were injected connection/indicator of angiogenesis in the treated groups filler ×100, connection And has such a result as T/S=53% at a dose of 50 mg/kg

Example 7

Inhibition of expression of integrin2 on endothelial cells of the umbilical vein of a person (HUVEC)

Endothelial cells of the umbilical vein of a person (HUVEC) in an amount of 5×105sown at 75 cm2the culture vessel and then were cultured using the medium EGM (Sanko Junyaku) at 37°C in CO2-incubator. Then, 3 hours later, the medium EGM was replaced with the same medium containing the compound at a concentration of 0.5 μg/ml, and then Ego bovine serum albumin, and to this was added the above buffer solution containing mouse antibody against human integrin2, and the solution was allowed to stand at 4°C for 30 minutes. After washing, cells were added associated with FITZ (FITC) antibody against mouse IgG and then the content was allowed to stand for 30 minutes and again washed. Then the cells were fixed and determined the number of antibodies bound per cell, as the number of FITZ (FITC) using the flow cytometer. The inhibitory activity of each compound is represented by the ratio (%) the level of expression (in the case of processing a connection) to the level of expression obtained in the absence of processing the connection. The name of each connection is represented by a number of synthetic example.

As shown in Fig.4, each compound inhibits the expression of integrin2 on the cell surface at a concentration of 0.5 μg/ml

Compounds in accordance with the present invention specifically disclosed in JP-A 7-165708 and JP-A 8-231505. In addition, examples of the preparation and synthetic examples of typical compounds of the compounds of the present invention will be presented here nigeshinia 1

Etherpiraat-N-(5-methyl-2-nitrophenyl)hydrazone

75,0 g (493 mmol) 5-methyl-2-nitroaniline is added in a mixed solution of 160 ml of water and 170 ml of concentrated hydrochloric acid and the mixture is stirred. To the mixture is added dropwise 80 ml of an aqueous solution containing 36,0 g (517 mmol) of sodium nitrite at -20°C. the Reaction solution is added to a solution obtained by dissolving ethyl-2-methylacetoacetate in 100 ml of ethanol and then adding back 200 ml 12 N. aqueous potassium hydroxide, at -20°C for 30 minutes under stirring. After stirring at the same temperature for 30 minutes the reaction mixture was added 100 ml of concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water and dried under reduced pressure over night. Add mixed solution of diethyl ether and hexane and collect the crystals by filtration, receiving 130 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): of 1.29 (3H, t, J=7.2 Hz), of 2.16 (3H, s), is 2.40 (3H, s), 4,25 (2N, K, J=7,2 Hz), 6,91 (1H, DD, J=8,8, 2.0 Hz), 7,63 (1H, s), 8,07 (1H, d, J=8,8 Hz), 10,69 (1H, s).

Example of getting 2

Ethyl-4-methyl-7-nitro-1H-indole-2-carboxylate

To a suspension of 25.0 g (a 94.2 mmol) connect the under reflux for 3 hours. Under ice cooling to the reaction mixture is added 80 ml of water and 300 ml of ethyl acetate. The insoluble substance is filtered off and washed with 1.5 l of ethyl acetate and the filtrate is extracted with ethyl acetate. The organic layer is successively washed with aqueous saturated sodium bicarbonate, water and saturated salt solution, dried over magnesium sulfate and concentrated to dryness. To the residue add mixed solution of tert-butylmethylether simple ether and hexane and the crystals are collected by filtration, receiving 11.1 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): to 1.35 (3H, t, J=7.2 Hz), 2,65 (3H, s), to 4.38 (2H, K, J=7,2 Hz), 7,16 (1H, d, J=8,4 Hz), 7,51 (1H, s), 8,19 (1H, d, J=8,4 Hz), of 11.29 (1H, CL).

Example for the preparation of 3

4-Methyl-7-nitro-1H-indole-2-carboxylic acid

150 ml of 1 N. aqueous sodium hydroxide is added to tertrahydrofuran ring solution (150 ml) containing 11,0 g (44,3 mmol) of the compound of example get 2, and then heated under stirring at 80°C for 30 minutes. The reaction solution is concentrated and to the residue while cooling with ice, add 40 ml of 5 N. hydrochloric acid to bring the pH to 1. The precipitate is collected by filtration and washed with water. The residue is dissolved in 300 ml dried over magnesium sulfate and concentrated to dryness, getting 9.60 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 2,62 (3H, s), 7,13 (1H, d, J=8.0 Hz), 7,42 (1H, s), 8,15 (1H, d, J=8.0 Hz), 11,00 (1H, CL).

Example 4

4-Methyl-7-nitro-1H-indol

9,58 g (of 43.5 mmol) of the compound of example for the preparation of 3 was dissolved in 60 ml of 1,3-dimethyl-2-imidazolidinone. To the mixture is added 1.04 g (4.35 mmol) of basic copper carbonate followed by heating under stirring at 180°C for 4 hours. To the reaction solution while cooling with ice, add 120 ml of ethyl acetate, the insoluble substance is filtered off and the filtrate is extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated. Then the resulting residue is purified column chromatography on silica gel, getting to 4.87 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): at 2.59 (3H, s), 6,74 (1H, s), 7,03 (1H, d, J=8,4 Hz), of 7.48 (1H, s), of 8.00 (1H, d, J=8,4 Hz), up 11,86 (1H, CL).

Example of getting 5

3-Formyl-4-methyl-7-nitro-1H-indol

1.5 ml (16,1 mmol) of ferric oxychloride of phosphorus added to 12 ml (154 mmol) of dimethylformamide at 0°C in nitrogen atmosphere, followed by stirring at the same teeeeeeeny of example 4, followed by heating under stirring at 90°C for 21 hours. In the reaction solution under ice cooling was added 100 ml of 1 N. aqueous sodium hydroxide and the mixture extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated to dryness. To the residue add mixed solution of tert-butylmethylether simple ether and hexane and the crystals are collected by filtration, receiving of 2.23 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 2,90 (3H, s), 7,21 (1H, d, J=8,4 Hz), 8,11 (1H, d, J=8,4 Hz), 8,39 (1H, s), of 10.01 (1H, s), 12,71 (1H, CL).

An example of obtaining 6

3-Cyano-4-methyl-7-nitro-1H-indol

of 2.21 g (10,8 mmol) of the compound of example, getting 5 are dissolved in 100 ml of dimethylformamide followed by the addition there of 900 mg (13,0 mmol) hydroxylamine hydrochloride and 1.05 ml (13,0 mmol) of pyridine. After heating under stirring at 60°C for 40 minutes in the reaction solution while cooling with ice add 1,1-carbonyldiimidazole or 53.9 mmol). After heating under stirring at 60°C for a further 30 minutes the reaction solution was added 3.0 ml (21.5 mmol) of triethylamine and the mixture is heated under stirring at the ode and the mixture is extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated to dryness. To the residue add mixed solution of tert-butylmethylether simple ether and hexane and the crystals are collected by filtration, getting 1,95 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 2,78 (3H, s), 7,22 (1H, d, J=8.0 Hz), 8,14 (1H, d, J=8.0 Hz), to 8.41 (1H, s), of 12.76 (1H, CL).

Example of getting 7

7-Bromo-4-methyl-1H-indol

1 l (1 mol) of tertrahydrofuran ring solution containing 1.0 M of vinylmania add to tertrahydrofuran ring solution (300 ml) containing 65.0 g (301 mmol) of 2-bromo-5-methylnitrobenzene, at -60°C under stirring for one hour in nitrogen atmosphere. To a solution of the reaction mixture is added aqueous saturated ammonium chloride and ethyl acetate and insoluble substance is filtered off. The filtrate is dried over magnesium sulfate and concentrated. Then the resulting residue is purified by chromatography on a column of silica gel, receiving 35.5 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): to 2.42 (3H, s), 6,55 (1H, s), of 6.73 (1H, d, J=7,6 Hz), 7,16 (1H, d, J=7,6 Hz), 7,35 (1H, s), 11,24 (1H, CL).

Example obtain 8

4-Methyl-1H-ind is receiving 7, at -78°C under stirring in nitrogen atmosphere add 240 ml (384 mmol) of hexane solution containing 1.6 M, utility. After stirring under ice cooling for 40 minutes, through the reaction solution at -50°With miss carbon dioxide and the mixture is stirred for 15 minutes. To a solution of the reaction mixture at the same temperature, water is added and the solvent is evaporated. The precipitate is collected by filtration and washed with water. The residue is dissolved in 300 ml of tetrahydrofuran, dried over magnesium sulfate and concentrated to dryness, obtaining of 25.9 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): of 2.51 (3H, s), 6,53 (1H, s), to 6.88 (1H, d, J=7,6 Hz), 7,31 (1H, s), a 7.62 (1H, d, J=7,6 Hz), 10,99 (1H, CL), 12,79 (1H, CL).

Example of getting 9

7-(N-tert-Butoxycarbonyl)amino-4-methyl-1H-indol

7.0 g (40.0 mmol) of the compound of example obtaining 8 are suspended in 80 ml of toluene to the mixture in an atmosphere of nitrogen was added 22 ml (160 mmol) of triethylamine and 11.2 ml (52 mmol) diphenylphosphinite and the mixture is stirred at room temperature for 30 minutes. In the reaction solution is added 8 ml (84 mmol) of tert-butanol, followed by heating under stirring at 100°C for 2.5 hours. After that reactiontoradol acid, water and saturated salt solution, dried over magnesium sulfate and concentrated to dryness. To the residue add a solution of a mixture of diethyl ether and hexane and the crystals are collected by filtration, getting 7,87 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 1,48 (N, C) of 2.38 (3H, s), 6,37-6,44 (1H, m), of 6.68 (1H, d, J=8,4 Hz), 7,22-7,31 (2H, m), 8,86 (1H, CL), of 10.73 (1H, CL).

Example 10

7-(N-tert-Butoxycarbonyl)-amino-3-formyl-4-methyl-1H-indol

40 ml (429 mmol) of ferric oxychloride of phosphorus added to 400 ml (5.2 mol) of dimethylformamide at 0°C in nitrogen atmosphere, followed by stirring at the same temperature for 25 minutes. There at 0°With the type of 74.0 g (300 mmol) of the compound of example obtaining 9, and then stirred at room temperature for 1.5 hours. The reaction mixture is brought to pH 8 by adding 250 ml of 5 N. aqueous sodium hydroxide under ice cooling. The organic layer is separated, adding in a mixture of tetrahydrofuran, ethyl acetate and water. It sequentially washed with water and saturated salt solution and dried over magnesium sulfate. After that, the solvent is evaporated, to the residue add mixed solution of diethyl ether and hexane and the crystals collected fil border="0">(M. D.): 1,50 (N, C), a 2.71 (3H, s), make 6.90 (1H, d, J=7,6 Hz), 7,32-7,41 (1H, m), 8,21 (1H, d, J=1.6 Hz), 8,99 (1H, CL), to 9.93 (1H, s), 11,88 (1H, CL).

Example of getting 11

7-(N-tert-Butoxycarbonyl)amino-3-cyano-4-methyl-1H-indol

4,43 g (16.2 mmol) of the compound of example 10 is dissolved in 50 ml of dimethylformamide followed by the addition there 1.35 g (to 19.4 mmol) of hydroxylamine hydrochloride and 1.6 ml (to 19.8 mmol) of pyridine. After heating under stirring at 60°C for 45 minutes in the reaction solution while cooling with ice add 1,1-carbonyldiimidazole (80,8 mmol). After heating under stirring at 60°C for a further 30 minutes the reaction solution was added to 4.5 ml (32,3 mmol) of triethylamine and the mixture is heated with stirring at the same temperature for another 30 minutes. In the solution of the reaction mixture under ice cooling, water is added and the mixture extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and then concentrated to dryness, obtaining 4,27 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 1,49 (N, C) 2,60 (3H, s), 6.89 in (1H, d, J=8.0 Hz), 7,34-7,42 (1H, m), to 8.20 (1H, d, J=2,8 Hz), 9,04 (1H, CL), RS 11.80 (1H, CL).

Example 12

7-Amino-3-cyano-4-Maturana and 100 ml of methanol and the mixture hydronaut at ordinary temperature under 3 atmospheres in the presence of 430 mg (of 1.87 mmol) of platinum oxide. The catalyst is filtered off and the filtrate concentrated to dryness. Then to the residue add mixed solution of tert-butylmethylether simple ether and hexane and the crystals are collected by filtration, receiving 10.7 g specified in the connection header. 50.5 g (186 mmol) of the compound of example, receiving 11 dissolved in 400 ml of dichloromethane. In nitrogen atmosphere there at 0°With add 210 ml (was 2.76 mol) triperoxonane acid, followed by stirring at room temperature for 40 minutes. The reaction mixture is brought to pH 7 by adding 5 N. aqueous sodium hydroxide. The solvent is removed and then the residue is extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated to dryness. To the residue add mixed solution of diethyl ether and hexane and the crystals are collected by filtration, receiving 24.5 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 2,47 (3H, s), 5,07 (2H, s), 6,34 (1H, d, J=7,6 Hz), only 6.64 (1H, d, J=7,6 Hz), 8,10 (1H, s), 11,70 (1H, CL).

Example of getting 13

3-Cyanobenzenesulfonyl

25,0 g (212 mmol) of 3-cyanoaniline added to a mixed solution of 200 ml of water and 250 ml of concentrated chlorophyll is holding 15.5 g (223 mmol) of sodium nitrite. The reaction solution are added to a solution of acetic acid saturated with sulfur dioxide (solution obtained by saturation of 250 ml of acetic acid and sulfur dioxide and then by adding 2.1 g of the chloride of monovalent copper) under cooling with ice and with stirring. One hour later, the reaction solution was poured into 500 ml of a mixture of ice - water and extracted with diethyl ether. The extract is successively washed with aqueous saturated sodium bicarbonate, water and saturated salt solution and dried over magnesium sulfate. The solvent is evaporated and to the residue is added a mixed solution of diethyl ether and hexane. The crystals are collected by filtration, getting 16.0 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): at 7.55 (1H, t, J=8.0 Hz), 7,78 (1H, DD, J=8,0, 1.2 Hz), 7,86-a 7.92 (2H, m).

Example of getting 14

4-Sulfamoylanthranilic

25,0 g (145 mmol) of 4-aminobenzenesulfonamide added to a mixed solution of 80 ml of water and 50 ml of concentrated hydrochloric acid, followed by stirring. To the mixture is added dropwise an aqueous solution (20 ml) containing 10.5 g (152 mmol) of sodium nitrite at a temperature from -13 to -10°C for 15 minutes. After 10 minutes the reaction solution is kusnoy acid and 12.5 ml of concentrated hydrochloric acid and sulfur dioxide and then the addition of 3.7 g of the chloride of monovalent copper) at -30°C under stirring. After one hour the reaction solution was added 500 ml of a mixture of ice - water and the precipitate collected by filtration. The residue was dissolved in a mixed solution of 450 ml of toluene and 150 ml of ethyl acetate. After filtering off insoluble matters, the filtrate is extracted with ethyl acetate. The organic layer is successively washed with aqueous saturated sodium bicarbonate and saturated salt solution and dried over magnesium sulfate. The solvent is evaporated and to the residue was added 100 ml of toluene. The crystals are collected by filtration, getting to 20.9 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): the 7.65 of 7.69 (2H, m), 7,71 for 7.78 (4H, m).

Example get 15

5-Bromo-3-chloro-7-nitro-1H-indol

1,4 ml of dimethylformamide and 6,98 g (52,3 mmol) N-chlorosuccinimide add to tertrahydrofuran ring solution (140 ml) containing 12.00 g (49,8 mmol) 5-bromo-7-nitro-1H-indole, followed by stirring at room temperature over night. There is added 10% aqueous sodium thiosulfate, with subsequent extraction with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated to dryness, obtaining 14,84 g specified in the connection header.

7-Amino-5-bromo-3-chloro-1H-indole hydrochloride

70 ml of concentrated hydrochloric acid and 31,97 g (269 mmol) of the powder of tin added to a methanol solution (250 ml) containing 14,84 g (53,9 mmol) of the compound of example obtaining 15, and the mixture is stirred at room temperature for 80 minutes. Under ice cooling, the mixture is brought to pH 10 by adding a 5 n aqueous solution of sodium hydroxide. After that, the obtained precipitate is filtered off and the filtrate is extracted with ethyl acetate. The organic layer is successively washed with aqueous saturated sodium bicarbonate and saturated salt solution, dried over magnesium sulfate and concentrated. Then the residue purified column chromatography on silica gel, receiving 14,35 g 7-amino-5-bromo-3-chloro-1H-indole. The product is dissolved in ethyl acetate and there is added 17 ml of a mixture of 4 N. aqueous hydrochloric acid - ethyl acetate. The precipitate is collected by filtration and washed with hexane, getting 13,23 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 5,11 (3H, CL), only 6.64 (1H, s), 6,93 (1H, s) to 7.50 (1H, d, J=2.0 Hz), 11,38 (1H, CL).

Example of getting 17

Etherpiraat 2-(4-methyl-2-nitrophenyl)hydrazone

30,00 g (0,197 mo is aristolochioides acid. To the mixture at 10°C or lower are added dropwise an aqueous solution (35 ml) containing 16,33 g (0,237 mol) of sodium nitrite and the mixture is stirred under ice cooling for 40 minutes, obtaining a solution of diazonium salts.

28,43 g (0,197 mol) ethyl 2-methylacetoacetate dissolved in a mixed solution of 150 ml of ethanol and 300 ml of water. Under ice cooling there is added an aqueous solution (120 ml) containing 53,36 g (0,808 mol) of potassium hydroxide. Consistently there is added dropwise at the same temperature a solution of diazonium salts obtained in advance, and the resulting mixture is stirred under ice cooling for 20 minutes. The mixture is brought to pH 1 by adding concentrated hydrochloric acid. The precipitate is collected by filtration, washed with water and dried over phosphorous pentoxide under reduced pressure, getting 46,42 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): of 1.40 (3H, t, J=7.2 Hz), of 2.23 (3H, s), a 2.36 (3H, s), 4,35 (2N, K, J=7,2 Hz), 7,44 (1H, DD, J=8,8, 1,6 Hz), to 7.93 (1H, d, J=8,8 Hz), 8,00 (1H, s), 10,87 (1H, CL)

Example of getting 18

Ethyl-5-methyl-7-nitro-1H-indole-2-carboxylate

65,33 g of polyphosphoric acid added to the solution (320 ml) of xylene containing 15,92 g (60 mmol) of the compound of example polute and ethyl acetate and insoluble substance is filtered off. The organic layer was separated, sequentially washed with water and saturated salt solution, dried over magnesium sulfate and concentrated. Then the resulting residue is purified column chromatography on silica gel, getting to 7.32 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): of 1.34 (3H, t, J=7.0 Hz), 2,47 (3H, s), 4,36 (2N, K, J=7,0 Hz), 7,35 (1H, s), to 7.99 (1H, s), 8,11 (1H, s), 11,25 (1H, CL).

Example of getting 19

5-Methyl-7-nitro-1H-indol

150 ml of 1 N. aqueous sodium hydroxide solution is added to tertrahydrofuran ring solution (80 ml) containing 7,86 g (and 31.7 mmol) of the compound of example 19 and the mixture is stirred at room temperature for 3.5 hours. Under ice cooling, the mixture is brought to pH 1 by adding 2 N. hydrochloric acid and then extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated to dryness, obtaining 7,13 g 5-methyl-7-nitro-1H-indole-2-carboxylic acid. The product is dissolved in 160 ml of 1,3-dimethyl-2-imidazolidinone, there is added 716 mg (3,24 mmol) of basic copper carbonate and the mixture is stirred at 185°C for 2 hours. The reaction solution was poured into water, the insoluble matter is filtered off and filali, dried over magnesium sulfate and concentrated. Then the resulting residue is purified column chromatography on silica gel, receiving 4,50 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): the 2.46 (3H, s), 6,62 (1H, d, J=2,8 Hz), 7,47 (1H, d, J=2,8 Hz), 7,87 (1H, s), 7,92 (1H, s), 11,77 (1H, CL).

Example of getting 20

3-Bromo-5-methyl-7-nitro-1H-indol

0.7 ml of dimethylformamide and 4,78 g (26.9 mmol) of N-bromosuccinimide add to tertrahydrofuran ring solution (70 ml) containing 4,50 g (25.5 mmol) of the compound of example obtaining 20, followed by stirring at room temperature for 70 minutes. There is added 10% aqueous sodium thiosulfate solution and the mixture extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and then concentrated to dryness, obtaining 6,53 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 2,50 (3H, s), to 7.67 (1H, s), 7,73 (1H, s), 8,02 (1H, s), 12,10 (1H, CL).

Example of getting 21

7-Amino-3-bromo-5-methyl-1H-indol

6,76 g (of 26.5 mmol) of the compound of example receive 20 is suspended in a solution of a mixture of 150 ml of methanol and 75 ml of water. To this mixture 11,34 g (212 mmol) of ammonium chloride and of 5.92 g (106 mmol is t and the filtrate is brought to pH 8, adding aqueous saturated sodium bicarbonate solution. The mixture is extracted with ethyl acetate and the organic layer is successively washed with aqueous saturated bicarbonate, water and saturated salt solution, dried over magnesium sulfate and concentrated. Then the residue purified column chromatography on silica gel, receiving 3,30 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 2,24 (3H, s) 5,08 (2H, CL), of 6.20 (1H, s) 6,41 (1H, s), 7,35 (1H, s), 10,86 (1H, CL).

Example of getting 22

6-Amino-3-pyridinesulfonamide

Under ice cooling 10,00 g (0,106 mol) of 2-aminopyridine is added gradually to 123,8 g (1.06 mol) chlorosulfonic acid. To this mixture 50,56 g (0,425 mol) of thionyl chloride. The mixture is heated at the boil under reflux for 2.5 hours and further stirred at 150°C for 7 hours. The reaction solution was poured into a mixture of ice - water, neutralized by adding sodium bicarbonate and extracted with ethyl acetate. The organic layer is successively washed with aqueous saturated sodium bicarbonate, water and saturated salt solution, dried over magnesium sulfate and then concentrated to dryness. The residue is suspended in ethyl ether and versatility ether/hexane, getting to 6.58 g specified in the connection header.

An example of retrieving 23

4,7-Dibromo-1H-indole

Specified in the header connection to 27.2 g) is obtained from 62,0 g (0,224 mol) of 2,5-dibromantratsena in the same manner as in the example of getting 1 of JP-A 7-165708.

1H-NMR (DMSO-d6)(M. D.): of 6.52 (1H, d, J=3.2 Hz), 7,18 (1H, d, J=8.0 Hz), 7,26 (1H, d, J=8.0 Hz), 7,53 (1H, d, J=3.2 Hz), 11,75 (1H, CL).

Example of getting 24

7-Amino-4-bromo-1H-indole hydrochloride

In tertrahydrofuran ring solution (300 ml) containing 27,2 g (the 98.9 mmol) of the compound of example, receiving 23, is added dropwise 186 ml (116,3 mmol) of hexane solution containing 1.6 M n-utility -78°C in nitrogen atmosphere, followed by stirring under ice cooling for one hour. After cooling again to -78°C in the reaction mixture is added dropwise 28 ml (0.13 mmol) diphenylphosphinite. The mixture was stirred at -78°C for one hour and then at -40°C for one hour. At -40°To the mixture was added toluene solution (150 g) containing 3.4 M sodium bis(2-methoxyethoxy) aluminiumhydride, followed by stirring at room temperature for one hour. Add water (120 ml), the insoluble matter is collected by filtration and the filter is of the atrium and a saturated solution of salt, dried over magnesium sulfate and concentrated. After that, the residue is dissolved in ethyl ether and there is added 50 ml of a mixture of 4 N. hydrochloric acid/ethyl acetate. The precipitate is collected by filtration, getting 14.5 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 6,41-to 6.43 (1H, m), to 6.80 (1H, d, J=8.0 Hz), 7,16 (1H, d, J=8.0 Hz), 7,54 (1H, t, J=2,8 Hz), 11,57 (1H, CL).

Example get 25

7-Bromo-4-chloro-1H-indole

Specified in the header of the connection receives the same way as in the example of obtaining 23.

1H-NMR (DMSO-d6)(M. D.): 6,60-of 6.61 (1H, m),? 7.04 baby mortality (1H, d, J=8.1 Hz), 7,32 (1H, d, J=8.1 Hz), 7,53 (1H, t, J=2.7 Hz), 11,74 (1H, CL).

Example of getting 26

7-Amino-4-chloro-1H-indole hydrochloride

Specified in the header of the connection receives the same way as in the example of obtaining 24.

1H-NMR (DMSO-d6)(M. D.): 6,54-6,55 (1H, m), 7,05 (1H, d, J=8.1 Hz), 7,11 (1H, d, J=8.1 Hz), 7,60 (1H, t, J=2.7 Hz), 11,82 (1H, CL).

Example of getting 27

5-Bromo-2-thiophenecarboxaldehyde

to 27.0 ml (about 43.4 mmol) of hexane solution containing 1.6 M n-utility, is added dropwise in tertrahydrofuran ring solution (80 ml) containing 10.0 g (a 41.3 mmol) 5-dibromothiophene at -78°With the second mixture at the same temperature, add 3.5 ml (to 45.5 mmol) of dimethylformamide, followed by stirring for 20 minutes. Add water and the mixture extracted with ethyl acetate. The organic layer is successively washed with 0.1 N. aqueous solution of hydrochloric acid, water and saturated salt solution, dried over magnesium sulfate and concentrated to dryness, obtaining 6.4g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 7,49 (1H, d, J=4.0 Hz), 7,87 (1H, d, J=3,9 Hz), 9,81 (1H, s).

Example of getting 28

5-Bromo-2-thiophenecarbonitrile

3.3 grams (of 51.7 mmol) hydroxylamine hydrochloride and 4.1 g (of 51.7 mmol) of pyridine are added to a solution (40 ml) of dimethylformamide containing 8.2 g (to 43.1 mmol) of the compound of example, receiving 28, and the mixture is stirred at room temperature for 30 minutes. Then, while cooling with ice add 34,9 g (215,5 mmol) of 1,1’-carbonyldiimidazole and the resulting mixture was stirred at room temperature for one hour. To the reaction solution was added a mixture of ice - water and the mixture extracted with ethyl acetate. The organic layer is successively washed with 0.1 G. of aqueous hydrochloric acid, water and saturated salt solution, dried over magnesium sulfate and concentrated. Then the resulting residue is purified column chromatography on silica gel, gaining 6.7 g is specified in the header with the p>

An example of obtaining 29

5-Benzylthio-2-thiophenecarbonitrile

585 mg (13,4 mmol, oily component: 55%) of sodium hydride are suspended in 10 ml of dimethyl sulfoxide, there is added 1.4 g in (11.2 mmol) of benzylmercaptan and the mixture is stirred for 10 minutes. Then add 2.1 g in (11.2 mmol) of the compound of example obtaining 14, followed by stirring at room temperature for one hour. In the reaction solution is added water and the mixture extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated. Then the resulting residue is purified column chromatography on silica gel, receiving 1.51 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 4.26 deaths (2H, s), 7,18 (1H, d, J=4.0 Hz), 7,27-7,30 (5H, m), 7,83 (1H, d, J=4.0 Hz).

Example 30

4-Bromo-1H-indolocarbazole acid

34 g specified in the connection header is obtained from 51 g of compound of example getting 23 in the same manner as in example receipt 8.

1H-NMR (CDCl3)(M. D.): 6,51-of 6.52 (1H, m), 7,35 (1H, D, J=8.0 Hz), of 7.48 (1H, t, J=2,8 Hz), 7,66 (1H, d, J=8 Hz), and 11.4 (1H, CL), and 13.2 (1H, CL)

An example of retrieving 31

7-(N-tert-Butoxycarbonyl)Aminu way as in the example of a 9.

1H-NMR (CDCl3)(M. D.): 1,51 (N, C), 6,38-to 6.39 (1H, m), 7,13 (1H, d, J=8.0 Hz), 7,44-7,46 (2H, m), 9,11 (1H, CL), and 11.2 (1H, CL).

Example of getting 32

7-(N-tert-Butoxycarbonyl)amino-4-bromo-3-chloro-1H-indole

N-Chlorosuccinimide treated in a solution of a mixture of tetrahydrofuran - dimethylformamide containing the compound of example obtaining 31 receiving specified in the header of the connection.

1H-NMR (CDCl3)(M. D.): 1,50 (N, C), 7,19 (1H, d, J=8,4 Hz), was 7.45 (1H, d, J=8,4 Hz), a 7.62 (1H, d, J=2,8 Hz), the remaining 9.08 (1H, CL), 11,41 (1H, CL).

An example of obtaining 33

7-Amino-4-bromo-3-chloro-1H-indole hydrochloride

10,87 (to 31.5 mmol) of the compound of example obtaining 32 is dissolved in methanol (120 ml). To the mixture is added concentrated hydrochloric acid (20 ml) followed by stirring at 60°C for 40 minutes. After completion of the reaction the solvent is removed and the mixture is subjected to azeotropic distillation for 3 times using ethanol. The obtained solid is washed with ether, obtaining 8.5 g specified in the connection header.

1H-NMR (CDCl3)(M. D.): to 6.67 (1H, d, J=8.0 Hz), 7,13 (1H, d, J=8.0 Hz), the 7.65 (1H, d, J=2,8 Hz), 11,74 (1H, CL).

An example of retrieving 34

2-Amino-5-pyrimido the Institute gradually add 3 g (to 0.032 mol) of 2-aminopyrimidine. Then add to 9.2 ml (0,126 mol) of thionyl chloride, followed by stirring at 150°C for 70 hours. The reaction solution is cooled to room temperature, poured into water and extracted with ethyl acetate. The extract is dried over sodium sulfate and then concentrated to dryness, obtaining 1.7 g specified in the connection header.

1H-NMR (CDCl3)(M. D.): 5,97 (2N, W), 8,83 (2H, s).

Synthetic example 1

N-(3-Cyano-4-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonyl

a 2.00 g (11.7 mmol) of the compound of example 12 are dissolved in 60 ml of tetrahydrofuran, followed by adding a solution of 4.0 ml (a 49.5 mmol) of pyridine and 2,60 g (12.9 mmol) of the compound of example, receiving 13. After stirring at room temperature for 16 hours the mixture was adjusted to pH 1-2 by adding 2 N. hydrochloric acid, and extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated. Then the resulting residue is purified column chromatography on silica gel, receiving 3,90 g specified in the connection header. (The connection is further referred to as compound A.)

Melting point: 220-221°C (PE is.): to 2.55 (3H, C) 6,50 (1H, d, J=8.0 Hz), 6,77 (1H, d, J=8.0 Hz), 7,71 (1H, t, J=8.0 Hz), of 7.90 (1H, d, J=8.0 Hz), 8,05-8,13 (2H, m), 8,16 (1H, s), 10,11 (1H, CL), 12,01 (1H, CL).

Synthetic example 2

N-(3-Cyano-4-methyl-1H-indol-7-yl)-6-chloro-3-pyridinesulfonamide

700 mg (4.09 to mmol) of the compound of example 12 was dissolved in 20 ml of tetrahydrofuran, followed by adding a solution of 1.3 ml (16,1 mmol) of pyridine and 950 mg (4,48 mmol) 6-chloro-3-pyridinesulfonamide. After stirring at room temperature for 2 hours, the reaction solution was adjusted to pH 1-2 by adding 1 N. hydrochloric acid, and extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated. Then the residue purified column chromatography on silica gel, receiving 1,16 g specified in the connection header.

Melting point: 262-263°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): to 2.57 (3H, s), 6,55 (1H, d, J=7,6 Hz), PC 6.82 (1H, d, J=7,6 Hz), 7,69 (1H, d, J=8,4 Hz), 8,01 (1H, DD, J=8,4, 2.4 Hz), 8,17 (1H, d, J=2,8 Hz), at 8.60 (1H, d, J=2.4 Hz), of 10.21 (1H, CL), a 12.03 (1H, CL).

Synthetic example 3

N-(3-Bromo-5-methyl-1H-indol-7-yl)-4-sulfamoylbenzoyl ml of tetrahydrofuran, followed by adding a solution of 0.3 ml (3,71 mmol) of pyridine and 300 mg (1,17 mmol) of the compound of example, receiving 14. After stirring at room temperature for 48 hours the mixture was adjusted to pH 1-2 by adding 1 N. hydrochloric acid, and extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated. Then to the residue add a solution of a mixture of diethyl ether and hexane and the resulting crystals are collected by filtration, getting 387 mg specified in the connection header.

Melting point: 196-197°C (recrystallized from a mixture of ethanol/n-hexane)

1H-NMR (DMSO-d6)(M. D.): 2,24 (3H, s), 6,60 (1H, s), 6,98 (1H, s), 7,44 (1H, s), 7,55 (2H, CL), a 7.85-of 7.95 (4H, m), 10,13 (1H, CL), br11.01 (1H, CL)

Synthetic example 4

N-(5-Bromo-3-chloro-1H-indol-7-yl)-6-amino-3-pyridinesulfonamide

to 1.00 g (3,55 mmol) of the compound of example 16 is suspended in 25 ml of tetrahydrofuran and then adding to the suspension 0,86 ml (10.6 mmol) of pyridine and 718 mg (3.73 mmol) of the compound of example obtaining 8 while cooling with ice. After stirring at room temperature for 3 hours, there is added water and the mixture extracted with ethyl acetate. The organic layer is successively washed with water and nasyshennaya on silica gel, getting 1.27 g specified in the connection header.

Melting point: the connection was started to get the color at a temperature close to 237°C and decomposed at a temperature in the range from 240 to 242°C (recrystallized from a mixture of ethanol - water).

1H-NMR (DMSO-d6)(M. D.): 6,37 (1H, d, J=8,8 Hz) 6,94 (2H, CL), 6,97 (1H, s), of 7.36 (1H, s), 7,54-EUR 7.57 (2H, m), 8,16 (1H, d, J=2,8 Hz), 9,94 (1H, CL), 11,17 (1H, CL).

Hydrochloride

1H-NMR (DMSO-d6)(M. D.): 6,59 (1H, d, J=9,2 Hz), 7,00 (1H, s), 7,40 (1H, s), 7,56 (1H, d, J=2.4 Hz), of 7.70 (1H, DD, J=9,2, 2.0 Hz), to 8.20 (1H, d, J=2.0 Hz), and 10.20 (1H, CL), 11,37 (1H, CL).

Synthetic example 5

N-(3-Bromo-5-methyl-1H-indol-7-yl)-3-cyanobenzenesulfonyl

Under ice cooling to tertrahydrofuran ring solution (6 ml) containing 260 mg (1,16 mmol) of the compound of example obtaining 22 add to 0.19 ml (2,35 mmol) of pyridine and 280 mg (1,39 mmol) 3-cyanobenzenesulfonyl, followed by stirring at room temperature over night. Then there is added to 0.2 N. hydrochloric acid and the mixture extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and the head of the connection.

Melting point: gradual decomposition, starting with the temperature close to 148°C, and the compound decomposes at a temperature 163-164°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): of 2.25 (3H, s), is 6.54 (1H, s), 7,01 (1H, s), 7,42 (1H, d, J=2,8 Hz), 7,71 (1H, t, J=7,6 Hz), to 7.93 (1H, d, J=7,6 Hz), 8.07-a 8,11 (2H, m), of 10.09 (1H, CL), 11,04 (1H, CL).

Synthetic example 6

N-(4-Bromo-1H-indol-7-yl)-4-cyanobenzenesulfonyl

700 mg (2.8 mmol) of the compound of example obtaining 25 and 685 mg (3.4 mmol) of 4-cyanobenzenesulfonyl processed in the same manner as in synthetic example 1, getting 686 mg specified in the connection header.

Melting point: 214-216°C

1H-NMR (DMSO-d6)(M. D.): 6.35mm (1H, d, J=2.6 Hz), 6,53 (1H, d, J=8.0 Hz),? 7.04 baby mortality (1H, d, J=8.0 Hz), 7,41 (1H, t, J=2,8 Hz), the 7.85 (2H, d, J=8.0 Hz), 8,00 (2H, d, J=8.0 Hz), 10,24 (1H, CL), 11,19 (1H, CL).

Synthetic example 7

N-(4-Chloro-1H-indol-7-yl)-6-amino-3-pyridinesulfonamide

1330 mg (6.4 mmol) of the compound of example, receiving 23 and 1000 mg (4.9 mmol) of the compound of example 12 was processed in the same manner as in synthetic example 1 src="https://img.russianpatents.com/chr/948.gif" border="0">(M. D.): 6,38 (1H, d, J=9.0 Hz), to 6.43 (1H, t, J=2.2 Hz), 6,77 (1H, d, J=7,7 Hz) 6,86 (2H, CL), 7,42 (1H, t, J=2,6 Hz), 7,56 (1H, DD, J=2,6, 9.0 Hz), 8,14 (1H, d, J=2.6 Hz), to 9.70 (1H, CL), 11,07 (1H, CL).

Synthetic example 8

N-(3-Bromo-4-chloro-1H-indol-7-yl)-6-amino-3-pyridinesulfonamide and its hydrochloride

To tertrahydrofuran ring solution (10 ml) containing 650 mg (2.0 mmol) of the compound of synthetic example 7, was added 1 ml of dimethylformamide and 359 mg (2.0 mmol) of N-bromosuccinimide, followed by stirring at room temperature over night. Then there is added 0.2 n aqueous hydrochloric acid and the mixture extracted with ethyl acetate. The organic layer is successively washed with aqueous sodium thiosulfate, water and saturated salt solution, dried over magnesium sulfate and concentrated. Then the residue purified column chromatography on silica gel, getting 662 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 6,38 (1H, d, J=8,8 Hz), 6,76 (1H, d, J=8,4 Hz), to 6.88 (2H, CL), 6,97 (1H, q, j=8,4 Hz), 7,52-7,56 (2H, m) to 8.12 (1H, d, J=2.4 Hz), 9,68 (1H, CL), 11,44 (1H, CL).

Received specified in the title compound (660 mg) was dissolved in 3 ml of acetone, then the solution is added to 0.62 ml of a mixture of 4N-chlorite is melting Point: gradual decomposition starting temperature, close to 267°C.

1H-NMR (DMSO-d6)(M. D.): of 6.65 (1H, d, J=9,2 Hz), 6,78 (1H, d, J=8.1 Hz), 6,98 (1H, d, J=8,2 Hz), EUR 7.57 (1H, d, J=2.6 Hz), 7,73 (1H, DD, J=2.0 a, 9,0 Hz), 8,15 (1H, d, J=2.4 Hz), 10,00 (1H, CL), 11,67 (1H, CL).

Synthetic example 9

N-(3-Bromo-5-methyl-1H-indol-7-yl)-5-cyano-2-thiophenesulfonyl

Under ice cooling to a solution (15 ml) of concentrated hydrochloric acid containing 1.3 g (5.6 mmol) of the compound of example 30, introducing gaseous chlorine. After stirring for 30 minutes the reaction solution is added to a mixture of ice - water and extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated. The residue is added to a solution of pyridine (6 ml) containing 1.2 g (to 5.35 mmol) of the compound of example obtaining 22, followed by stirring at room temperature over night. There is added water and the mixture extracted with ethyl acetate. The organic layer is successively washed with 1 N. aqueous hydrochloric acid, water and saturated salt solution, dried over magnesium sulfate and concentrated. Then the residue purified column chromatography on silica compound(DMSO-d6)(M. D.): 2,30 (3H, s), of 6.65 (1H, s), 7,07 (1H, s), 7,44 (1H, s), 7,54 (1H, d, J=4.0 Hz), 7,94 (1H, d, J=4.0 Hz), of 10.47 (1H, CL), 11,04 (1H, CL)

Synthetic example 10

N-(4-Bromo-3-chloro-1H-indol-7-yl)-2-amino-5-pyrimidinemethanol

513 mg (approximately 2.65 mmol) of the compound of example obtaining 35 add to 5 ml of pyridine containing 712 mg (2,52 mmol) of the compound of example, receiving 34, followed by stirring for 15 hours. In the reaction solution is added water and extracted with a solution of a mixture of ethyl acetate - tetrahydrofuran (10:1). The organic layer is dried over magnesium sulfate and then concentrated. The residue is purified column chromatography on silica gel, getting 950 mg specified in the connection header.

Melting point: 285-289°C

1H-NMR (DMSO-d6)(M. D.): to 6.75 (1H, d, J=8.0 Hz), 7,19 (1H, d, J=8.0 Hz), to 7.59 (1H, d, J=3.0 Hz), the 7.65 (2H, s) of 8.37 (2H, s), 9,82 (1H, s) 11,43 (1H, s).

Synthetic example 11

N-(3-Chloro-1H-indol-7-yl)-4-sulfamoylanthranilic

767 mg (3.0 mmol) of 4-sulfamoylanthranilic subjected to interaction with 264 mg (2.0 mmol) of 7-amino-1H-indole and processing of obtaining 445 mg of N-(1H-indol-7-yl)-4-sulfamoyl specified in the connection header.

Melting point: starts staining partially in black color at a temperature close to 220°C, and the compound slowly decomposes at a temperature close to 240°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): to 6.75 (1H, d, J=7,6 Hz), of 6.96 (1H, DD, J=8.0 a, 7,6 Hz), 7,29 (1H, d, J=7,6 Hz) to 7.50 (1H, d, J=2,8 Hz), 7,58 (2H, s), of 7.90-7,98 (4H, m), 10,23 (1H, s), 11,07-11,17 (1H, m).

An example of obtaining 1a

7-Bromo-1H-indole

100 ml (100 mmol) of a solution of tetrahydrofuran containing 1.0 M of vinylmania, are added to a solution (250 ml) of tetrahydrofuran containing of 5.05 g (25 mmol) of 2-bromonitromethane at -40°C in nitrogen atmosphere, followed by stirring for 40 minutes. The reaction mixture is poured into 500 ml of aqueous saturated ammonium chloride and the mixture is extracted with ethyl ether. The extract is dried over magnesium sulfate and concentrated. Then the residue purified column chromatography on silica gel, receiving 2,89 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 6,56 (1H, DD, J=2,9, 1.8 Hz), 6,94 (1H, t, J=7.8 Hz), 7,30 (1H, d, J=7.8 Hz), 7,40 (1H, t, J=2,9 Hz), 7,56 (1H, d, J=7.8 Hz), 11,16-11,46 (1H, CL).

An example of obtaining 2A

7-Amino-1H-indole

of 16.5 ml (41,3 mmol) solution GE,8 mmol) of the compound of example obtaining 1A, at -70°C in nitrogen atmosphere and the mixture is stirred at 70°C for 15 minutes and then at -20 - -10°C for 30 minutes. After cooling again to -70°there is added dropwise a 3.9 ml (18 mmol) diphenylphosphinite. The mixture is stirred at -70°C for one hour and then at -40°C for one hour. After addition of 22.3 ml (or 75.8 mmol) of a toluene solution containing 3.4 M sodium bis(2-methoxyethoxy)aluminiumhydride at -40°C, the mixture is stirred at a temperature of from -30 to -20°C for 30 minutes and then at room temperature for 30 minutes. There is added buffer solution on the basis of phosphoric acid having a pH of 7.0, the insoluble matter is collected by filtration and the filtrate is extracted with ethyl ether. The organic layer is successively washed with aqueous saturated sodium bicarbonate and saturated salt solution, dried over magnesium sulfate and concentrated. Then the residue purified column chromatography on silica gel, receiving 1.29 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): free 5.01 (2H, CL), 6,25-6,33 (2H, m), 6,70 (1H, DD, J=7,9, and 7.3 Hz), 6,78 (1H, DD, J=7,9, 0.7 Hz), 7.23 percent (1H, t, J=2.7 Hz), 10,48-of 10.72 (1H, CL).

Following the initial compounds are synthesized from the produ

7-amino-4-bromo-1H-indole

An example of obtaining 3A

7-Bromo-3-chloro-4-methyl-1H-indol

4.0 g (30.0 mmol) of N-chlorosuccinimide added to a solution (250 ml) of acetonitrile containing 5.8 g (27.6 mmol) of 7-bromo-4-methyl-1H-indole was synthesized from 2-bromo-5-methylnitrobenzene in the same way as in the example of obtaining 1A, followed by stirring at room temperature over night. There is added 50 ml of 1 N. aqueous sodium hydroxide and the mixture extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated. Then the residue purified column chromatography on silica gel, gaining 6.7 g specified in the connection header.

1H-NMR (CDCl3)(M. D.): is 2.74 (3H, s), 6.75 in-7,26 (3H, m), 8,23 (1H, CL).

An example of retrieving 4A

7-Amino-3-chloro-4-methyl-1H-indol

2.6 g specified in the connection header is obtained from 6,37 g (of 26.1 mmol) of the compound of example obtaining 3A in the same manner as in the example of obtaining 2A.

1H-NMR (CDCl3)(M. D.): 2,70 (3H, s), 6,39-7,14 (3H, m), 8,15 (1H, CL).

An example of retrieving 5A

4-Sulfamoylanthranilic

6.4 g (37,2 mmol) of 4-aminobenzenesulfonamide added to a solution mixture of 12.5 ml of water and 6.3 ml conse dropwise aqueous saturated solution, containing of 2.56 g (37,1 mmol) of sodium nitrite. The reaction solution are added to a solution of acetic acid saturated with sulfur dioxide (solution obtained by saturating 35 ml of acetic acid and sulfur dioxide and then add 1.5 g of the chloride of copper(II)·dihydrate) under cooling with ice and stirring. After 10 minutes the reaction solution is poured into a mixture of ice - water and the precipitate collected by filtration and washed with water. The residue is dissolved in tetrahydrofuran, dried over magnesium sulfate and then concentrated to dryness, obtaining 3.5 g specified in the connection header.

An example of obtaining 6A

4-(Sulfanilyl)benzosulphochloride

5.0 g (23,1 mmol) of 4-nitrobenzenesulfonamide suspended in 90% acetic acid and the suspension is subjected to hydrogenation at ordinary temperature and at atmospheric pressure in the presence of a catalyst of palladium-carbon. After filtering off the catalyst the filtrate is concentrated to dryness, obtaining 4.3 g of 4-aminobenzenesulfonamide. The compound obtained is added to the solution a mixture of 40 ml of water and 4.1 ml of concentrated hydrochloric acid, followed by stirring. Dropwise at 0°C or less, the mixture was added aqueous saturated solution containing 1.63 g (23,6 m(solution, obtained by saturating 30 ml of acetic acid and sulfur dioxide and then added 0.97 g of the chloride of copper(II)·dihydrate) under cooling with ice and with stirring. After stirring at room temperature for 40 minutes, the reaction solution is poured into a mixture of ice - water and the mixture is saturated with sodium chloride. The mixture is extracted with ethyl acetate and the extract is dried over magnesium sulfate and then concentrated to dryness, obtaining 1.7 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 4.26 deaths (2H, s), 7,32 (2H, d, J=8,4 Hz), to 7.59 (2H, d, J=8,4 Hz).

The following compounds are synthesized in the same manner as in the example of a 5A or 6A.

4-(N-methylsulfonyl)benzosulphochloride

4-(N-ethylsulfonyl)benzosulphochloride

4-(N-methoxymethanol)benzosulphochloride

4-[(methanesulfonamido)methyl]benzosulphochloride

4-(N-methylmethanesulfonamide)benzosulphochloride

4-(1-pyrrolidinylcarbonyl)benzosulphochloride

4-(1-pyrrolidinylcarbonyl)benzosulphochloride

3-cyanobenzenesulfonyl

4-(methylsulphonyl)benzosulphochloride

4-[(N-methylmethanesulfonamide)methyl]benzosulphochloride.

An example of obtaining 7a

3-Cyanobase 3,93 g (56.0 mmol) of hydroxylamine hydrochloride and 4.5 ml (55,6 mmol) of pyridine. After heating under stirring at a temperature of from 70 to 80°C for 2 hours there is added 6.3 g (56,8 mmol) of selenium dioxide and about 5 g of magnesium sulfate. After heating at a temperature of from 70 to 80°C for 2.5 hours, the insoluble matter is filtered off and the filtrate concentrated. Add to this water and the resulting crystals are collected by filtration and sequentially washed with water and ethyl ether. The crystals are dissolved in a mixed solution of tetrahydrofuran and acetone, and insoluble matter is filtered off. After concentration of the filtrate the residue is added ethyl acetate, and the crystals are collected by filtration, getting 8,61 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): of 7.48 (1H, t, J=8.1 Hz), 8,17 (1H, d, J=8.1 Hz), of 8.27 (1H, d, J=8.1 Hz), of 8.47 (1H, s), 12,70-13,00 (1H, sh).

An example of obtaining 8A

7-Amino-3-cyano-1H-indol

2,80 g (15.0 mmol) of the compound of example obtaining 7a is suspended in 100 ml of methanol and subjected to hydrogenation at atmospheric pressure and ordinary temperature in the presence of a catalyst of palladium - carbon. After filtering off the catalyst, the reaction mixture was concentrated to dryness, obtaining 2,31 g specified in the connection header.

An example of obtaining 9a

7-Amino-3,4-dichloro-1H-indole

7-Bromo-4-chloro-1H-indole was obtained from 2-bromo-5-chloronitrobenzene in the same way as in the example of obtaining 1A, first subjected to chlorination in the same manner as in the example of obtaining 3A, and then braugruppe transformed into the amino group, receiving specified in the header of the connection.

1H-NMR (DMSO-d6)(M. D.): of 5.26 (2H, s), of 6.29 (1H, d, J=8.1 Hz), 6,74 (1H, d, J=8.1 Hz), 7,45-7,51 (1H, m), 11,08-11,27 (1H, m).

In the same way synthesize 7-amino-4-tert-butyldimethylsilyloxy-3-chloro-1H-indole.

An example of obtaining 10A

7-Amino-3-chloro-1H-indole

1,076 g (6,64 mmol) of 7-nitro-1H-indole are dissolved in 30 ml of acetonitrile and to the solution add 920 mg (6,89 mmol) N-chlorosuccinimide. After stirring at room temperature for 36 hours, add aqueous saturated sodium bicarbonate. The precipitate is collected by filtration and washed with water, obtaining 1.2 g of 3-chloro-7-nitro-1H-indole. 863 mg (4,39 mmol) powder suspended in 10 ml of ethanol and to this type of 4.95 g (21.9 mmol) chloride tin(II)·dihydrate and 100 µl of concentrated hydrochloric acid. After heating at boiling under reflux for 30 minutes there doba is the addition of ethyl acetate, the extract is dried over magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel, getting 490 mg specified in the connection header.

Specified in the title compound is also obtained by hydrogenation of 3-chloro-7-nitro-1H-indol at ordinary temperature and at atmospheric pressure in the presence of a catalyst of platinum - carbon.

1H-NMR (DMSO-d6)(M. D.): 5,14 (2H, s), 6,36 (1H, DD, J=7,5, 1.0 Hz), of 6.68 (1H, DD, J=7,9, to 0.73 Hz), for 6.81 (1H, DD, J=7,9, 7.5 Hz), 7,39 (1H, d, J=2.7 Hz), 10,85 (1H, CL).

Example of getting 11a

4-(2-Sulphatoethyl)benzosulphochloride

to 1.3 g (7.3 mmol) of 2-phenylethanolamine added to 2.4 g (to 36.5 mmol) chlorosulfonic acid under ice cooling for 20 minutes, followed by stirring at room temperature for another 90 minutes. Solution the reaction mixture is poured into a mixture of ice - water and then extracted with ethyl acetate. The extract is successively washed with aqueous saturated sodium bicarbonate and saturated salt solution and dried over magnesium sulfate. The solvent is evaporated, obtaining 1.6 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 2,97-to 3.02 (2H, m), 3,21-3,26 (2H, m), 7,21 (2H, d, J=8,4 Hz), 7,53 (benzosulphochloride

4-[2-(N-methylmethanesulfonamide)ethyl]benzosulphochloride

4-[2-(methanesulfonamido)ethyl]benzosulphochloride

4-(N-methylacetamide)benzosulphochloride

Example of getting 12A

5-Bromo-7-nitro-1H-indol

of 5.05 g (17,7 mmol) 1-acetyl-5-bromo-7-nitroindoline dissolved in a mixed solution of 6 ml of ethanol and 40 ml of 6 N. hydrochloric acid followed by heating at boiling under reflux for 3 hours. After neutralization with sodium carbonate, the mixture is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and concentrated. Then the residue purified column chromatography on silica gel, receiving of 4.13 g of 5-bromo-7-nitroindoline. 301 mg (1,24 mmol) of the compounds added to 10 ml of toluene and then to this add 580 mg (2.55 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone. After heating at boiling under reflux for 3.5 hours under stirring, the insoluble substance is filtered off and the filtrate concentrated. The residue is purified column chromatography on silica gel, getting 252 mg specified in the connection header.

Example of getting 13A

5-Bromo-3-formyl-7-nitro-1H-indol

210 mg (1.4 mmol) of phosphorus oxychloride (III) are added to 1.0 g (14 m is this added 240 mg (1.0 mmol) of the compound of example obtaining 12A and the mixture was stirred at 0°C for 20 minutes and then at 100°C for 30 minutes. The reaction mixture is cooled with ice and then poured into a mixture of ice - water. The mixture is stirred for 30 minutes, while maintaining it at a pH in the range from 7 to 8 by adding 1 N. aqueous sodium hydroxide. The resulting precipitate is collected by filtration, washed with water and then purified column chromatography on silica gel, getting 239 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 8,31 (1H, d, J=1,8 Hz), 8,55 (1H, s), 8,65 (1H, d, J=1,8 Hz), of 10.05 (1H, s), 12,89 (1H, CL).

Example of getting 14a

7-Amino-5-bromo-3-cyano-1H-indol

214 mg (0.8 mmol) of 5-bromo-3-cyano-7-nitro-1H-indole obtained from the compound of example obtaining 13A in the same manner as in the example of obtaining 7a, dissolved in a mixed solution of 10 ml of methanol and 10 ml of tetrahydrofuran. The mixture hydronaut at 3.0 kg/cm2in the presence of platinum oxide, and then the catalyst is filtered off and the filtrate is concentrated to dryness, obtaining 189 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 5,68-5,71 (2H, m), 6,60 (1H, d, J=2.0 Hz), 6,91 (1H, d, J=2.0 Hz), 8,16 (1H, s).

Example of getting 15A

3-Acetyl-7-amino-1H-indole

11 ml (11 mmol) of a hexane solution containing 1.0 M of dimethylammoniumchloride, and. Then if 0°With add 2.1 ml (29.5 mmol) of acetylchloride, followed by stirring at room temperature for 4 hours. To the reaction system add aqueous saturated ammonium chloride and the precipitate collected by filtration. The residue is thoroughly washed with hot ethanol. The wash solution was combined with the filtrate and the combined solution concentrate. To the residue water is added and the mixture extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over magnesium sulfate. The solvent is evaporated and the residue purified column chromatography on silica gel, receiving 3-acetyl-7-nitro-1H-indole. The product is dissolved in 100 ml of methanol and hydronaut at ordinary temperature and at atmospheric pressure in the presence of a catalyst of palladium - carbon. After filtering off the catalyst the filtrate is concentrated to dryness, obtaining 790 mg specified in the connection header.

Synthetic example 1A

N-(1H-Indol-7-yl)-4-nitrobenzenesulfonamide

1.50 g (11.3 mmol) of the compound of example obtaining 2A are dissolved in 40 ml of pyridine, followed by addition of solution to 2.57 g (11.6 mmol) of 4-nitrobenzenesulfonamide at room temperature under stirring. After stirring prioritisation acid. The organic layer was separated, washed with water, dried over magnesium sulfate. Then the solvent is evaporated and the residue purified column chromatography on silica gel, receiving 3.50 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 6.42 per (1H, DD, J=2,8, 2.0 Hz), of 6.66 (1H, d, J=7,6 Hz), 6,83 (1H, DD, J=8.0 a, 7,6 Hz), 7,31 (1H, DD, J=3.2, and 2.8 Hz), was 7.36 (1H, d, J=8.0 Hz), 7,94-8,02 (2H, m), 8,30 is 8.38 (2H, m), 10,23 (1H, s), a 10.74-10,87 (1H, m).

Synthetic example 2A

N-(3-Chloro-1H-indol-7-yl)-4-nitrobenzenesulfonamide

8,98 g (28.3 mmol) of the compound of synthetic example 1A was dissolved in a mixed solution of 280 ml of dichloromethane and 7 ml of dimethylformamide, followed by addition of 4.16 g (% 31.2 mmol) N-chlorosuccinimide under stirring in nitrogen atmosphere. After stirring at room temperature for 1.5 hours there is added 50 ml of water and the mixture is concentrated until then, until the mixture reaches 80 ml.

The organic layer is separated, by adding to a mixture of ethyl acetate and 0.2 N. hydrochloric acid, successively washed with aqueous saturated sodium bicarbonate and saturated salt solution and dried over magnesium sulfate. Then the solvent is evaporated and the residue purified column chromatography on silica gel, peforma).

1H-NMR (DMSO-d6)(M. D.): 6,72 (1H, d, J=7,6 Hz), of 6.96 (1H, DD, J=8.0 a, 7,6 Hz), 7,31 (1H, d, J=8.0 Hz), 7,47-7,53 (1H, m), 7,92-8,02 (2H, m), 8,30-to 8.41 (2H, m), 10,33 (1H, s), 11,07-11,22 (1H, m).

Synthetic example 3A

4-Amino-N-(3-chloro-1H-indol-7-yl)benzosulfimide

7.98 g (22.7 mmol) of the compound of synthetic example 2A are dissolved in 220 ml of methanol followed by heating at boiling under reflux with stirring. 10 ml of concentrated hydrochloric acid and yield of 7.40 g of powdered zinc add back three times at intervals of 10 minutes, and then refluxed for a further 10 minutes. After cooling, the reaction mixture is neutralized by adding a considerable excess of sodium bicarbonate, and the insoluble substance is filtered off. After concentration of the filtrate the residue is dissolved in ethyl acetate. The mixture was sequentially washed with aqueous saturated sodium bicarbonate, 2 N. aqueous sodium carbonate solution and saturated salt solution, dried over magnesium sulfate and then the solvent is evaporated. The residue is purified column chromatography on silica gel, receiving 7,21 g specified in the connection header.

Melting point: of 174.5-176°C (recrystallized from a mixture of ethanol/n-GCGC), to 6.95 (1H, DD, J=8.0 a, 7,6 Hz), 7,19 (1H, d, J=8.0 Hz), was 7.36 (2H, d, J=8,8 Hz), 7,46 (1H, d, J=2.4 Hz), of 9.56 (1H, s), 10,86-10,98 (1H, m).

Synthetic example 4A

N-(3-Chloro-1H-indol-7-yl)-4-(methanesulfonamido)benzosulfimide

68 mg (0,211 mmol) of the compound of synthetic example 3A was dissolved in 1 ml of pyridine, followed by adding a solution of 15 μl (0,194 mmol) methanesulfonanilide. After stirring at room temperature over night add aqueous sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is successively washed with diluted hydrochloric acid and water, dried over magnesium sulfate and concentrated. Then the resulting residue is purified by thin-layer chromatography on silica gel, receiving 76 mg specified in the connection header.

Melting point: 213,5-214°C (decomp.) (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): is 3.08 (3H, s), 6,83 (1H, d, J=7.5 Hz), of 6.96 (1H, DD, J=7,9, 7,7 Hz), 7.23 percent (2H, d, J=8,8 Hz), 7,24 (1H, d, J=7.5 Hz), 7,47 (1H, d, J=2.7 Hz), to 7.68 (2H, d, J=8,8 Hz), 9,92 (1H, CL), 10,38 (1H, CL), 10,99 (1H, CL).

Synthetic example 5A

4-methyl bromide-N-(1H-indol-7-yl)benzosulfimide

4-Bromocinnamaldehyde and the compound of example obtaining 2A is subjected to interaction in t is the forward way, as in synthetic example 1A, getting listed at the beginning of the connection.

1H-NMR (DMSO-d6)(M. D.): 4,70 (2H, s) 6,40 (1H, DD, J=3.1 and 1.1 Hz), of 6.71 (1H, DDD, J=7,4, 3,2, 0,92 Hz), for 6.81 (1H, DDD, J=8,1, 7,4, 0,92 Hz), 7,29-to 7.32 (2H, m), EUR 7.57 (2H, d, J=8,2 Hz), 7,73 (2H, d, J=8,4 Hz), 9,96 (1H, CL), is 10.75 (1H, CL).

Synthetic example 6A

N-(1,3-Dihydro-2H-indol-2-one-7-yl)-4-methylbenzenesulfonamide

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

Melting point: gradual decomposition starting temperature close to 246°C, and the compound decomposes at a temperature 267-269°C (recrystallized from dioxane).

Synthetic example 7a

3-Chloro-N-(3-chloro-1H-indol-7-yl)benzosulfimide

2,18 g (7,11 mmol) 3-chloro-N-(1H-indol-7-yl)benzosulfimide synthesized in the same manner as in synthetic example 1A, glorious in the same way as in example 2A, receiving 1.86 g specified in the connection header.

Melting point: 180-181°C (recrystallized from a mixture of dichloromethane/diisopropyl ether).

1H-NMR (DMSO-d6)(M. D.): was 6.73 (1H, d, J=7,6 Hz), 6,97 (1H, DD, J=8.0 a, 7,6 Hz), 7,30 (1H, d, J=8.0 Hz), 7,45-7,51 (1H, m), 7,51-7,76 (4H, m), of 10.09 (1H, s), 11,02-11,18 (1H, m).

compounds derived from 2,43 g (6,29 mmol) of N-(3,4-dichloro-1H-indol-7-yl)-4-nitrobenzenesulfonamide, synthesized in the same manner as in synthetic example 1A, in the same manner as in example 3A.

Melting point: 205-206,5°C (decomp.) (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): 6,00 (2H, s), 6,50 (2H, d, J=8,4 Hz), 6,77 (1H, d, J=8.0 Hz), 6,94 (1H, d, J=8.0 Hz), 7,35 (2H, d, J=8,4 Hz), 7,51-7,58 (1H, m), to 9.57 (1H, s), 11,20-11,38 (1H, m).

Synthetic example 9a

4-[N-(1H-Indol-7-yl)sulfamoyl]benzoic acid

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): 6,40 (1H, DD, J=2,9, 1.9 Hz), to 6.67 (1H, d, J=7.5 Hz), PC 6.82 (1H, DD, J=7,9, 7.5 Hz), 7,31 (1H, DD, J=2,9, 2.7 Hz), 7,33 (1H, d, J=7.9 Hz), 7,81-7,88 (2H, m), 7,99-8,07 (2H, m), 10,07 (1H, s), of 10.73-10,83 (1H, m), 13,30-of 13.58 (1H, sh).

Synthetic example 10A

N-(3-Chloro-1H-indol-7-yl)-4-cyanobenzenesulfonyl

76 mg specified in the header connections get in the same way as in example 2A from 100 mg of 4-cyano-N-(1H-indol-7-yl)bemeasured synthesized in the same manner as in synthetic example 1A.

Melting point: 210-211°C (recrystallized from a mixture of ethyl acetate/n-hexane).

1H-NMR (DMSO-d6)(M. D.): of 6.71 (1H, DD, J=7,6, 0.8 Hz), of 6.96 (1H, DD, the measures 11a

3-Chloro-N-(3-chloro-4-hydroxy-1H-indol-7-yl)benzosulfimide

52 mg specified in the header connections get in the same way as in example 2A from 100 mg of 3-chloro-N-(4-methoxy-1H-indol-7-yl)benzosulfimide synthesized in the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): with 3.79 (3H, s), 6,37 (1H, d, J=8,4 Hz), of 6.45 (1H, d, J=8,4 Hz), 7.24 to 7,31 (1H, m), of 7.48-to 7.77 (4H, m), 9,76 (1H, s), 11,06-11,17 (1H, m).

Synthetic example 12A

3-Chloro-N-(3-chloro-4-hydroxy-1H-indol-7-yl)benzosulfimide

220 mg (0.47 mmol) of N-(4-tert-butyldimethylsilyloxy-3-chloro-1H-indol-7-yl)-3-chlorobenzenesulfonamide synthesized in the same manner as in synthetic example 1A are added to a solution (2 ml) mixture (1:10) 40% aqueous solution of hydrogen fluoride/acetonitrile. After stirring at room temperature overnight, water is added and the mixture extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated. Then the resulting residue is purified column chromatography on silica gel, getting 141 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): x 6.15 (1H, DD, J=8,2, 1.5 Hz), of 6.26 (1H, d, J=8,2 Hz), 7,12 (1H, s), 7,47-to 7.64 (4H, m), 9,54 (1H, s), 10,85 (1H, s).

Synthetic when the e way, as in synthetic example 1A.

Melting point: 155-156°C (recrystallized from a mixture of ethyl acetate/n-hexane).

1H-NMR (DMSO-d6)(M. D.): of 3.77 (3H, s), 6,91-6,99 (2H, m), 6,98-7,07 (2H, m), 7,45-7,53 (1H, m), of 7.64-7,74 (2H, m), 8,01-8,07 (1H, m), becomes 9.97 (1H, s), 12,61-12,72 (1H, m).

Synthetic example 14a

6-Chloro-N-(3-chloro-1H-indol-7-yl)-3-pyridinesulfonamide

Specified in the title compound is obtained by chlorination of 6-chloro-N-(1H-indol-7-yl)-3-pyridinesulfonamide obtained by the interaction of 6-chloro-3-pyridinesulfonamide, and connection example of obtaining 2A in the same manner as in example 1A.

1H-NMR (DMSO-d6)(M. D.): was 6.73 (1H, d, J=7,7 Hz), 6,97 (1H, DD, J=7,9, 7,7 Hz), 7,30 (1H, d, J=7.9 Hz), 7,46 (1H, d, J=2.6 Hz), to 7.67 (1H, d, J=8,4 Hz), 8,03 (1H, DD, J=8,4, and 2.6 Hz), to 8.62 (1H, d, J=2.6 Hz), 10,18-10,34 (1H, W), 11,06-11,17 (1H, m).

Synthetic example 15A

N-(3-Chloro-1H-indol-7-yl)-4-(methylthiomethyl)benzosulfimide

of 1.97 g (5.37 mmol) of the compound of synthetic example 5A was dissolved in 10 ml of tetrahydrofuran. To this mixture 10 ml (39,4 mmol) of a 15% aqueous solution mertiolate sodium and a catalytic amount of a chloride of methyltrioctylammonium at room temperature, followed by stirring over night. Add 20 ml of water and CME. the donkey this residue purified column chromatography on silica gel, receiving 1.51 g of N-(1H-indol-7-yl)-4-(methylthiomethyl)benzosulfimide. Product hairout in the same way as in example 2A, getting 839 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): to 1.87 (3H, s), 3,70 (2H, s), 6,77 (1H, DD, J=7,6, and 2.1 Hz), 6,94 (1H, DD, J=7,9, 7,7 Hz), 7,24 (1H, d, J=7.9 Hz), 7,42 (2H, d, J=8,2 Hz), 7,47 (1H, d, J=2.6 Hz), to 7.67 (2H, d, J=8,4 Hz), 9,96 (1H, SHS), br11.01 (1H, CL).

Synthetic example 16A

3-Chloro-N-(3-formyl-1H-indol-7-yl)benzosulfimide

1.3 ml (a 13.9 mmol) of phosphorus oxychloride (III) is added dropwise to a 14.5 ml of dimethylformamide at 10°C or lower with stirring in nitrogen atmosphere. After stirring at about 5°C for 30 minutes to this add three servings of 2.50 g (8,15 mmol) 3-chloro-N-(1H-indol-7-yl)benzosulfimide synthesized in the same manner as in example 1. After stirring at about 5°C for another 30 minutes add 200 ml of chilled water. The reaction mixture was adjusted to pH 14 by adding 1 N. aqueous sodium hydroxide solution and then to pH 2 by adding 1 N. hydrochloric acid, and then extracted, adding there ethyl acetate. The organic layer was washed with saturated salt solution, dried nazalnogo in the connection header.

1H-NMR (DMSO-d6)(M. D.): 6,70 (1H, DD, J=7,6, 0.8 Hz), 7,06 (1H, DD, J=8.0 a, 7,6 Hz), 7,51 to 7.75 (4H, m), to 7.93 (1H, d, J=8.0 Hz), by 8.22-of 8.28 (1H, m), to 9.93 (1H, s), 10,17 (1H, s), up 11,86-11,98 (1H, m).

Synthetic example 17 and

3-Chloro-N-(3-cyano-1H-indol-7-yl)benzosulfimide

274 mg (3,94 mmol) hydroxylamine hydrochloride and 0.32 ml (3,96 mmol) of pyridine are added to a solution (18 ml) of dimethylformamide containing 1.20 g (3.58 mmol) of the compound of synthetic example 16A, at a temperature of from 70 to 80°C under stirring. After stirring for 2.5 hours there is added 437 mg (3,94 mmol) of selenium dioxide and about 100 mg of powder of magnesium sulfate. After stirring at the same temperature for a further 2 hours the solvent is evaporated. To the residue is added ethyl acetate, and the insoluble matter is collected by filtration. The filtrate is successively washed with 0.1 N. hydrochloric acid and saturated salt solution, dried over magnesium sulfate and the solvent is evaporated. The residue is purified column chromatography on silica gel, getting 678 mg specified in the connection header.

Melting point: 204,5-205°C (recrystallized from a mixture of ethyl acetate/n-hexane).

1H-NMR (DMSO-d6)(M. D.): of 6.71 (1H, d, J=7 18a

6-Chloro-N-(3-cyano-1H-indol-7-yl)-3-pyridinesulfonamide

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): 6,77 (1H, d, J=7.9 Hz), 7,12 (1H, t, J=7.9 Hz), to 7.50 (1H, d, J=7.9 Hz), 7,72 (1H, d, J=8,4 Hz), of 8.06 (1H, DD, J=8,4, and 2.6 Hz), 8,23 (1H, d, J=2.6 Hz), 8,65 (1H, d, J=2.6 Hz), 10,34-10,48 (1H, sh), 11,98-12,12 (1H, m).

Synthetic example 19a

N-(3-Chloro-1H-indol-7-yl)-4-sulfamoylanthranilic

767 mg (3.0 mmol) of the compound of example obtaining 5A and 264 mg (2.0 mmol) of the compound of example obtaining 2A is subjected to interaction and processing in the same manner as in example 1A, getting 445 mg of N-(1H-indol-7-yl)-4-sulfamoylanthranilic. Product hairout in the same manner as in example 2A, getting 349 mg specified in the connection header.

Melting point: starts a partial coloring in black color at a temperature close to 220°C and the connection is gradually decomposed, since the temperature close to 240°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): to 6.75 (1H, d, J=7,6 Hz), of 6.96 (1H, DD, J=8.0 a, 7,6 Hz), 7,29 (1H, d, J=7,6 Hz) to 7.50 (1H, d, J=2,8 Hz), 7,58 (2H, s), of 7.90-7,98 (4H, m), 10,23 (1H, s), 11,07-11,17 (1H, m).

Synthetic example 20A

3-the mixed solution of tetrahydrofuran and water and the solution is added a solution of tetrahydrofuran, containing 1.90 g (9.0 mmol) of 3-chlorobenzenesulfonamide. After stirring at room temperature overnight the mixture was concentrated and to the residue is added water and dichloromethane. The organic layer is separated and the wall of the reactor scraped. The resulting crystals are collected by filtration, receiving of 1.41 g of N-(2-amino-3-pyridine)-3-chlorobenzenesulfonamide. 530 mg (of 1.87 mmol) of the crystals dissolved in methanol and to this add 367 mg (of 1.87 mmol) of 40% aqueous solution of chloroacetaldehyde. After heating at boiling under reflux for 4 hours the mixture is concentrated to dryness. To the residue is added a small amount of methanol and the crystals are collected by filtration, getting 373 mg specified in the connection header.

Melting point: gradually decomposed, since the temperature close to the 210°C (recrystallized from ethanol).

Synthetic example 21A

N-(3,4-Dichloro-1H-indol-7-yl)-4-sulfamoylanthranilic

429 mg (1,68 mmol) of the compound of example obtaining 5A and 250 mg (1,24 mmol) of the compound of example obtaining 9a is subjected to interaction and processing in the same manner as in example 1a, receiving 200 mg specified in the connection header.

Melting point: there is staining since Tammy ether).

1H-NMR (DMSO-d6)(M. D.): 6,62 (1H, d, J=8.1 Hz), to 6.95 (1H, d, J=8.1 Hz), 7,53 to 7.62 (3H, m), 7,87-to 7.99 (4H, m), 10,17-10,33 (1H, sh), 11,44-to 11.56 (1H, m).

Synthetic example 22A

N-(3-Chloro-1H-indol-7-yl)-4-(methylthio)benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic examples 1A and 2A.

1H-NMR (DMSO-d6)(M. D.): 2,48 (3H, s), PC 6.82 (1H, DD, J=7,9, 1.5 Hz), of 6.96 (1H, DD, J=8,1, 7.5 Hz), 7,25 (1H, DD, J=7,9, 0,92 Hz), 7,33 (2H, d, J=8,8 Hz), 7,49 (1H, d, J=2.7 Hz), a 7.62 (2H, d, J=8.6 Hz), 9,96 (1H, CL), 11,02 (1H, CL).

Synthetic example 23a

N-(3-Chloro-1H-indol-7-yl)-4-(methylsulphonyl)benzosulfimide

a 54.2 mg (0,154 mmol) of the compound of synthetic example 22 was dissolved in a mixed solution of 2 ml of methanol and 1.2 ml of water, then to this solution was added 30 mg tetrahydrate of ammonium molybdate and 0.6 ml of 30% aqueous hydrogen peroxide at room temperature. After stirring overnight, water is added and the mixture extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and concentrated. Then the residue purified column chromatography on silica gel, getting to 29.4 mg specified in the connection header.

Melting point: staining occurs when the temperature is).

1H-NMR (DMSO-d6)(M. D.): of 3.28 (3H, s), of 6.75 (1H, d, J=7,7 Hz), 6,97 (1H, DD, J=7,9, 7,7 Hz), 7,30 (1H, d, J=8.1 Hz), to 7.50 (1H, d, J=2.7 Hz), of 7.97 (2H, d, J=8,2 Hz), of 8.09 (2H, d, J=8,4 Hz), 10,29 (1H, CL), 11,12 (1H, CL).

Synthetic example 24 and

N-(3-Chloro-1H-indol-7-yl)-4-(methylsulfinyl)benzosulfimide

to 19.9 mg (0,056 mmol) of the compound of synthetic example 22 was dissolved in 2 ml of dichloromethane and then adding to the solution of 10 mg (0,058 mmol) m-chloroperbenzoic under stirring and cooling with ice. One hour later, add aqueous saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and concentrated. Then the residue purified by thin-layer chromatographies on silica gel, getting to 14.4 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): was 2.76 (3H, s), is 6.78 (1H, DD, J=7,5, 1.1 Hz), of 6.96 (1H, dt, J=0,55 Hz, From=7,8 Hz), 7,28 (1H, DD, J=7,6, 0,82 Hz), of 7.48 (1H, d, J=2.7 Hz), 7,82 (2H, d, J=8.6 Hz), 7,89 (2H, d, J=8,8 Hz), 10,15 (1H, CL), 11,06 (1H, CL).

Synthetic example 25A

3-Chloro-N-(3-chloro-1H-pyrrolo[3,2-C]pyridine-7-yl)benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic examples 1A and 2A.

1H-NMR (DMSO-d6)Synthetic example 26a

4-Ndimethylacetamide-N-(3-chloro-4-methyl-1H-indol-7-yl)benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

Melting point: gradually decomposed since the temperature close to 225°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): 2,03 (3H, s), of 2.56 (3H, s), 6,54-6,60 (2H, m), 7,33 (1H, d, J=2.6 Hz), 7,60 (2H, d, J=9.0 Hz), to 7.64 (2H, d, J=9.0 Hz), 9,63 (1H, CL), 10,24 (1H, CL), 10,92 (1H, CL).

Synthetic example 27A

4-Amino-N-(3-chloro-4-methyl-1H-indol-7-yl)benzosulfimide

3.75 g (9.9 mmol) of the compound of synthetic example 26a dissolved in 25 ml of 2 N. aqueous sodium hydroxide, followed by stirring at 100°C for 2 hours. After cooling to room temperature, the mixture is brought to pH 6 by adding acetic acid. The precipitate is collected by filtration and purified column chromatography on silica gel, obtaining 1.1 g specified in the connection header.

Melting point: gradually decomposed since the temperature close to 230°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): of 2.56 (3H, s), to 5.93 (2H, CL), 6,46 (2H, d, J=8, what 28a

4-Cyano-N-(3-cyano-1H-indol-7-yl)benzosulfimide.

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

Melting point: 250,5-252°C (recrystallized from a mixture of ethyl acetate/n-hexane).

1H-NMR (DMSO-d6)(M. D.): to 6.67 (1H, d, J=7,7 Hz), 7,05 (1H, t, J=7.9 Hz), 7,44 (1H, d, J=7,7 Hz), 7,78-7,87 (2H, m), 7,97-with 8.05 (2H, m), 8,16-8,23 (1H, m), 10,28-10,43 (1H, sh), 11,92-12,09 (1H, m).

Synthetic example 29A

4-Carbarnoyl-N-(3-chloro-1H-indol-7-yl)benzosulfimide

To a solution of 1.0 g (3,01 mmol) of the compound of synthetic example 10A, added to 4.8 ml of ethanol, first add 2.4 ml of 30% aqueous hydrogen peroxide and then with stirring three portions add 360 ál of 6 N. aqueous sodium hydroxide (reaction temperature: about 50°C). After stirring at 50°C for another 30 minutes, the reaction mixture is acidified by adding diluted hydrochloric acid and then extracted with ethyl acetate. The organic layer is collected by fractionation, washed with water, dried over magnesium sulfate and concentrated. The residue is purified column chromatography on silica gel, receiving 600 mg specified in the connection header.

Melting point: there is staining and RA begins the TES from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): 6,76 (1H, d, J=7.5 Hz), to 6.95 (1H, DD, J=8,1, 7.5 Hz), 7,27 (1H, d, J=8.1 Hz), 7,49 (1H, d, J=2.6 Hz), to 7.59 (1H, CL), 7,76-7,83 (2H, m), to $ 7.91-7,98 (2H, m) to 8.12 (1H, CL), 10,10 (1H, s), br11.01-11,12 (1H, m).

Synthetic example 30A

N-(4-Bromo-1H-indol-7-yl)-4-nitrobenzenesulfonamide

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): 6.35mm-6,41 (1H, m), 6,56 (1H, d, J=8,4 Hz), 7,06 (1H, DD, J=8,4, 0.8 Hz), 7,41-of 7.48 (1H, m), 7,92-8,02 (2H, m), 8,30-to 8.41 (2H, m), 10,34 (1H, s), 11,18 made 11.32 (1H, m).

Synthetic example 31A

N-(3-Chloro-4-cyano-1H-indol-7-yl)-4-nitrobenzenesulfonamide

200 mg (worn: 0.505 mmol) of the compound of synthetic example 30A dissolved in 0.8 ml of N-methylpyrrolidone and then adding to this solution of 83 mg (of 0.91 mmol) of copper cyanide (I). After stirring at a temperature of from 180 to 190°C for 3 hours there is added 40 ml of a mixture of ice - water. The insoluble matter is collected by filtration, washed with water and extracted with hot ethanol and hot chloroform. The extract was concentrated and the residue purified by thin-layer chromatography on silica gel, receiving 65 mg of N-(4-cyano-1H-indol-7-yl)-4-nitrobenzenesulfonamide. Specified product hairout the same the https://img.russianpatents.com/chr/948.gif" border="0">(M. D.): 6,98 (1H, d, J=8.0 Hz), 7,51 (1H, d, J=8.0 Hz), 7,79 (1H, d, J=2,8 Hz), 7,99-8,08 (2H, m), 8,31-to 8.40 (2H, m), 10,75-10,95 (1H, sh), are 11.62-11,73 (1H, m).

Synthetic example 32A

4-Amino-N-(3-chloro-4-cyano-1H-indol-7-yl)benzosulfimide

Specified in the title compound is obtained from the compound of synthetic example 31A in the same manner as in synthetic example 3A.

Melting point: decomposition begins with the temperature close to 232°C, and the compound decomposes quickly when 249,5-255°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): 6,09 (2H, s), of 6.52 (2H, d, J=8,8 Hz), 7,10 (1H, d, J=8,4 Hz), 7,46 (2H, d, J=8,8 Hz) to 7.50 (1H, d, J=8,4 Hz), 7,72-7,79 (1H, m), and 10.20 (1H, s), 11,40-11,59 (1H, m).

Synthetic example 33a

6-Amino-N-(3-chloro-1H-indol-7-yl)-3-pyridinesulfonamide

2,48 g (of 7.25 mmol) of the compound of synthetic example 14a and 679 mg (5,07 mmol) of lithium iodide is added to 25 ml of ethanol. To this add 10 ml of liquid ammonia and the mixture is heated at 120°C for 26 hours in a sealed vessel and then concentrated. The residue is dissolved in ethyl acetate and the mixture is successively washed with aqueous saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated. Then the residue purified column x is recrystallization of ethyl-n-hexane).

1H-NMR (DMSO-d6)(M. D.): 6,37 (1H, d, J=8,8 Hz), 6,83-6,94 (1H, m), to 6.88 (2H, CL), of 6.99 (1H, DD, J=7,9, 7,7 Hz), 7,25 (1H, DD, J=7,9, 0.7 Hz), of 7.48 (1H, d, J=2.7 Hz), 7,56 (1H, DD, J=8,8, 2.4 Hz), 8,14 (1H, d, J=2.4 Hz), to 9.70 (1H, s), 10,92-11,03 (1H, m).

Synthetic example 34a

N-(3-Chloro-1H-indol-7-yl)-4-(methylsulfonylmethyl)benzosulfimide

Specified in the title compound is obtained by oxidation of the compound of synthetic example 15A in the same manner as in example 24A.

1H-NMR (DMSO-d6)(M. D.): to 2.41 (3H, s), 3,98 (1H, d, J=12,6 Hz), 4,18 (1H, d, J=12,8 Hz), 6,77 (1H, d, J=7.5 Hz), 6,94 (1H, DD, J=7,9, 7,7 Hz), 7,25 (1H, d, J=7.9 Hz), the 7.43 (2H, d, J=8.1 Hz), 7,47 (1H, d, J=2,8 Hz), 7,73 (2H, d, J=8.1 Hz), 10,01 (1H, CL), 11,03 (1H, CL).

Synthetic example 35A

N-(3-Chloro-1H-indol-7-yl)-4-(2-sulphatoethyl)benzosulfimide

865 mg (3,05 mmol) of the compound of example obtaining 11a is subjected to interaction with 376 mg (2,84 mmol) of the compound of example obtaining 2A and processed in the same manner as in example 1A. Received 957 mg of N-(1H-indol-7-yl)-4-(2-sulphatoethyl)benzosulfimide subjected to chlorination in the same way as in example 2A, getting 980 mg specified in the connection header.

Melting point: 217-219°C (decomp.) (recrystallized from a mixture of ethanol/n-hexane).

1H-AN, DD, J=8,1, 7.5 Hz), 7,24 (1H, DD, J=7,8, 0,37 Hz), 7,42 (2H, d, J=8,4 Hz), 7,49 (1H, d, J=2.6 Hz), to 7.68 (2H, d, J=8,2 Hz), 9,99 (1H, CL), 11,02 (1H, CL).

Synthetic example 36A

N-(3-Chloro-1H-indol-7-yl)-4-[2-(methylsulphonyl)ethyl]benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic examples 1A and 2A.

Melting point: you receive the dyeing at a temperature close to 180°C, and the compound decomposes at 201-203°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): 2,92 (3H, s), 3,01-of 3.07 (2H, m), 3,40-of 3.46 (2H, m), for 6.81 (1H, d, J=7.9 Hz), 6,94 (1H, DD, J=7,9, 7,7 Hz), 7,24 (1H, d, J=7,7 Hz), was 7.45 (2H, d, J=8,2 Hz), 7,49 (1H, d, J=2.7 Hz), to 7.68 (2H, d, J=8,2 Hz), 9,99 (1H, CL), 11,03 (1H, CL).

Synthetic example 37A

6-Amino-N-(3-cyano-1H-indol-7-yl)-3-pyridinesulfonamide

The compound of synthetic example 18a is subjected aminating the same way as in example 33a, getting listed at the beginning of the connection.

Melting point: 300°C or higher (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.) grades: 6.39 (1H, d, J=9.0 Hz), to 6.88 (1H, d, J=7,7 Hz), 6.89 in (2N, C), 7,11 (1H, DD, J=7,9, 7,7 Hz), 7,41 (1H, DD, J=7,9, 0.7 Hz), 7,55 (1H, DD, J=9,0, 2,6 Hz) to 8.12 (1H, d, J=2.6 Hz), 8,19 (1H, s), 9,72-9,90 (1H, sh), 11,78-11,92 (1H, m).

ke connection receive in the same way, as in synthetic examples 1A and 2A.

1H-NMR (DMSO-d6)(M. D.): 2,14 (3H, s), 6,77 (1H, d, J=7,7 Hz), 6,98 (1H, DD, J=7,9, 7,7 Hz), 7,29 (1H, d, J=7.9 Hz), to 7.50 (1H, d, J=2.7 Hz), to 7.64 (1H, DD, J=8,6 and 2.2 Hz), of 7.75 (1H, d, J=2.2 Hz), of 8.04 (1H, d, J=8.6 Hz), RS 9.69 (1H, CL), 10,04 (1H, CL), of 11.11 (1H, CL).

Synthetic example 39A

N-(3-cyano-1H-indol-7-yl)-8-chinaincorporated

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): of 6.68 (1H, d, J=7,3 Hz), 6.89 in (1H, DD, J=7,9, 7,7 Hz), 7,25 (1H, d, J=8.1 Hz), 7,69-7,74 (2H, m), 8,21 (1H, d, J=2,9 Hz), 8,30 (1H, DD, J=8,2, 1.3 Hz), 8,35 (1H, DD, J=7,4, and 1.4 Hz), 8,54 (1H, DD, J=8,3) and 1.7 Hz) to 9.15 (1H, DD, J=4,3, 1.7 Hz), 10,04 (1H, CL), 12,14 (1H, CL).

Synthetic example 40A

5-Chloro-N-(3-cyano-1H-indol-7-yl)-2-thiophenesulfonyl

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): to 6.88 (1H, DDD, J=7,7, 2,2, 0,73 Hz), 7,16 (1H, DD, J=7,9, 7,7 Hz), 7,20 (1H, d, J=4.0 Hz), was 7.36 (1H, d, J=4, 2 Hz), 7,51 (1H, d, J=8.1 Hz), 8,23 (1H, d, J=3.1 Hz), 10,42 (1H, CL), 12,01 (1H, CL).

Synthetic example 41A

N-(3-Chloro-1H-indol-7-yl)-4-(methoxycarbonylamino)benzosulfimide

170 mg (1.8 mmol) of methylchloroform added to a solution (1 ml) of pyridine, comperatore during the night. The reaction mixture was concentrated and the residue purified column chromatography on silica gel, receiving 20 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): the 3.65 (3H, s), to 6.80 (1H, d, J=7,7 Hz), 6,93 (1H, t, J=7.9 Hz), 7,21 (1H, DD, J=7,7, 0,37 Hz), was 7.45 (1H, d, J=2.7 Hz), 7,51 (2H, d, J=9.0 Hz), 7,63 (2H, d, J=8,8 Hz), 9,85 (1H, CL), 10,07 (1H, s), 10,97 (1H, CL).

Synthetic example 42

4-Acetyl-N-(3-cyano-1H-indol-7-yl)benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): 2,60 (3H, s), 6,74 (1H, d, J=7,7 Hz), 7,05 (1H, DD, J=7,9, 7,7 Hz), 7,42 (1H, d, J=7.9 Hz), 7,81-7,88 (2H, m), 8,03-8,10 (2H, m), 8,21 (1H, s), 10,18-10,50 (1H, sh), 11,92-12,07 (1H, m).

Synthetic example 43A

N-(3-Chloro-1H-indol-7-yl)-4-(N-methoxymethanol)benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic examples 1A and 2A.

1H-NMR (DMSO-d6)(M. D.): the 3.65 (3H, s), of 6.73 (1H, d, J=7,6 Hz), of 6.96 (1H, DD, J=8.0 a, 7,6 Hz), 7,30 (1H, d, J=8.0 Hz), to 7.50 (1H, d, J=2.4 Hz), 7,98 (4H, s), 10,29 (1H, CL), of 10.76 (1H, CL), 11,12 (1H, CL).

Synthetic example 44a

N-(3-Cyano-1H-indol-7-yl)--styrelseledamot

Specified in �https://img.russianpatents.com/chr/948.gif" border="0">(M. D.): 7,14-7,20 (2H, m), 7,32 (2H, s), 7,35-7,47 (4H, m), 7,60-to 7.68 (2H, m), 8,23 (1H, s), 9,70-there is a 10.03 (1H, sh), 11,85-12,12 (1H, sh).

Synthetic example 45A

3-Chloro-N-(3-cyano-1H-indol-7-yl)-2-methylbenzenesulfonamide

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): 2,61 (3H, s), 6,69 (1H, d, J=7,7 Hz),? 7.04 baby mortality (1H, t, J=7.9 Hz), was 7.36 (1H, DD, J=8,1, 7.9 Hz), 7,42 (1H, d, J=7.9 Hz), 7,73 (1H, DD, J=8,1, 1.1 Hz), to 7.77 (1H, DD, J=8,0, 0,82 Hz), of 8.25 (1H, d, J=3.1 Hz), 10,37 (1H, s), 11,99 (1H, CL).

Synthetic example 46a

N-(3-Chloro-1H-indol-7-yl)-6-isopropylamino-3-pyridinesulfonamide

400 mg (1,17 mmol) of the compound of synthetic example 14a and 0.80 ml (9,39 mmol) Isopropylamine added to 5 ml of dioxane, followed by heating at 100°C for 7.5 hours in a sealed vessel. After concentrating the mixture is dissolved in ethyl acetate and the solution successively washed with aqueous dilute citric acid, water, saturated sodium bicarbonate and water. The mixture is dried over magnesium sulfate and then concentrated. The residue is purified by thin-layer chromatography on silica gel, getting 235 mg specified in the connection header.

Melting point: starts painting at a temperature close to the 210°C, and CCO-d6)(M. D.): 1,09 (6N, d, J=6.6 Hz), 3,90-4,08 (1H, m), to 6.39 (1H, d, J=9.0 Hz), 6.90 to-7,05 (2H, m), 7,24 (1H, d, J=7.9 Hz), 7,33 (1H, d, J=7,7 Hz), of 7.48 (1H, d, J=2.4 Hz), 7,54 (1H, DD, J=9,0, 2.6 Hz), by 8.22 (1H, d, J=2.6 Hz), 9,65-9,84 (1H, sh), 10,88-11,04 (1H, m).

Synthetic example 47A

N-(3-Chloro-1H-indol-7-yl)-6-[[2-(dimethylamino)ethyl]amino]-3-pyridinesulfonamide

Specified in the title compound is obtained from the compound of synthetic example 14a and N,N-dimethylethylenediamine in the same manner as in synthetic example 46a.

1H-NMR (DMSO-d6)(M. D.): 2,14 (6N, C) to 2.35 (2H, t, J=6.6 Hz), 3,24-3,44 (2H, m), 6.48 in (1H, d, J=9.0 Hz), 6,92 (1H, d, J=7,7 Hz), of 6.99 (1H, DD, J=7,9, 7,7 Hz), 7,22 (1H, d, J=7.9 Hz), 7,27-7,39 (1H, m), 7,47 (1H, d, J=2.4 Hz), 7,54 (1H, DD, J=9,0, 2.6 Hz), 8,21 (1H, d, J=2.6 Hz), 10,91-11,03 (1H, m).

Synthetic example 48A

N-(3-Cyano-1H-indol-7-yl)-2-furazolidone

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): 6,62 (1H, DDD, J=3,7, 1,8, 0,37 Hz), 6,78 (1H, d, J=7.5 Hz),? 7.04 baby mortality (1H, d, J=3.5 Hz), 7,12 (1H, t, J=7.9 Hz), 7,49 (1H, d, J=8.1 Hz), 7,99-8,00 (1H, m), 8,23 (1H, d, J=3.1 Hz), 10,49 (1H, CL), 12,04 (1H, CL).

Synthetic example 49A

N-(3-Chloro-1H-indol-7-yl)-4-[(dimethylaminoacetyl)amino]benzosulfimide

Specified in the header of IC in synthetic example 1a.

1H-NMR (DMSO-d6)(M. D.): 2,66 (6N, (C), for 6.81 (1H, DD, J=7,7, 0,92 Hz), to 6.95 (1H, DD, J=7,9, 7,7 Hz), 7,20 (2H, d, J=8,8 Hz), 7.23 percent (1H, d, J=8.1 Hz), 7,47 (1H, d, J=2.7 Hz), to 7.64 (2H, d, J=8,8 Hz), 10,98 (1H, CL).

Synthetic example 50A

N-(3-Methyl-1H-indol-7-yl)-4-(methylsulphonyl)benzosulfimide

580 mg of 15.3 mmol) of sodium borohydride and 150 mg of 10% palladium-carbon is added to 25 ml of suspension in 2-propanol containing 300 mg (1,58 mmol) of 3-formyl-7-nitro-1H-indole, followed by boiling under reflux for 6 hours. After adding to the reaction system of water, the catalyst is filtered off. The filtrate is extracted with ethyl acetate and the extract washed with saturated salt solution and then dried over magnesium sulfate. The solvent is evaporated and the residue is dissolved in 5 ml of pyridine. The mixture is subjected to interaction and processing of 170 mg (0.67 mmol) of 4-(methylsulphonyl) benzosulfimide in the same manner as in example 1A, getting 149 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): to 2.18 (3H, s), 3,24 (3H, s), 6,69 (1H, d, J=7,7 Hz), for 6.81 (1H, t, J=7,7 Hz), 7,06 (1H, CL), 7,25 (1H, d, J=7.8 Hz), 7,95 (2H, d, J=8,8 Hz), of 8.04 (2H, d, J=8,2 Hz), 10,14 (1H, CL), the 10.40 (1H, CL).

Synthetic example 51A

3-Cyano-N-(3-cyano-1H-indol-7-yl)benzols the

1H-NMR (DMSO-d6)(M. D.): of 6.71 (1H, D, J=7,2 Hz), to 7.09 (1H, DD, J=8.0 a, 7,6 Hz), 7,49 (1H, d, J=8.0 Hz), 7,74 (1H, DD, J=8.0 a, 7,6 Hz), 7,94 (1H, d, J=8.0 Hz), 8,11-to 8.14 (2H, m), 8,23 (1H, d, J=2,8 Hz), 10,30 (1H, CL), a 12.05 (1H, CL).

Synthetic example 52a

N-(3-Chloro-1H-indol-7-yl)-4-(N-methylmethanesulfonamide)benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic examples 1A and 2A.

Melting point: 199-201°C (decomp.) (recrystallized from a mixture of ethanol/n-hexane)

1H-NMR (DMSO-d6)(M. D.): 2,98 (3H, s), 3,24 (3H, s), 6,83 (1H, DD, J=7,7, 0,37 Hz), of 6.96 (1H, DD, J=7,9, 7,7 Hz), 7,26 (1H, DD, J=7,9, of 0.55 Hz), of 7.48 (1H, d, J=2.7 Hz), 7,50-rate of 7.54 (2H, m), 7,72-7,76 (2H, m), 10,04 (1H, CL), 11,02 (1H, CL).

Synthetic example 53A

N-(3-Chloro-1H-indol-7-yl)-4-[(methanesulfonamido)methyl]benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic examples 1A and 2A.

Melting point: starts painting at a temperature close to 180°C, and the compound decomposes at 189-191°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): 2,81 (3H, s), 4,19 (2H, d, J=6.0 Hz), 6,79 (1H, d, J=7,7 Hz) 6,94 (1H, DD, J=7,9, 7,7 Hz), 7,24 (1H, d, J=7.9 Hz), 7,47 (2H, d, J=8,8 Hz), 7.4 for the l)-4-(1-pyrrolidinylcarbonyl)benzosulfimide

Specified in the title compound is obtained from 4-(1-pyrrolidinylcarbonyl)benzosulfimide and connection example of obtaining 10A in the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): 1,55-to 1.59 (4H, m), 3,07-3,11 (4H, m), of 6.71 (1H, d, J=7,6 Hz), to 6.95 (1H, DDD, J=8,2, to 7.4, 1.2 Hz), 7,30 (1H, d, J=8.0 Hz), 7,46 (1H, d, J=2.4 Hz), 7,89 (2H, d, J=8,8 Hz), 7,92 (2H, d, J=8,4 Hz), 10,18 (1H, CL), 11,03 (1H, CL).

Synthetic example 55A

N-(3-Cyano-1H-indol-7-yl)-1-methyl-4-imidazolecarboxamide

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): 3,61 (3H, s), 7,00 (1H, DD, J=7,7, 0,92 Hz), 7,07 (1H, DD, J=7,9, 7,7 Hz), 7,35 (1H, d, J=7.9 Hz), 7,75-7,76 (2H, m), 8,19 (1H, d, J=3.1 Hz), there is a 10.03 (1H, CL), 11,92 (1H, CL).

Synthetic example 56a

N-(3-Chloro-1H-indol-7-yl)-6-[(2-hydroxyethyl)amino]-3-pyridinesulfonamide

Specified in the title compound is obtained from the compound of synthetic example 14a 2-aminoethanol in the same manner as in synthetic example 46a.

1H-NMR (DMSO-d6)(M. D.): 3,24 is 3.40 (2H, m), 3,42-to 3.52 (2H, m), 4,66-of 4.77 (1H, m), 6.48 in (1H, d, J=9.3 Hz), 6,92 (1H, d, J=7,7 Hz), 7,00 (1H, t, J=7,7 Hz), 7,24 (1H, d, J=7,7 Hz), 7,40 to 7.62 (2H, m), of 7.48 (1H, d, J=2.2 Hz), by 8.22 (1H, d, J=2,6 ID

340 mg (0,99 mmol) of the compound of synthetic example 14a and 151 mg (1,98 mmol) of thiourea is added to 5 ml of ethanol followed by heating at boiling under reflux for 2 hours. After concentration the residue add 1.6 ml of water and 57 mg of sodium carbonate and the resulting mixture was stirred at room temperature for 10 minutes. To this add 85 mg of sodium hydroxide and the mixture is additionally stirred for 10 minutes and then filtered off the insoluble substance. The filtrate is acidified with hydrochloric acid and the precipitate collected by filtration, washed with water, then dissolved in tetrahydrofuran and dried over magnesium sulfate. After concentration the residue is purified by thin-layer chromatography on silica gel, getting 121 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): at 6.84 (1H, d, J=7,6 Hz), 7,03 (1H, t, J=7,6 Hz), 7,28 (1H, d, J=9,2 Hz), 7,31 (1H, d, J=7,6 Hz), 7,44 (1H, DD, J=9,2, 2.4 Hz), of 7.48 (1H, d, J=2.6 Hz), to 7.68 (1H, d, J=2.4 Hz), 9,58-9,80 (1H, sh), 11,08-11,19 (1H, m).

Synthetic example 58A

7-(4-Chlorobenzenesulfonamide)-1H-indole-2-carboxylic acid

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1

Synthetic example 59A

N-(3-Chloro-1H-indol-7-yl)-6-cyclopropylamino-3-pyridinesulfonamide

Specified in the header of the connection will receive the same manner as in synthetic example 46a.

Melting point: starts painting at a temperature close to 228°C, and the compound decomposes at 233,5-235°C (recrystallized from a mixture of ethyl acetate/n-hexane).

1H-NMR (DMSO-d6)(M. D.): 0,36-0,46 (2H, m), is 0.63 to 0.75 (2H, m), 2,44-of 2.64 (1H, m), 6,45-only 6.64 (1H, m), 6,93 (1H, d, J=7,7 Hz), 7,00 (1H, DD, J=7,9, 7,7 Hz), 7,24 (1H, d, J=7.9 Hz), 7,49 (1H, d, J=2.7 Hz), EUR 7.57-7,73 (2H, m), of 8.25 (1H, d, J=2.6 Hz), 9,68-9,90 (1H, sh), 10,92-11,04 (1H, m).

Synthetic example 60A

N-(3-Cyano-1H-indol-7-yl)-5-methyl-3-pyridinesulfonamide

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

Melting point: gradually decomposed at a temperature close to 288°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): of 2.33 (3H, s), of 6.75 (1H, d, J=7,7 Hz), to 7.09 (1H, DD, J=7,9, 7,7 Hz), of 7.48 (1H, d, J=7.9 Hz), 7,87-to $ 7.91 (1H, m), by 8.22 (1H, d, J=3.1 Hz), 8,58-8,67 (2H, m), 10,28 (1H, CL), 11,95-12,08 (1H, m).

Synthetic example 61A

N-(3-Chloro-1H-indol-7-yl)-4-(N-methylsulfonylamino 1A and 2A.

1H-NMR (DMSO-d6)(M. D.); 2,39 (3H, d, J=5,2 Hz), of 6.71 (1H, DD, J=7,8, 2.0 Hz), of 6.96 (1H, DD, J=8.0 a, 7,6 Hz), 7,30 (1H, d, J=8.0 Hz), of 7.48 (1H, d, J=2,8 Hz), 7,68 (1H,, J=4,9 Hz), 7,87-to 7.93 (4H, m), and 10.20 (1H, CL), 11,08 (1H, CL).

Synthetic example a

N-(3-Chloro-1H-indol-7-yl)-4-[2-(methanesulfonamido)ethyl]benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic examples 1A and 2A.

1H-NMR (DMSO-d6)(M. D.): 2,73-of 2.81 (5H, m), 3,13-3,19 (2H, m), PC 6.82 (1H, d, J=7,7 Hz), to 6.95 (1H, DC, J=8,1, 7,7 Hz), to 7.09 (1H, t, J=5,9 Hz), 7,24 (1H, d, J=8.1 Hz), 7,39 (2H, d, J=8,2 Hz), of 7.48 (1H, d, J=2.7 Hz), to 7.68 (2H, d, J=8,4 Hz), becomes 9.97 (1H, CL), 11,02 (1H, CL).

Synthetic example 63A

N-(3-Chloro-1H-indol-7-yl)-4-(sulfanilyl)benzosulfimide

389 mg (1.44 mmol) of the compound of example obtaining 6A is subjected to interaction with 159 mg (1.2 mmol) of the compound of example obtaining 2A and the reaction product is treated in the same manner as in example 1A, getting 233 mg of N-(1H-indol-7-yl)-4-(sulfanilyl)benzosulfimide. Connection glorious in the same way as in example 2A, receiving 160 mg specified in the connection header.

Melting point: 237-238,5°C (decomp.) (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)Synthetic example 64A

N-(3-Chloro-1H-indol-7-yl)-4-thiocarbamoylation

400 mg (1,21 mmol) of the compound of synthetic example 10A dissolved in 10 ml of dimethylformamide and to this solution add 0.5 ml of triethylamine. The hydrogen sulfide is bubbled through the mixture at a bath temperature of from 60 to 70°C for 45 minutes. After concentration the residue is dissolved in ethyl acetate, successively washed with diluted hydrochloric acid, aqueous saturated sodium bicarbonate and water and dried over magnesium sulfate. After evaporation of the solvent the residue is purified column chromatography on silica gel, getting 355 mg specified in the connection header.

Melting point: 223-225°C (decomp.) (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): for 6.81 (1H, d, J=7,7 Hz), of 6.96 (1H, DD, J=7,9, 7,7 Hz), 7,27 (1H, d, J=7.9 Hz), to 7.50 (1H, d, J=2.7 Hz), 7,73-7,80 (2H, m), 7,86-to 7.93 (2H, m), 9,58-9,73 (1H, BL), 10,02-10,18 (1H, BL), 10,15 (1H, s), 11,03-11,12 (1H, m).

Synthetic example 65A

5-Bromo-N-(3-cyano-1H-indol-7-yl)-2-pyridinesulfonamide

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

Melting point: 245,5-246,5°C (der="0">(M. D.): PC 6.82 (1H, d, J=7,7 Hz), 7,07 (1H, DD, J=7,9, 7,7 Hz), 7,44 (1H, d, J=7.9 Hz), 7,80 (1H, d, J=8,2 Hz), 8,23 (1H, d, J=2.2 Hz), 8,29 (1H, DD, J=8,2, 2.2 Hz), of 8.92 (1H, d, J=2.2 Hz), 10,42-10,67 (1H, W), 11,93-12,08 (1H, m).

Synthetic example 66A

N-(3-Cyano-1H-indol-7-yl) -2-naphthalenesulfonate

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): 6,74 (1H, DD, J=7,6, 2,8 Hz), 7,00 (1H, DD, J=7,9, 7,7 Hz), 7,39 (1H, DD, J=8.0 a, 0,46 Hz), to 7.61-7,72 (2H, m), 7,80 (1H, DD, J=8,6, 1.8 Hz), 8,01 (1H, d, J=8.1 Hz), 8,08 (1H, s), 8,10 (1H, s), 8,21 (1H, d, J=2,9 Hz), a 8.34 (1H, d, J=1.6 Hz), 10,23 (1H, CL), 12,01 (1H, CL).

Synthetic example 67a

N-(3-Acetyl-1H-indol-7-yl)-3-chlorobenzenesulfonamide

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): 2,44 (3H, s), of 6.65 (1H, d, J=7.5 Hz), 7,01 (1H, DD, J=7,9, 7,7 Hz), 7,53-7,63 (2H, m), 7,69-7,73 (2H, m), 8,01 (1H, DD, J=8,1, to 0.73 Hz), compared to 8.26 (1H, d, J=2,9 Hz), 10,10 (1H, s), 11,75 (1H, CL).

Synthetic example 68A

4-Amino-N-(5-bromo-3-cyano-1H-indol-7-yl)benzosulfimide

Specified in the title compound is obtained by hydrogenation of N-(5-bromo-3-cyano-1H-indol-7-yl)-4-nitrobenzenesulfonamide obtained from 4-nitrobenzenesulfonamide and connection example of getting 14a tatini.

1H-NMR (DMSO-d6)(M. D.): 6,07 (2H, CL), of 6.52 (2H, d, J=8,4 Hz), 6,97-6,99 (1H, m), of 7.36 (2H, DD, J=8,7, 1,6 Hz), 7,51 (1H, CL), of 8.25 (1H, s), to 9.93 (1H, d, J=5.5 Hz), of $ 11.97 (1H, CL).

Synthetic example 69A

N-(3-Chloro-1H-indol-7-yl)-4-(N-ethylsulfonyl)benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic examples 1A and 2A.

Melting point: 213,5-215°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): of 0.90 (3H, t, J=7.2 Hz), was 2.76 (2H, DK, J=5.8 Hz, J=7,2 Hz), 6,70 (1H, d, J=7,4 Hz), to 6.95 (1H, DD, J=8.0 a, 7,6 Hz), 7,29 (1H, d, J=8.0 Hz), 7,47 (1H, d, J=2,8 Hz), 7,78 (1H, t, J=5.6 Hz), of 7.90 (4H, C), 10,18 (1H, CL), 11,06 (1H, CL).

Synthetic example 70A

N-(3-Chloro-1H-indol-7-yl)-4-(econsultant)benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic example 4A.

Melting point: 214-215°C (decomp.) (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): to 1.14 (3H, t, J=7,3 Hz), and 3.16 (2H, K, J=7,3 Hz), PC 6.82 (1H, d, J=7.5 Hz), of 6.96 (1H, DD, J=7,9, 7,7 Hz), 7.23 percent (2H, d, J=8,8 Hz), 7,24 (1H, d, J=7.5 Hz), 7,47 (1H, d, J=2.6 Hz), 7,66 (2H, d, J=8,8 Hz), for 9.90 (1H, CL), 10,37 (1H, CL), 10,96 (1H, CL).

Synthetic example 71A

N-(3-Chloro-1H-indol-7-yl)-6-[(2 - synthetic example 46a.

1H-NMR (DMSO-d6)(M. D.): a rating of 2.72 (2H, t, J=6.4 Hz), 3.46 in-3,55 (2H, m), 6,53 (1H, d, J=9.0 Hz), 6.90 to (1H, d, J=7,7 Hz), of 6.99 (1H, DD, J=7,9, 7,7 Hz), 7,25 (1H, d, J=7.9 Hz), of 7.48 (1H, d, J=2.6 Hz), to 7.61 (1H, DD, J=9,0, the 2.4 Hz), 7,78-7,87 (1H, m), of 8.25 (1H, d, J=2.4 Hz), 9,70-9,95 (1H, sh), 10,92-11,04 (1H, m).

Synthetic example 72A

N-(3-Chloro-1H-indol-7-yl)-4-(N-methylcarbamoyl)benzosulfimide

533 mg (1,68 mmol) of the compound of synthetic example 9 was dissolved in a mixed solution of 5 ml of dimethylformamide and 2.5 ml of dimethyl sulfoxide and to this solution is then added 171 mg (2,53 mmol) of methylamine hydrochloride and 705 μl (of 5.06 mmol) of triethylamine. Add 436 ml (2.02 mmol) diphenylphosphinite, followed by stirring at room temperature over night. The mixture is then concentrated and extracted with ethyl acetate. The extract is successively washed with diluted hydrochloric acid, aqueous saturated sodium bicarbonate and water and dried over magnesium sulfate. After concentration the residue is purified column chromatography on silica gel, getting 465 mg of N-(1H-indol-7-yl)-4-(N-methylcarbamoyl) benzosulfimide. The compound obtained glorious in the same manner as in synthetic example 2A, getting 413 mg specified in the connection header.

Tacked src="https://img.russianpatents.com/chr/948.gif" border="0">(M. D.): was 2.76 (3H, d, J=4.6 Hz), 6,74 (1H, d, J=7,7 Hz) 6,94 (1H, DD, J=7,9, 7,7 Hz), 7,27 (1H, d, J=7.9 Hz), 7,49 (1H, d, J=2.7 Hz), 7,76-7,83 (2H, m), 7,87-7,94 (2H, m), 8,61 (1N, K, J=4.6 Hz), 10,10 (1H, s), 11,03-11,13 (1H, m).

Synthetic example 73a

N-(3-chloro-1H-indol-7-yl)-4-(methylsulfonylmethyl)benzosulfimide

510 mg of the compound of synthetic example 34a oxidized using 30% aqueous hydrogen peroxide, in the same manner as in example 23a, getting 307 mg specified in the connection header.

Melting point: you receive the dyeing at a temperature close to 225°C, and the connection is gradually decomposed, since the temperature close to 235°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): is 2.88 (3H, s), of 4.57 (2H, s), 6,77 (1H, d, J=7,6 Hz) 6,94 (1H, DD, J=7,9, 7,7 Hz), 7,25 (1H, d, J=8.0 Hz), 7,47 (1H, d, J=2.7 Hz), 7,51-7,56 (2H, m), 7,73 for 7.78 (2H, m), of 10.05 (1H, CL), 11,04 (1H, CL).

Synthetic example a

N-(3-Chloro-1H-indol-7-yl)-4-(N,N-dimethylsulphamoyl)benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic examples 1A and 2A.

1H-NMR (DMSO-d6)(M. D.): 2.57 m (6N, (C), of 6.71 (1H, DD, J=7,4, 0.6 Hz), 6,97 (1H, DD, J=8.0 a, 7,6 Hz), 7,31 (1H, d, J=8.0 Hz), 7,47 (1H, d, J=2,8 Hz), 7,86 (2H, d, J=8,4 Hz), to $ 7.91 (2H, d, J=8,4 Hz), 10,19 (1H, CL), 11,0 Specified in the header of the connection receives the same way as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): 1,79 (2H, dt, J=12,8 Hz, From=6,4 Hz), of 1.85 (2H, dt, J=13,6 Hz, From=6,8 Hz), up 3.22 (2H, t, J=6.4 Hz), 3,44 (2H, t, J=6.8 Hz), 6,78 (1H, d, J=7,2 Hz), of 6.96 (1H, DD, J=8.0 a, 7,2 Hz), 7,28 (1H, d, J=8.0 Hz), 7,47 (1H, d, J=2.4 Hz), 7,60 (2H, d, J=8.0 Hz), 7,74 (2H, d, J=8,4 Hz), 10,06 (1H, CL), br11.01 (1H, CL).

Synthetic example 76A

3-Chloro-N-(3-chloro-1H-indol-7-yl)-N-methylbenzenesulfonamide

120 mg (0,352 mmol) of the compound of synthetic example 7a was dissolved in 10 ml of dimethylformamide and to this solution is then added to 19.2 mg (0,479 mmol) of sodium hydride (60%). After stirring at room temperature for 30 minutes there is added 30 μl (0,482 mmol) under the conditions. After two hours, add water and then extracted with ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate. After concentration the residue is purified by thin-layer chromatography on silica gel, receiving 87 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 3,26 (3H, s), 6,51 (1H, DD, J=7,6, of 0.64 Hz), 7,00 (1H, DD, J=7,9, 7,7 Hz), 7,47 (1H, d, J=8.1 Hz), 7,53 (1H, d, J=2.7 Hz), 7,54-to 7.59 (2H, m), the 7.65 (1H, t, J=7.9 Hz), to 7.84 (1H, DDD, J=8,1, 2,1, 1,1 Hz), are 11.62 (1H, CL).

Synthetic example 77A

N-(3,4-Dichloro-1H-indol-7-yl)-4-(sulfanilyl)benzols

Melting point: gradually decomposed, since the temperature close to 297°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): 4,34 (2H, s), 6,72 (1H, d, J=8.1 Hz), 6,93 (2H, s) 6,94 (1H, d, J=8.1 Hz), 7,51 (2H, d, J=8.1 Hz), EUR 7.57 (1H, DD, J=2.7, and of 0.55 Hz), of 7.75 (2H, d, J=8,2 Hz), 10,10 (1H, CL), 11,44 (1H, CL).

Synthetic example 78A

N-(3-Cyano-1H-indol-7-yl)-4-[2-(methylsulphonyl)ethyl]benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic example 1A.

1H-NMR (DMSO-d6)(M. D.): to 2.94 (3H, s), 3,03-is 3.08 (2H, m), 3,42-3,47 (2H, m), 6,77 (1H, DD, J=7,7, 0,37 Hz), 7,05 (1H, t, J=7.9 Hz), 7,41 (1H, d, J=8.1 Hz), 7,46 (2H, d, J=8,2 Hz), 7,66 (2H, d, J=8,2 Hz), to 8.20 (1H, s), to 10.09 (1H, CL), 11,92 (1H, CL).

Synthetic example 79A

N-(3-Chloro-1H-indol-7-yl)-4-(N-methylacetamide)benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic examples 1A and 2A.

1H-NMR (DMSO-d6)(M. D.): 1,84 (3H, CL), and 3.16 (3H, s), for 6.81 (1H, d, J=7,7 Hz), of 6.96 (1H, DD, J=8.0 a, 7,6 Hz), 7,27 (1H, d, J=7.9 Hz), 7,45-7,49 (2H, m), 7,47 (1H, d, J=2.7 Hz), 7,70 to 7.75 (2H, m), 10,02 (1H, CL), br11.01 (1H, CL).

Synthetic example 80A

N-(3-Chloro-1H-indol-7-yl)-6-hydroxy-3-pyridinesulfonamide

When ohla billaut dropwise 1 ml of an aqueous solution, containing 32 mg (0.46 mmol) of sodium nitrite. After stirring for one hour the mixture is brought to pH 8 by adding aqueous sodium bicarbonate, and then stirred for 10 minutes. The reaction mixture was extracted with ethyl acetate and the extract washed with water, dried over magnesium sulfate and concentrated. Then the residue purified by thin-layer chromatography on silica gel, receiving 54 mg specified in the connection header.

Melting point: 244-245°C (decomp.) (recrystallized from a mixture of ethyl acetate/n-hexane).

1H-NMR (DMSO-d6)(M. D.) grades: 6.39 (1H, d, J=9.5 Hz), to 6.88 (1H, d, J=7,7 Hz),? 7.04 baby mortality (1H, DD, J=7,9, 7,7 Hz), 7,32 (1H, d, J=7.9 Hz), to 7.50 (1H, d, J=2.7 Hz), 7,58 (1H, DD, J=9,5, 3.1 Hz), to 7.64 (1H, d, J=3.1 Hz), 9,76-9,94 (1H, W), br11.01-11,13 (1H, m), 11,98-12,15 (1H, sh).

Synthetic example 81a

N-(3-Chloro-1H-indol-7-yl)-4-[2-(N-methylmethanesulfonamide)ethyl]benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic examples 1A and 2A.

1H-NMR (DMSO-d6)(M. D.): 2,69 (3H, s), was 2.76 (3H, s), of 2.86 (2H, t, J=7.5 Hz), 3,26 (2H, t, J=7.5 Hz), 6,78 (1H, DD, J=7,4, of 0.55 Hz) 6,94 (1H, t, J=7,7 Hz), 7,24 (1H, DD, J=7,7, 0,37 Hz), 7,39 (2H, d, J=8,2 Hz), of 7.48 (1H, d, J=2.6 Hz), 7,66 (2H, d, J=8,2 Hz), 9,94 (1H, CL), 11,02 (1H, CL).

Synthetic example a

econsultancy acid are added to a solution (5 ml) of pyridine, containing 62 mg (0,19 mmol) of the compound of synthetic example 3A, 0°C, followed by stirring over night. The reaction solution is evaporated. Add buffer solution on the basis of phosphoric acid having a pH of 7, followed by extraction with ethyl acetate. Then the extract was washed with saturated salt solution and dried over magnesium sulfate. The solvent is evaporated and the residue purified column chromatography on silica gel, receiving 20 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 6,79 (1H, d, J=7,7 Hz) 6,94 (1H, DD, J=7,9, 7,7 Hz), 7,16 (2H, d, J=8.6 Hz), 7.23 percent (1H, d, J=7.9 Hz), 7,46 (1H, d, J=2.7 Hz), 7,58 (2H, d, J=8.1 Hz), 9,84 (1H, CL), 10,98 (1H, CL).

Synthetic example 83A

N-(3-Chloro-1H-indol-7-yl)-4-[(N-methylmethanesulfonamide)methyl]benzosulfimide

Specified in the header of the connection will receive the same manner as in synthetic examples 1A and 2A.

Melting point: 200,5-202°C (recrystallized from ethanol).

1H-NMR (DMSO-d6)(m d): 2,63 (3H, s) to 2.94 (3H, s), 4,27 (2H, s), to 6.80 (1H, d, J=7,3 Hz), to 6.95 (1H, DD, J=8,1, 7.5 Hz), 7,25 (1H, d, J=7.9 Hz), was 7.45 (2H, d, J=8,2 Hz), 7,47 (1H, d, J=2.7 Hz), 7,74 (2H, d, J=8,2 Hz), 10,00 (1H, s) 11,00 (1H, CL).

Synthetic example a

3-Chloro-N-(3-chloro-1H-pyrrolo[2,3 the m-1H-pyrrolo[2,3-C]pyridine, synthesized from 2-bromo-3-nitropyridine in the same way as in the example of obtaining 1A, 194 mg of copper powder and 603 mg of copper chloride (I). The mixture is heated in a sealed vessel at 120°C for 15 hours and then treated, receiving 170 mg 7-amino-1H-pyrrolo[2,3-C]pyridine. The resulting product is subjected to interaction and processing in the same manner as in examples 1A and 2A, receiving 57 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 6,93 (1H, d, J=6.6 Hz), was 7.45 (1H, DD, J=6,6, 5.8 Hz), 7,53 (1H, DD, J=8.0 a, 7,6 Hz), to 7.61 (1H, d, J=7,6 Hz), 7,73 (1H, d, J=2,8 Hz), the 7.85 (1H, d, J=8.0 Hz), of 7.96 (1H, d, J=1.2 Hz), 11,90-12,10 (1H, m), 12,72 (1H, CL).

Synthetic example 85a

N-(3-Chloro-1H-indol-7-yl)-4-[3-(1-imidazolyl)propyl]benzosulfimide

To 4-(3-bromopropyl)-N-(3-chloro-1H-indol-7-yl)benzosulfimide (213 mg, 0.5 mmol) is added 170 mg (2.5 mmol) of imidazole and 6 ml of dimethylformamide, followed by heating at 80°C for 3 hours in nitrogen atmosphere. Then the reaction mixture was poured into water and extracted with chloroform. The extract is dried over magnesium sulfate and concentrated. Then the resulting residue is purified column chromatography on silica gel, receiving 160 mg specified in the connection header.

Melting point: 86-90°C.

1H-NMR (DMSO-d b, t, J=1.1 Hz), 6,94 (1H, DD, J=7,9, 7,7 Hz), 7,16 (1H, t, J=1.2 Hz), 7.23 percent (1H, d, J=7,7 Hz), 7,32 (2H, d, J=8,4 Hz), 7,47 (1H, d, J=2.7 Hz), 7,60 (1H, CL), the 7.65 (2H, d, J=8,4 Hz), to 9.91-of 10.01 (1H, m), 10,98-11,02 (1H, m).

Synthetic example 86a

N-(3-Chloro-1H-indol-7-yl)-4-[N-[2-(2-pyridinyl)ethyl]carbarnoyl]benzosulfimide

2,82 g (12.8 mmol) of 4-(chlorosulfonyl)benzoic acid and 1.42 g (8,54 mmol) 7-amino-3-chloro-1H-indole are interacting with each other in pyridine at room temperature under stirring over night, receiving of 2.33 g of 4-[N-(3-chloro-1H-indol-7-yl)sulfamoyl]benzoic acid. To 303 mg (0.86 mmol) of the product successively added 260 μl of dimethylformamide, 204 μl (0.95 mmol) diphenylphosphoryl, 132 μl (0.95 mmol) of triethylamine and 113 μl (0,94 mmol) of 2-(2-amino-ethyl)pyridine, followed by stirring at room temperature over night. After concentration added ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer is separated and washed with a saturated solution of salt. After evaporation of the solvent the residue is purified column chromatography on silica gel, receiving 175 mg specified in the connection header. Melting point: 220,5-222°C.

1H-NMR (DMSO-d6)(M. D.): 2,95-to 2.99 (2H, m), 3,56-3,62 (2H, m), of 6.75 (1H , ,48-8,51 (1H, m), is 8.75 (1H, t, J=5,2 Hz), to 10.09-10,12 (1H, m), 11,06-11,09 (1H, m).

Synthetic example 87a

4-Amidino-N-(3-chloro-1H-indol-7-yl)benzosulfimide

of 3.3 ml (3.3 mmol) of a hexane solution containing 1.0 M of trimethylaluminum, and 10 ml of toluene is added to 162 mg (3.0 mmol) of ammonium chloride. After cessation of gas evolution, the mixture is evaporated until then, until the solution reaches about 3 ml Under stirring to the solution was added 97 mg (0.30 mmol) of the compound of example obtaining 4A and the mixture is heated at 80°C for 4 hours. After cooling, to the mixture concentrated ammonia, insoluble matter is filtered off and the filtrate concentrated. Add ethyl acetate, the insoluble substance is filtered off and the filtrate concentrated. The residue is purified column chromatography on silica gel, receiving 35 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 6,93 (1H, DD, J=7,7, 1.5 Hz), of 6.96 (1H, DD, J=7,7, 7.5 Hz), 7,24 (1H, DD, J=7,5, 1.3 Hz), to 7.50 (1H, d, J=2.7 Hz), of 7.90 (2H, d, J=8.6 Hz), 8,01 (2H, d, J=8.6 Hz), 9,16-9,62 (2N, W),-the 10.40-of 10.75 (1H, W), 11,50 (1H, s).

Synthetic example a

N-(3-Chloro-1H-indol-7-yl)-4-[N-[2-(1-imidazolyl)ethyl]sulfamoyl]benzosulfimide

557 mg (1.13 mmol) of 4-[N-(2-bromacil)sulfamoyl]-N-(3-chloro-1H-indole-7-and the#176;C for 2 days. After concentration the residue is dissolved in ethyl acetate. The mixture is washed with water, dried over sodium sulfate and concentrated. The residue is purified column chromatography on silica gel, getting 324 mg specified in the connection header.

Melting point: gradual staining begins with a temperature close to 200°C, and the compound decomposes at 218 to 221°C (recrystallized from a mixture of ethanol/n-hexane).

1H-NMR (DMSO-d6)(M. D.): 3,05 (2H, DDD, J=6,2, 6,0, 5,9 Hz), of 3.96 (2H, DD, J=6,0, 5,9 Hz), 6,69-6,72 (1H, m), at 6.84 (1H, CL), 6,92 (1H, DD, J=7,9, 7,7 Hz), was 7.08 (1H, CL), 7,26 (1H, d, J=7.5 Hz), 7,44 (1H, d, J=2.7 Hz), 7,55 (1H, SHS), 7,82-7,88 (4H, m), of 8.06 (1H, t, J=5,9 Hz), 10,18-10,36 (1H, sh), 11,09 (1H, d, J=2,4 Hz).

Synthetic example 89a

3-(5-Bromonicotinate)-N-(3-cyano-1H-indol-7-yl)benzosulfimide

785 mg (3.54 mmol) of 3-nitrobenzenesulfonamide subjected to interaction with 506 mg (3,22 mmol) of the compound of example obtaining 3A in the same manner as in example receiving 4A, and process, getting 950 mg of N-(3-cyano-1H-indol-7-yl)-3-nitrobenzenesulfonamide. The product is restored in accordance with a customary method using powder zinc/concentrated hydrochloric acid, 30 ml of methanol, getting 459 mg of 3-amino-N-(3-cyano-1H-indol-7-yl)benzols inorganic hydrochloride. After stirring at room temperature overnight the mixture was concentrated. To the residue add water dilute citric acid. The precipitate is collected by filtration and sequentially washed with water, aqueous dilute sodium bicarbonate, water and ether. The residue is dissolved in tetrahydrofuran and the mixture is dried over magnesium sulfate and concentrated. The crystals precipitated by adding ether and n-hexane, collected by filtration, getting 108 mg specified in the connection header.

1H-NMR (DMSO-d6)(m d): for 6.81 (1H, DD, J=7,7, 0.7 Hz), 7,07 (1H, t, J=7.9 Hz), 7,42 (1H, DD, J=7,9, 0.7 Hz), 7,47-7,51 (1H, m), 7,55 (1H, t, J=7.9 Hz), 7,93-of 7.97 (1H, m), 8,21-8,23 (1H, m), 8,31 (1H, t, J=1,8 Hz), 8,55 (1H, DD, J=2,4, 2.0 Hz), 8,93 (1H, d, J=2.4 Hz), 9,06 (1H, d, J=2.0 Hz), 10,23-of 10.25 (1H, m), is 10.75 (1H, CL), 11,94-11,96 (1H, m).

Synthetic example 90A

N-(3-Chloro-1H-indol-7-yl)-4-[N-(2-thiazolyl)sulfamoyl]benzosulfimide

to 5.2 g (to 20.4 mmol) sulfathiazole added to a mixed solution of 14 ml of water and 3.4 ml of concentrated hydrochloric acid and the mixture is stirred. To the mixture is added dropwise aqueous saturated solution of 2.1 g (30.4 mmol) of sodium nitrite at 0°C or less. Then add 5 ml of acetic acid, followed by stirring at 5°With those who acid, saturated with sulfur dioxide (solution obtained by saturation of 18 ml of acetic acid and sulfur dioxide and then by adding 830 mg of copper chloride (II)·dihydrate). After 5 minutes the reaction mixture is then poured into a mixture of ice - water. The precipitate is collected by filtration, washed with water and dried, obtaining 2.9 g of 4-chlorosulfonyl-N-(2-thiazolyl)benzosulfimide. 570 mg (1,68 mmol) of the product is subjected to interaction with 200 mg (1.2 mmol) of the compound of example obtaining 1A in the same manner as in example receiving 4A, and process, getting 456 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): of 6.68 (1H, DD, J=7,5, to 0.73 Hz), 6.87 in (1H, d, J=4.6 Hz), 6,93 (1H, DD, J=8,1, 7.5 Hz), 7,26-7,30 (1H, m), 7,28 (1H, d, J=4.6 Hz), 7,46 (1H, d, J=2.7 Hz), 7,82-7,88 (2H, m), 7,88-7,94 (2H, m), 10,10-10,26 (1H, sh), 11,04-11,10 (1H, m), 12,83-13,01 (1H, sh).

Synthetic example 91a

5-Chloro-N-(3-chloro-1H-indol-7-yl)-4-(5-methyl-3-pyridinesulfonamide)-2-thiophenesulfonyl

645 mg (2,46 mmol) 5-chloro-4-nitro-2-thiophenesulfonyl subjected to interaction with 410 mg (2,46 mmol) of the compound of example obtaining 1A in the same manner as in example receiving 4A, and process, getting 194 mg of 5-chloro-N-(3-chloro-1H-indol-7-yl)-4-nitro-2-thiophenesulfonyl. The product is restored in accordance with a customary method, Corr-N-(3-chloro-1H-indol-7-yl)-2-thiophenesulfonyl. 72 mg (0.20 mmol) dissolved in 2 ml of tetrahydrofuran and there add 18 μl of pyridine and 38 mg (0.2 mmol) of 5-methyl-3-pyridinesulfonamide. After stirring at room temperature over night the organic layer is separated, adding to the reaction mixture ethyl acetate and 1 N. hydrochloric acid. It washed sequentially with water, aqueous sodium bicarbonate and water, dried over magnesium sulfate and concentrated. Then the resulting residue is purified column chromatography on silica gel, receiving 82 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): of 2.33 (3H, s) 6,76 (1H, d, J=7,7 Hz), 7,03 (1H, DD, J=7,9, 7,7 Hz), 7,35 (1H, s), 7,38 (1H, d, J=7.9 Hz), 7,51 (1H, d, J=2.7 Hz), 7,80 (1H, DD, J=2.0 a, 1.5 Hz), at 8.60 (1H, DD, J=2.0 a, 0,4 Hz), 8,71 (1H, DD, J=1,5, 0,4 Hz), 10,35-the 10.40 (1H, m), of 10.73-10,80 (1H, sh), 11,16-11,19 (1H, m).

An example of obtaining 1b

2-Amino-5-bronchioles

2-Bromo-6-nitrobenzaldehyde (30,4 g), magnesium oxide (75 g) and dimethyl sulfoxide (11.3 ml) mix thoroughly for one minute. Then to the mixture is added diethyl(cyanomethyl) phosphonate (25,8 ml) and the mixture is stirred for a further 2 hours. Stirring is stopped and the reaction mixture allow to stand over night. After that it was added ethyl acetate and polucen the on silica gel, getting 32 g of 3-(2-bromo-6-nitrophenyl)-2-propenenitrile (E isomer Z isomer = 3:1).

1H-NMR (DCl3)(M. D.): 5,63 (d, J=16.5 Hz, E isomer 1H), of 5.81 (d, J=10,8 Hz, Z-isomer 1H), 7,42-7,52 (m, E-isomer 1H, Z isomer 2H), 7,56 (d, J=16.5 Hz, E isomer 1H), of 7.90-8,16 (m, E-2H isomer, Z-isomer 2N).

Then 32 g of 3-(2-bromo-6-nitrophenyl)-2-propenenitrile (E isomer Z isomer = 3:1) add ethanol (250 ml), tin (60 g) and distilled water (150 ml) followed by heating under stirring at 90°C. To the mixture is added dropwise concentrated hydrochloric acid (256 ml) followed by stirring at the same temperature for 3 hours. After returning to room temperature liquid layer is decanted and cooled to 0°C. the Obtained solid is collected by filtration. To it add aqueous ammonia and the mixture is extracted with ethyl acetate. The extract was concentrated and the residue purified column chromatography (ethyl acetate), using a column of silica gel, receiving 5.0 g specified in the connection header.

1H-NMR (DCl3)(M. D.): 4,88 (2H, CL), 6,79 (1H, d, J=9.3 Hz), 7,39 (1H, t, J=8,9 Hz), 7,51 (1H, d, J=8,9 Hz), to 7.61 (1H, d, J=8,9 Hz), of 8.27 (1H, d, J=9,3 Hz).

An example of obtaining 2b

2-Amino-5-chlorhydrin

Specified/p>

1H-NMR (DCl3)(M. D.): the 5.25 (2H, CL), to 6.80 (1H, d, J 9.7 Hz), 7,32 (1H, DD, J=7.5 Hz, 1.5 Hz), 7,46 (1H, t, J=7.5 Hz), EUR 7.57 (1H, m), 8,30 (1H, d, J=9.7 Hz, 1.0 Hz).

An example of obtaining 3b

3 Carbethoxy-4-hydroxy-8-bronchioles

A mixture of 50 g (0,291 mol) 2-bromoaniline and 63 g (0,291 mol) diethylethanolamine of malonate heated at 100°C under reduced pressure for 3 hours and then at 200°C for 12 hours. Upon completion of the reaction, the solid reaction mixture is washed with ethyl acetate and the crystals are collected by filtration and dried, receiving 50 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): of 1.26 (3H, t, J=7.2 Hz), 4,21 (2N, K, J=7,2 Hz), 7,34 (1H, t, J=7,6 Hz), 8,03 (1H, DD, J=1.6 Hz and 7.6 Hz), 8,15 (1H, DD, J=1.6 Hz and 7.6 Hz), 8,43 (1H, s), to 11.56 (1H, S).

An example of obtaining 4b

3 Carbethoxy-8-bronchioles

A mixture of 2.5 g (8.4 mmol) of 3-carbethoxy-4-hydroxy-8-brainline and 10 ml of phosphorus oxychloride (III) heated to boiling under reflux for one hour. After the reaction is complete, phosphorus oxychloride (III) is removed and the residue purified using NH silica gel, obtaining 2.6 g of chlorine-containing compounds. Then 500 mg (1.6 mmol) of chlorine-containing compounds dissolved in 20 ml of dioxane, is added to nomu solution was added ethyl acetate and the mixture filtered through celite. The filtrate is washed with saturated salt solution, dried over magnesium sulfate and concentrated. To the residue was added 1 ml of acetic acid mixture and allow to stand for 12 hours and then acetic acid is removed. The residue is subjected to chromatography on a column of silica gel and elute with the solvent (mixture utilized/n-hexane = 1/7) to provide 180 mg specified in the connection header.

1H-NMR (CDCl3)(M. D.): to 1.47 (3H, t, J=7.2 Hz), 4,50 (2N, K, J=7,2 Hz), to 7.50 (1H, t, J=7,6 Hz), to 7.93 (1H, DD, J=1.2 Hz and 7.6 Hz), 8,18 (1H, DD, J=1.2 Hz and 7.6 Hz), cent to 8.85 (1H, d, J=2 Hz), to 9.57 (1H, d, J=2 Hz).

An example of obtaining 5b

3-Amino-8-bronchioles

500 mg (1.8 mmol)of 3-carbethoxy-8-brainline added to a mixture of ethanol (10 ml)/1 n aqueous NaOH solution (10 ml) and the mixture is stirred at room temperature for 3 hours. The ethanol is removed and the residue neutralized 1 N. Hcl. The obtained solid is collected by filtration, washed with water and dried, receiving 450 mg of carboxylic acid. Then 450 mg (1.8 mmol) of carboxylic acid added to 25 ml of tert-butanol. Then added to the mixture of 0.58 ml (2.7 mmol) of DFFA (DPPA) and 0.37 ml (2.7 mmol) of triethylamine, followed by heating at boiling under reflux for 12 hours. The reaction process is/n-hexane = 1:4), getting 352 mg of amide compounds. Then 350 mg (1.1 mmol) of the amide compound is added to a mixed solution of 4 ml methanol/2 ml of concentrated Hcl and the mixture is stirred at room temperature for one hour. The reaction solution is alkalinized water ammonia and extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and then concentrated, receiving 240 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 5,88 (2H, s), 7,13 (1H, d, J=2,8 Hz), 7,24 (1H, DD, J=7,6 Hz and 8.4 Hz), to 7.59-the 7.65 (2H, m), 8,49 (1H, d, J=2,8 Hz).

Example of getting 6b

3-Amino-8-eothinon

Specified in the title compound is obtained from 2-iodoaniline in the same manner as in examples get (3b-5b).

1H-NMR (DMSO-d6)(M. D.): to 5.85 (2H, s), 7,07 (1H, d, J=2,8 Hz), 7,10 (1H, t, J=7,6 Hz), a 7.62 (1H, DD, J=1.2 Hz and 7.6 Hz), of 7.90 (1H, DD, J=1.2 Hz and 7.6 Hz), to 8.45 (1H, d, J=2,8 Hz).

Example of getting 7b

3 Amino-8-cyanohydrin

Specified in the title compound is obtained from 2-cyanoaniline in the same manner as in examples get (3b-5b).

1H-NMR (DMSO-d6)(M. D.): 6,03 (2H, CL), 7,22 (1H, d, J=2,8 Hz), of 7.48 (1H, DD, J=7,2 Hz and 8.4 Hz), to 7.84 (1H, d is n

Specified in the header of the connection will receive the same manner as in examples get (3b-5b).

1H-NMR (CDCl3)(M. D.): 6,00 (2H, s), 7,26 (1H, d, J=2.4 Hz), 7,53 (1H, t, J=7.2 Hz), to $ 7.91 (1H, DD, J=1.6 Hz, 7.2 Hz), of 7.96 (1H, DD, J=1.2 Hz, 8,4 Hz), 8,58 (1H, d, J=2,8 Hz).

Example of getting 9b

3-Amino-8-chlorhydrin

Specified in the header of the connection will receive the same manner as in examples get (3b-5b).

1H-NMR (DMSO-d6)(M. D.): 5,90 (2H, s), 7,17 (1H, d, J=2,8 Hz), 7,33 (1H, t, J=7,6 Hz), 7,46 (1H, d, J=7,6 Hz), 7,58 (1H, d, J=7,6 Hz), charged 8.52 (1H, d, J=2,8 Hz).

Example of getting 10b

3-Amino-8-trifloromethyl

Specified in the header of the connection will receive the same manner as in examples get (3b-5b).

1H-NMR (DMSO-d6)(M. D.): 5,94 (2H, s), 7.23 percent (1H, d, J=2,8 Hz),- of 7.48 (1H, t, J=7,6 Hz), 7,69 (1H, d, J=7,6 Hz), to $ 7.91 (1H, d, J=7,6 Hz), 8,55 (1H, d, J=2,8 Hz).

Example of getting 11b

Ethyl-8-chloro-4-vinylphenol-3-carboxylate

Tributyltinhydride (2.8 ml) and tetranitropentaerithrite (171 mg) are added to 20 ml of a toluene solution containing 2.0 g (7.4 mmol) of ethyl-4,8-dichlorohydrin-3-carboxylate obtained in the same manner as in the example of obtaining 4b, followed by stirring for 2 hours at their. Then the resulting residue is purified by chromatography on silica gel, receiving 1.92 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): of 1.36 (3H, t, J=7,6 Hz), 4,37 (2H, d, J=7,6 Hz), 5,52 (1H, d, J=18,0 Hz), to 5.58 (1H, d, J=16.4 Hz), 7,40 (1H, DD, J=16,4 and 18.0 Hz), of 7.70 (1H, t, J=8.0 Hz), 8,11 (1H, d, J=8.0 Hz), of 8.25 (1H, d, J=8.0 Hz), 9,24 (1H, s).

Example of getting 12b

3-Amino-8-chloro-4-vinylphenol

Specified in the title compound is obtained from ethyl-4-vinyl-8-chlorhydrin-3-carboxylate in the same manner as in the example of obtaining 5b.

1H-NMR (DMSO-d6)(M. D.): 5,69 (1H, DD, J=1,6 and 18.0 Hz), of 5.81 (2H, s), of 5.84 (1H, DD, J=1,6, and 11.6 Hz), 6,91 (1H, DD, J=11,6 and 18.0 Hz), 7,38 (1H, t, J=8.0 Hz), 7,52 (1H, DD, J=1,2, 8.0 Hz), the 7.85 (1H, DD, J=1,2, 8.0 Hz), at 8.60 (1H, s).

Example of getting 13b

Ethyl-7-amino-2-chlorhydrin-4-carboxylate 43 g (231 mmol) of diethylaminoacetate added to 25 g (231 mmol) of metaphenylenediamine and the mixture was stirred at 160°C for one hour. After cooling, the crystals are washed with methanol. To a solution (30 ml) of chloroform containing 3.0 g (13 mmol) of crystals, add oxychloride phosphorus (III) (3.6 ml) followed by heating at boiling under reflux for one hour. After cooling, the mixture was poured into a mixture of ice - water and alkalinized rat evaporated, getting 4,85 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): of 1.31-1.42 (3H, m), 4,34-to 4.46 (2H, m), 6,92 (1H, d, J=2.4 Hz), 7,12 (1H, DD, J=2,4, 9,2 Hz), 7,40 (1H, s), 8,21 (1H, d, J=9,2 Hz).

Example of getting 14b

2 Benzylthio-4-methoxypyridazine

843 mg (21 mmol, 55% oily) of sodium hydride are suspended in dimethyl sulfoxide (30 ml). Under ice cooling there is added 2.0 ml (16,7 mmol) benzylmercaptan, followed by stirring for 10 minutes. To the reaction mixture is added 2.5 g (17.6 mmol) of 4-methoxy-2-chloropyridazine, followed by stirring at room temperature over night. To the reaction mixture is added aqueous saturated ammonium chloride followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated. Then the resulting residue is purified by chromatography on silica gel, receiving 1.63 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 3,98 (3H, s), 4,48 (2H, s), 7,12 (1H, d, J=8,8 Hz), 7,22-7,26 (1H, m), 7,29-7,37 (2H, m), 7,41-7,44 (2H, m), EUR 7.57 (1H, d, J=8,8 Hz).

Example of getting 15b

2 Benzylthio-4-carboxamidine

Thionyl chloride (120 ml) are added to 25 g (159 mmol) of 2-chlorisondamine coldenia the mixture is evaporated, receiving the remainder. The solution (200 ml) of tetrahydrofuran containing residue is poured into a mixed solution of aqueous ammonia (200 ml) and tetrahydrofuran (200 ml) under cooling with ice. After stirring under ice cooling for 15 minutes, the mixture is evaporated. The crystals are collected by filtration and washed with water, receiving and 22.6 g of white crystals. of 4.2 ml (36 mmol) of benzyltoluene and 10 g (77 mmol) of potassium carbonate are added to a solution of dimethylformamide containing 5,13 g (32 mmol) of white crystals, and the mixture is stirred under heating at boiling under reflux for 3 hours. To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and evaporated. Then the resulting residue is purified by chromatography on silica gel and the obtained crystals are washed with hexane, gaining 6.3 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): to 4.46 (2H, s), 7,22-7,33 (3H, m), 7,41 (2H, d, J=7,2 Hz), 7,49 (1H, DD, J=1,6, 5,2 Hz), to 7.67 (1H, s), 7,73 (1H, s), 8,21 (1H, s), 8,58 (1H, d, J=5,2 Hz).

Example of getting 16b

7-Amino-2-chloro-4-methylinosine

32 ml (251 mmol) of ethylacetoacetate added to 27 g (251 mmol) of metaphenylenediamine and the mixture perimetre (III) are added to 9.5 g (54 mmol) of the crystals and then heated to boiling under reflux for 2 hours. After cooling, the reaction mixture was poured into a mixture of ice - water and alkalinized water saturated with ammonia. The resulting crystals are collected by filtration and washed with water. The crystals are washed with methanol and the filtrate is evaporated, getting 4,85 g specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 3,18 (3H, s), 5,95 (2H, s), PC 6.82 (1H, d, J=2.4 Hz), 6,98 (1H, s), 7,01 (1H, DD, J=2,4, 8,8 Hz), 7,76 (1H, d, J=8,8 Hz).

Example of getting 17b

3,4-Dihydroisoquinoline

N-Bromosuccinimide (39,2 g) are added to a solution (300 ml) of methylene chloride containing 26,67 g (0.2 mol) of 1,2,3,4-tetrahydroisoquinoline under ice cooling for 20 minutes. After stirring for 40 minutes to the reaction solution was added 30% aqueous sodium hydroxide solution (130 ml). The organic layer is washed with water and then extracted with 10% aqueous hydrochloric acid (200 ml). The aqueous layer was washed with methylene chloride and then alkalinized water ammonia and then extracted with methylene chloride. The extract is dried over magnesium sulfate and then evaporated. The obtained residue distil (approximately 16 mm Od, 120°C) receiving a 21.5 g specified in the connection header in the form of oil.

1H-NMR (DMSO-d6)

7-Nitroisoquinoline

15 g of potassium nitrite is added to concentrated sulfuric acid (70 ml) and there is added a solution containing 18 g (0.14 mol) of 3,4-dihydroisoquinoline at -15°C for 20 minutes. After stirring at room temperature for one hour, the mixture is heated at 60°C for 40 minutes. The reaction solution was poured into a mixture of ice - water and alkalinized water ammonia. The mixture is extracted with ethyl acetate and the organic layer was washed with saturated salt solution and dried over magnesium sulfate. After concentration the residue add decalin (100 ml), nitrobenzene (100 ml) and 2 g of Pd-mobiles and the mixture is heated at 200°C for the night in a stream of nitrogen. The reaction solution is washed with ethyl acetate and then extracted with 2 N. hydrochloric acid. The aqueous layer was washed with ethyl acetate and then there is added aqueous sodium hydroxide. The obtained precipitates are collected by filtration and washed with water, getting to 14.4 g specified in the connection header.

1H-NMR (CDCl3)(M. D.): 7,79 (1H, d, J=5.6 Hz), 8,00 (1H, d, J=9,2 Hz), 8,48 (1H, DD, J=2,4 Hz and 9.2 Hz), the rate of 8.75 (1H, d, J=5.6 Hz), 8,96 (1H, d, J=2 Hz), 9,48 (1H, s).

Example of getting 19b

4-Bromo-7-nitroisoquinoline

1.2 ml of water NVG and 3 ml of bromine dobergirl with ethyl acetate. The extract is successively washed with aqueous sodium hydroxide, aqueous sodium thiosulfate and saturated salt solution, dried over magnesium sulfate and concentrated. Then the obtained residue is purified column chromatography on silica gel (elute with hexane - hexane:ethyl acetate = 4:1) to give 500 mg specified in the connection header.

1H-NMR (CDCl3)(M. D.): at 8.36 (1H, d, J=9,2 Hz), 8,58 (1H, d, J=2,4 Hz and 9.2 Hz), 8,93 (1H, s), 8,96 (1H, d, J=3.2 Hz), 9,38 (1H, s).

Example of getting 20b

7-Amino-4-bromoisoquinoline

66 mg (0.26 mmol) of 7-nitro-4-bromoisoquinoline dissolved in 1 ml ethanol, 2 ml of tetrahydrofuran and 1 ml of water. To the mixture is added 70 mg of iron powder and 140 mg of ammonium chloride, followed by heating at 50°C for 3 hours. To the reaction solution was added 1 N. aqueous sodium hydroxide and the mixture extracted with chloroform. The organic layer is dried over magnesium sulfate and concentrated. The resulting residue is crystallized from isopropyl ether, receiving 33 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 5,98 (2H, s), 6,97 (1H, d, J=2.4 Hz), 7,31 (1H, DD, J=2,4 Hz and 8.8 Hz), of 8.28 (1H, s) 8,89 (1H, s).

Example of getting 21b

6-(4-Toluensulfonate)isoquinoline

6-Aminoleban by stirring at room temperature over night. To this water is added and the mixture extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and the residue recrystallized from ethanol, getting mentioned in the title compound (5,958 g, 85%) as pale yellow crystals.

1H-NMR (DMSO-d6)(M. D.): 2,28 (3H, s), 7,32 (2H, D, J=8,2 Hz), 7,40 (1H, DD, J=1,6, 9,2 Hz), 7,55 (1H, CL), to 7.67 (1H, d, J=5.6 Hz), 7,74 (2H, d, J=8,2 Hz), of 7.97 (1H, d, J=9,2 Hz), at 8.36 (1H, d, J=5.6 Hz), 9,10 (1H, s).

Example of getting 22b

1-Chloro-6-(4-toluensulfonate)isoquinoline

6-(4-Toluensulfonate)isoquinoline (3.0 g, an example of obtaining 21b) is dissolved in chloroform (100 ml). Under ice cooling, to the solution was added m-chloroperbenzoic acid (2.57 m) g), followed by stirring at room temperature over night. The solvent is evaporated and the resulting crystals are washed with diethyl ether, collected by filtration and dried, obtaining a pale-yellow crystals. The crystals are suspended in chloroform (83 ml) and to it added phosphorus oxychloride (III) (19 ml) followed by heating at boiling under reflux for 5 hours. After cooling, the solvent is evaporated. The residue is alkalinized by adding at xtract washed with saturated salt solution and dried over anhydrous magnesium sulfate and the solvent is evaporated. The residue is purified on a column of silica gel, give crude crystals specified in the connection header (1,630 g, 49,40%). The crystals are recrystallized from ethanol, getting mentioned in the title substance as a colorless crystals.

1H-NMR (DMSO-d6)(M. D.): to 2.29 (3H, s), 7,34 (2H, d, J=8.0 Hz), 7,52 (1H, DD, J=2.0 a, 9,0 Hz), the 7.65 (1H, d, J=2.0 Hz), 7,76 (1H, d, J=5.6 Hz), to 7.77 (2H, d, J=8.0 Hz), 8,14 (1H, d, J=9.0 Hz), 8,16 (1H, d, J=5.6 Hz).

Example of getting 23b

6-Amino-1-chloroisoquinoline

1-Chloro-6-(4-toluensulfonate)isoquinoline (3,323 g, an example of obtaining 22b) is dissolved in sulfuric acid (30 ml) followed by stirring at room temperature over night. The resulting solution was poured on ice and alkalinized by adding an aqueous solution of sodium hydroxide and then potassium carbonate, and then extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound (1,37 g, 76,81%) as yellowish-brown crystals.

1H-NMR (DMSO-d6)(M. D.): 6,23 (2H, CL), 6,76 (1H, s), to 7.09 (1H, d, J=9.6 Hz), 7,37 (1H, d, J=6.4 Hz), 7,89 (1H, d, J=9.6 Hz), of 7.90 (1H, d, J=6,4 Hz).

Example of getting 24b

2-Chloro-1,6-naphthiridine

1H-NMR (CDCl3)(M. D.): at 7.55 (1H, d, J=8,8 Hz), 7,86 (1H, d, J=6.0 Hz), of 8.28 (1H, d, J=8,8 Hz), 8,80 (1H, d, J=6.0 Hz), 9,29 (1H, s).

Example of getting 25b

2-Amino-1,6-naphthiridine

2-Chloro-1,6-naphthiridine (0,628 g, an example of obtaining 22b) and aqueous ammonia (40 ml) is heated at 130°C for 11 hours in a sealed vessel. After cooling, the mixture is extracted with ethyl acetate and the extract washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and the residue purified on a column of silica gel, receiving specified in the header connection (0,497 g, 89,73%) as pale yellow crystals.

1H-NMR (DMSO-d6)(M. D.): for 6.81 (1H, d, J=8,8 Hz), 7,24 (1H, d, J=5.8 Hz), of 7.97 (1H, d, J=8,8 Hz), a 8.34 (1H, d, J=5.8 Hz), 8,80 (1H, s).

Example of getting 26b

N-(3-Nitrophenacyl)phthalimide

3-Nitrophenetole alcohol (15 g) dissolved in tetrahydrofuran (225 ml).NML add diethylazodicarboxylate (15,5 ml). After stirring at room temperature for one hour, the resulting crystals are collected by filtration, washed with diethyl ether and dried, obtaining N-(3-nitrophenacyl)phthalimide in the form of colorless crystals.

1H-NMR (CDCl3)(M. D.): of 3.12 (2H, t, J=7.4 Hz), 3,98 (2H, t, J=7.4 Hz), 7,47 (1H, DD, J=8,0, 8.0 Hz), 7,60 (1H, d, J=8.0 Hz), 7,72 (2H, m), 7,83 (2H, m), of 8.09 (1H, d, J=8.0 Hz), to 8.12 (1H, s).

Example of getting 27b

3-Nitrophenetole

N-(3-Nitrophenacyl)phthalimide received in the sample receiving 26b, suspended in ethanol (150 ml). To the mixture is added hydrazine (5.7 ml) followed by heating at boiling under reflux for one hour. The reaction solution at a time is completely dissolved, however, crystals are precipitated again. The crystals are filtered and washed with chilled ethanol. Then the solvent is evaporated, getting mentioned in the title compound (5,559 g, 99%) as a yellow oil.

1H-NMR (CDCl3)(M. D.): 2,87 (2H, t, J=6.8 Hz), totaling 3.04 (2H, t, J=6.8 Hz), of 7.48 (1H, DD, J=7,6, and 8.4 Hz), 7,55 (1H, DDD, J=1,2, of 1.6 and 7.6 Hz), 8,08 (2H, m)

Example of getting 28b

N-Acetyl-N-(3-nitrophenacyl)Amin

3-Nitrovanillin (5,559 g, an example of obtaining 25b) is dissolved in pyridine (33 ml) and restore for 0.5 hours the mixture was again cooled with ice. It added water and extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound (6,323 g, 91%) as a yellow oil.

1H-NMR (CDCl3)(M. D.): 1,97 (3H, s), 2,95 (2H, t, J=7.0 Hz), 3,55 (2H, dt, J=6,0, 7,0 Hz), the ceiling of 5.60 (1H, CL), 7,49 (1H, DD, J=7,2, 8.0 Hz), 7,55 (1H, d, J=7,2 Hz), 8,07 (1H, s) to 8.12 (1H, d, J=8.0 Hz).

Example of getting 29b

N-Acetyl-N-(3-aminophenethyl)Amin

N-Acetyl-N-(3-nitrophenacyl)amine (2.1 g, an example of obtaining 28b) is dissolved in ethanol (40 ml). To the mixture is added iron powder (2.25 g), ammonium acetate (4.3 g) and water (20 ml) followed by heating at boiling under reflux for 1.5 hours. The solid is filtered off and washed with ethanol and then the filtrate is partially evaporated. The residue is extracted with ethyl acetate, washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound (1,723 g, 96%) as a yellow oil.

1H-NMR (CDCl3)(M. D.): 1,94 (3H, s), of 2.72 (2H, t, J=6.8 Hz), 3,50 (2H, dt, J=6,0, 6,8 Hz), 6,53 (1H, s), to 6.57 (1H, d, J=8.0 Hz), 6,59 (1H, d, J=7,2 Hz), 7,10 (1H, DD, J=7,2, 8.0 Hz).

Example of getting 30b

1H-NMR (CDCl3)(M. D.): of 1.29 (3H, t, J=7.2 Hz), of 1.93 (3H, s), was 2.76 (2H, t, J=7.0 Hz), 3,47 (2H, dt, J=6,0, 7,0 Hz), 4,20 (2N, K, J=7,2 Hz), to 5.57 (1H, CL), 6,86 (1H, d, J=7,2 Hz), 7,21 (1H, DD, J=7,2, 8.0 Hz), 7,28 (1H, d, J=8.0 Hz), 7,29 (1H, s).

Example of getting 31b

6 Ethoxycarbonyl-1-methyl-3,4-dihydroisoquinoline

Using N-acetyl-N-(3-ethoxycarbonylmethyl)amine (1.0 g, example get 30b), carry out the cyclization reaction according to the method described in Heterocycles 31 (2), 341 (1990). Upon completion of the reaction, the reaction solution was poured on ice and alkalinized with potassium carbonate. Then the solution is extracted with ethyl acetate and the extract washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound as a brown oil.

1H-NMR J=7,2 Hz), 7,31 (1H, d, J=6.8 Hz), 7,32 (1H, s), 7,34 (1H, d, J=6,8 Hz).

Example of getting 32b

6 Ethoxycarbonyl-1-methylisoquinoline

p-CYmen (100 ml) and palladium on carbon (0.9 g) is added to 6-ethoxycarbonyl-1-methyl-3,4-dihydroisoquinoline followed by heating under stirring at 195°C for one hour in nitrogen atmosphere. The catalyst is filtered off and washed with ethanol and then the filtrate is partially evaporated. After extraction with 1 N. hydrochloric acid extract is alkalinized with potassium carbonate and then extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous anhydride magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound (0,629 g, 69%, stage 2) in the form of pale yellow crystals.

1H-NMR (CDCl3)(M. D.): of 1.30 (3H, t, J=7.2 Hz), 2,89 (3H, s), 4.26 deaths (2N, K, J=7,2 Hz), 7,40 (1H, d, J=5.8 Hz), 7,56 (1H, DD, J=1,6, 8,8 Hz), to 7.99 (1H, d, J=8,8 Hz), with 8.05 (1H, d, J=1.6 Hz), 8,30 (1H, d, J=5.6 Hz), of 8.37 (1H, s).

Example of getting 33b

6-Amino-1-methylisoquinoline

6 Ethoxycarbonyl-1-methylisoquinoline (0,629 g, an example of obtaining 32b) is dissolved in ethanol (20 ml) and to this solution is added then 8 N. aqueous sodium hydroxide solution (6.8 ml) followed by heating at the boiling is on the ammonium chloride and the mixture extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound (0,311 g, 72%) as pale yellow crystals.

1H-NMR (CDCl3)(M. D.): 2,81 (3H, s), 4,24 (2H, CL), 6,60 (1H, d, J=2.0 Hz), 6,91 (1H, DDD, J=1,6, 2,0, 8,8 Hz), 7,18 (1H, d, J=5.6 Hz), to 7.84 (1H, d, J=8,8 Hz), 8,16 (1H, DD, J=1,6, 5,6 Hz).

Example of getting 34b

N-t-Butoxycarbonyl-3-nitrophenetole

3-Nitrovanillin (4,559 g, an example of obtaining 27b) is dissolved in tetrahydrofuran (130 ml) and to this solution is then added triethylamine (8,4 ml) and di-tert-BUTYLCARBAMATE (6.6 g), followed by stirring at room temperature for 2 hours. After evaporation of the solvent added a saturated salt solution and the mixture is then extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound (8,789 g, including impurities) as a yellow oil. Specified substance used in the next reaction without further purification.

1H-NMR (CDCl3)(M. D.): 1,53 (N, C) of 2.92 (2H, t, J=7,6 Hz), 3,42 (2H, dt, J=6,4, 6,8 Hz), 4,58 (1H, CL), of 7.48 (1H, DD, J=7,2, 8.0 Hz), 7,5 p>Specified in the header connection (5,521 g, 76%) was obtained as a yellow oil using N-tert-butoxycarbonyl-3-nitrovanillin (8,789 g, including impurities, the sample receiving 34b), in the same way as in the example of obtaining 170b.

1H-NMR (CDCl3)(M. D.): 1,44 (N, C) 2,70 (2H, t, J=7.4 Hz), to 3.36 (2H, SHK), of 4.54 (1H, CL), is 6.54 (1H, s), to 6.57 (1H, d, J=8.0 Hz), 6,60 (1H, d, J=7,2 Hz), 8,10 (1H, DD, J=7,2, 8.0 Hz).

Example of getting 36b

3-(2-Butoxycarbonylamino)ethoxycarbonylmethyl

Specified in the header connection (0,320 g) are obtained as a yellow oil by using 3-(2-tert-butoxycarbonylamino)aniline (5,521 g, an example of obtaining 35b) in the same way as in the example of obtaining 29b. Specified substance used in subsequent reactions without additional purification.

1H-NMR (CDCl3)(M. D.): is 1.31 (3H, t, J=7.2 Hz), 1,43 (N, C) 2,77 (2H, t, J=7.4 Hz), to 3.67 (2H, SHK), 4,22 (2N, K, J=7,4 Hz), 4,55 (1H, CL), of 6.52 (1H, CL), 6,89 (1H, m), 7,24 (1H, m).

Example of getting 37b

3-Ethoxycarbonylmethylene hydrochloride

3-(2-tert-Butoxycarbonylamino)ethoxycarbonylmethyl (14,96 g, an example of obtaining 36b) is dissolved in ethanol (15 ml) and to this were then added hydrochloric acid (15 ml) at okhlazhdennuyu acid (12 ml) and ethanol (15 ml) and then stirred at room temperature for 20 minutes. Then add hydrochloric acid (20 ml) and ethanol (30 ml) and stirred at room temperature for 30 minutes. After evaporation (exposing azeotropic distillation with toluene) solvent receive specified in the header connection (11,99 g) as pale yellow crystals.

1H-NMR (DMSO-d6)(M. D.): 1,22 (3H, t, J=7.2 Hz), 2,82 (2H, m), 2,95 (2H, m), 4,10 (2H, K, J=7,2 Hz), 6,86 (1H, d, J=7,6 Hz), 7,20 (1H, DD, J=7,6, and 8.4 Hz), 7,31 (1H, d, J=8,4 Hz), was 7.36 (1H, s), with 8.05 (2H, CL), being 9.61 (1H, C).

Example of getting 38b

6-amino-ethyl-1,2,3,4-tetrahydroisoquinoline

Specified the title compound (4,226 g, including impurities) are obtained as a yellow oil using 3-ethoxycarbonylmethylene hydrochloride (4.7 g) obtained in example obtaining 39b, in accordance with the method described in Chem. Pharm. Bull. 42 (8), 1676 (1994).

1H-NMR (CDCl3)(M. D.): of 1.29 (3H, t, J=7.2 Hz), 2,68 (1H, CL), and 2.83 (3H, m), of 3.73 (2H, m), 4,20 (2N, K, J=7,2 Hz), 6,77 (1H, s) 6,94 (1H, d, J=8,4 Hz), 7,07 (1H, d, J=8,4 Hz), 7,18 (1H, CL).

Example of getting 39b

6-Ethoxycarbonylmethylene

p-CYmen (100 ml) and palladium on carbon (0.9 g) is added to 6-amino-ethyl-1,2,3,4-tetrahydroisoquinoline (10 g, example get 38b) followed by heating under stirring at what anolon. Then, the filtrate evaporated and the obtained crystals are washed with diethyl ether and dried. The solvent is evaporated, getting mentioned in the title compound (6,51 g, 66%) as pale yellow crystals.

1H-NMR (CDCl3)(M. D.): of 1.36 (3H, t, J=7.2 Hz), 3,74 (1H, m), 4,29 (2N, K, J=7,2 Hz), 6,70 (1H, d, J=2.0 Hz), 7,46 (1H, DD, J=2.0 a, 8,8 Hz), 7,58 (1H, d, J=6.0 Hz), of 7.90 (1H, d, J=8,8 Hz), of 8.04 (1H, CL), 8,46 (1H, d, J=6.0 Hz), 9,13 (1H, s).

Example of getting 40b

6-Ethoxycarbonylmethyl-N-oxide

Specified in the title compound (293 mg) was obtained as yellow crystals using 6-ethoxycarbonylmethylene (250 mg, example of getting 39b), in the same way as in the example of obtaining 22b.

1H-NMR (DMSO-d6)(M. D.): a 1.25 (3H, t, J=7.2 Hz), 4.26 deaths (2N, K, J=7,2 Hz), to 7.61 (1H, DD, J=2.0 a, 8,8 Hz), 7,79 (1H, d, J=8,8 Hz), 7,81 (1H, d, J=7,2 Hz), of 8.04 (1H, DD, J=2.0 a, 7,2 Hz), 8,79 (1H, s), 8,46 (1H, d, J=6.0 Hz), 9,13 (1H, s).

Example of getting 41b

1-Chloro-6-ethoxycarbonylmethyl

Specified in the title compound (173 mg, 60%, stage 2) are obtained in the form of pale yellow crystals, using 6-ethoxycarbonylmethyl-N-oxide (250 mg) in the same way as in the example of obtaining 22b.

1H-NMR (CDCl3)(M. D.): of 1.34 (3H, t, J=7.2 Hz), 4,29 (42b is possible

1-Methoxy-6-methoxycarbonylaminophenyl

1-Chloro-6-ethoxycarbonylmethyl of 2.27 g, an example of obtaining 41b) dissolved in dimethyl sulfoxide (45 ml) and to this solution is then added a 28% solution of sodium methoxide (8,7 ml) followed by heating under stirring at 110°C for 1.5 hours. After cooling to room temperature, add aqueous saturated ammonium chloride and the mixture extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound (1.75 g, 84%) as a brown oil.

1H-NMR (CDCl3)(M. D.): 3,74 (3H, s), a 4.03 (3H, s), 7,05 (1H, d, J=5.8 Hz), 7,41 (1H, DD, J=2.0 a, 9,2 Hz), 7,86 (1H, d, J=5.8 Hz), of 7.90 (1H, CL), of 8.06 (1H, d, J=9,2 Hz), 8,08 (1H, CL).

Example of getting 43b

6-Amino-1-methoxyethanol

Specified in the title compound (1.04 g, 99%) was obtained as pale-brown crystals, using 1-methoxy-6-methoxycarbonylaminophenyl (1.75 g, an example of obtaining 42b) and methanol as a solvent, in the same way as in the example of obtaining 41b.

1H-NMR (CDCl3)(M. D.): 4,07 (3H, s) 4,07 (2H, CL), is 6.78 (1H, d, J=2.2 Hz), to 6.88 (1H, DD, J=2,2, 8,8 Hz) Specified in the header connection (3,070 g, 77%, including impurities) are obtained as a yellow oil using 3-nitrovanillin (3.0 g, an example of obtaining 27b) and propionate (2.5 ml), in the same way as in the example of obtaining 28b.

1H-NMR (CDCl3)(M. D.): to 1.14 (3H, t, J=7,6 Hz), 2,19 (2N, K, J=7,6 Hz), 2,96 (2H, t, J=6.8 Hz), of 3.56 (2H, dt, J=6,4, 6,8 Hz), 7,49 (1H, DD, J=7,6, 8.0 Hz), 7,55 (1H, d, J=7,6 Hz), 8,07 (1H, s), 8,10 (1H, d, J=8.0 Hz).

Example of getting 45b

N-Propionyl(3-aminophenethyl)Amin

N-Propionyl(3-nitrophenacyl)Amin (3,070 g, an example of obtaining 44b) is used to perform the reaction in the same manner as in the example of obtaining 29b. The resulting residue is purified by using a column with silica gel, receiving specified in the header connection (0,857 g, 32%) as a pale yellow oil.

1H-NMR (CDCl3)(M. D.): of 1.12 (3H, t, J=7,6 Hz), 2,19 (2N, K, J=7,6 Hz), a 2.71 (2H, t, J=6, 8 Hz), 3,49 (2H, dt, J=6,0, 6,8 Hz) to 5.56 (1H, CL), of 6.52 (1H, s), 6,56 (1H, d, J=7,6 Hz), 6,56 (1H, d, J=7,6 Hz), to 7.09 (1H, DD, J=7,6, 7,6 Hz).

Example of getting 46b

N-Propionyl(3-ethoxycarbonylmethyl)Amin

N-Propionyl(3-aminophenethyl)Amin (0,857 g, an example of obtaining 44b) is used to perform the reaction in the same manner as in the example of obtaining 30b. The obtained residue is purified on a column of silica gel, receiving specified in">(M. D.): of 1.12 (3H, t, J=7,6 Hz) of 1.30 (3H, t, J=7.0 Hz), 2,16 (2N, K, J=7,6 Hz), 2,78 (2H, t, J=6.8 Hz), 3,50 (2H, dt, J=6,0, 6,8 Hz), 4,21 (2N, K, J=7,0 Hz), to 6.67 (1H, CL), 6,87 (1H, d, J=6.8 Hz), 7,00 (1H, CL), 7,22 (1H, DD, J=6,8, and 8.4 Hz), 7,26 (1H, d, J=8,4 Hz), 7,28 (1H, s).

Example of getting 47b

6 Ethoxycarbonyl-1-utilizacion

6 Ethoxycarbonyl-1-ethyl-3,4-dihydroisoquinoline receive in the form of brown crystals using N-PROPYNYL-(3-ethoxycarbonylmethyl)Amin (0,747 g, an example of obtaining 46b), in the same manner as in examples get 31b-32b, and in this case, specified in the header connection (0,516 g, 75%, stage 2) are obtained in the form of a yellow oil.

Characteristics of the intermediate and specified in the header connections are as follows.

6 Ethoxycarbonyl-1-ethyl-3,4-dihydroisoquinoline

1H-NMR (CDCl3)(M. D.): to 1.21 (3H, t, J=7,6 Hz) of 1.30 (3H, t, J=7,0 Hz) to 2.66 (2H, t, J=7.4 Hz), 2,74 (2N, K, J=7,6 Hz) to 3.64 (2H, t, J=7.4 Hz), 4,23 (2N, K, J=7,0 Hz), 7,32 (1H, d, J=8,4 Hz), 7,37 (1H, s), the 7.43 (1H, d, J=8,4 Hz), 7,79 (1H, s).

6 Ethoxycarbonyl-1-utilizacion

1H-NMR (CDCl3)(M. D.): to 1.32 (3H, t, J=7.0 Hz), of 1.41 (3H, t, J=7,6 Hz), 3.27 to (2N, K, J=7,6 Hz), 4,27 (2N, K, J=7,0 Hz), 7,40 (1H, d, J=6.0 Hz), 7,52 (1H, DD, J=2.0 a, 8,8 Hz), 7,89 (1H, s), 8,02 (1H, d, J=2.0 Hz), of 8.25 (1H, d, J=8,8 Hz), a 8.34 (1H, J=6.0 Hz).

An example of receiving the x crystals, using 6-ethoxycarbonyl-1-utilizacion (0,516 g, an example of obtaining 47b), in the same way as in the example of obtaining 33b.

1H-NMR (CDCl3)(M. D.): is 1.31 (3H, t, J=7.2 Hz), 3,21 (2N, K, J=7,2 Hz), 4,20 (2H, CL), PC 6.82 (1H, d, J=2.4 Hz), to 6.95 (1H, DD, J=2,4, 8,8 Hz), 7,21 (1H, d, J=6.0 Hz), 7,94 (1H, d, J=8,8 Hz), 8,24 (1H, d, J=6.0 Hz).

Example of getting 49b

1-Methoxy-4-(3-nitrophenyl)propane-1-ene

Chloride methoxymetopon (31.1 grams) is suspended in tetrahydrofuran (200 ml) and then this under cooling with ice add tert-piperonyl potassium (10.2 g). After the reaction solution will change color to red, it gradually, using the eyedropper, add a solution obtained by dissolving 3-nitroacetophenone (10 g) in tetrahydrofuran (100 ml). After stirring at room temperature for 2.5 hours added under cooling with ice, aqueous saturated ammonium chloride. The mixture is extracted with ethyl acetate and the extract washed with saturated salt solution and dried over anhydride magnesium sulfate. The solvent is evaporated and the resulting residue is purified by using a column with silica gel, receiving specified in the header connection (8,010 g) as a yellow oil.

Example of getting 50b

2-(3-Nitrophenyl)propanal

2 N. hloristovodorodnykh 80°C for 4 hours. Then to this add hydrochloric acid (5 ml) followed by heating at boiling under reflux for 2.5 hours. After cooling, the mixture is neutralized with an aqueous solution of sodium hydroxide and extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound (7,531 g) as a yellow oil.

Example of getting 51b.

2-(3-Nitrophenyl)propan-1-ol

2-(3-Nitrophenyl)propanal (7,531 g) dissolved in ethanol (100 ml) and to this solution is then added borohydride sodium (1.9 g) under ice cooling, followed by stirring at room temperature for one hour. The reaction mixture was added a saturated salt solution, followed by extraction with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The residue obtained by evaporation of the solvent, purified through column with silica gel, receiving specified in the header connection (6,275 g, 57,19% for 3 stages) as a brown oil.

1H-NMR (CDCl3)(M. D.): of 1.34 (3H, d, J=6,8 Hz) and 1.51 (1H, CL), to 3.09 (1H, TK, J=6,8, 6,8 Hz), of 3.78 (2H, d, J=6.8 Hz), to 7.50 (1H, DD, J=7,6, 8,4 G is repellin

Specified in the title compound obtained as a yellow oil using 2-(3-nitrophenyl)propan-1-ol (1,908 g, an example of obtaining 51b), in the same manner as in examples get 26b-27b.

Example of getting 53b

1-tert-Butoxycarbonylamino-2-(3-nitrophenyl)propane

The reaction is carried out using 2-(3-nitrophenyl)Propylamine obtained in example obtaining 52b, in the same way as in the example of obtaining 35b. The obtained residue is purified on a column of silica gel, receiving specified in the header connection (2,626 g) as a yellow oil.

1H-NMR (CDCl3)(M. D.): 1,31 (3H, d, J=6.8 Hz), 1,40 (N, C) 3,10 (1H, m), 3,26 (1H, m) to 3.38 (1H, m), 7,49 (1H, DD, J=7,6, and 8.4 Hz), 7,56 (1H, d, J=7,6 Hz), 8,08 (1H, s), 8,10 (1H, d, J=8,4 Hz).

Example of getting 54b

2-(3-AMINOPHENYL)-1-tert-butoxycarbonylamino

Specified in the title compound obtained as a yellow oil, obtained using 1-tert-butoxycarbonylamino-2-(3-nitrophenyl)propane (2,626 g), in the same way as in the examples of the preparation 29b.

Example of getting 55b

1-tert-Butoxycarbonylamino-2-(3-ethoxycarbonylphenyl)propane

The reaction is carried out using the obtained 2-(3-AMINOPHENYL)-1-tert-butoxycarbonylamino, in the same way as in the example of obtaining 30b. Received stage) as a brown oil.

1H-NMR (CDCl3)(M. D.): a 1.25 (3H, d, J=7,6 Hz) is 1.31 (3H, t, J=7.2 Hz), 1,41 (N, C) 2,90 (1H, m), 3,18 (1H, DDD, J=4,2, 7,6, 9,2 Hz), 3,39 (1H, m), 4,42 (2N, K, J=7,6 Hz), of 4.45 (1H, CL), 6 87 (1H, CL), 6,94 (1H, m), 7,22 (3H, m).

Example of getting 56b

6 Ethoxycarbonyl-4-methyl-1,2,3,4-tetrahydroisoquinoline

Specified in the header connection (2,967 g, crude) receives a yellow solid, using 1-tert-butoxycarbonylamino-2-(3-ethoxycarbonylphenyl)propane (2,960 g, an example of obtaining 55b), in the same manner as in examples get 38b-39b.

Example of getting 57b

6 Ethoxycarbonyl-4-methylisoquinoline

Specified in the header connection (2,061 g, crude) obtained as pale yellow crystals, obtained using 6-ethoxycarbonyl-4-methyl-1,2,3,4-tetrahydroisoquinoline (2,967 g, crude), in the same way as in the example of obtaining 40b.

1H-NMR (CDCl3)(M. D.): of 1.36 (3H, t, J=7.2 Hz), 2,59 (3H, c), 4,30 (2N, K, J=7,2 Hz), 7,12 (1H, d, J=2.0 Hz), 7,49 (1H, DD, J=2.0 a, 8,8 Hz), to $ 7.91 (1H, d, J=8,8 Hz) to 8.12 (1H, s), 8,32 (1H, s), of 9.00 (1H, s).

Example of getting 58b

6-Amino-4-methylisoquinoline

The reaction is carried out using the obtained 6-ethoxycarbonyl-4-methylisoquinoline (2,061 g, crude), in the same way as in the example of the unintended (0,403 g, 27,75% over 4 steps) as pale yellow crystals.

1H-NMR (CDCl3)(M. D.): 2,48 (3H, s), 4,18 (2H, CL), to 6.95 (1H, d, J=2.0 Hz), 7,00 (1H, DD, J=2.0 a, 8,8 Hz), 7,76 (1H, d, J=8,8 Hz), 8,19 (1H, s), 8,86 (1H, s).

Example of getting 59b

2-(3-Nitrophenyl)butane-1-ol

Specified in the header connection (5,456 g, 50,08% for stage 3) are obtained as a yellow oil using 3-nitropropiophenone (10 g) in the same manner as in examples get 52b-55b.

1H-NMR (CDCl3)(M. D.): 0,86 (3H, t, J=7.4 Hz), and 1.63 (1H, m), of 1.85 (1H, m), 3,24 (1H, m), 3,83 (2H, m) to 7.50 (1H, DD, J=7,2, 8.0 Hz), EUR 7.57 (1H, d, J=8.0 Hz), 8,10 (1H, s), 8,13 (1H, d, J=7,2 Hz).

Example of getting 60b

2-(3-Nitrophenyl)butylamine

Specified in the header connection (5,247 g) are obtained as a yellow oil using 2-(3-nitrophenyl)butane-1-ol (5,456 g, an example of obtaining 59b), in the same manner as in examples get 26b-27b.

Example of getting 61b

1-tert-Butoxycarbonylamino-2-(3-nitrophenyl)butane

Consistently the reaction is carried out using the obtained 2-(3-nitrophenyl)butylamine (5,247 g), in the same way as in the example of obtaining 27b. The resulting residue is purified by using a column with silica gel, receiving specified in the header connection (7,679 g) as a pale yellow oil.

1H-NMR (CDCl

Example of getting 62b

2-(3-AMINOPHENYL)-1-tert-butoxycarbonylamino

Specified in the header connection (6,311 g, 85,40% through stage 4) are obtained in the form of a yellow oil, using 1-tert-butoxycarbonylamino-2-(3-nitrophenyl)butane (7,679 g), in the same way as in the example of obtaining 29b.

Example of getting 63b

1-tert-Butoxycarbonylamino-2-(3-ethoxycarbonylphenyl)Bhutan

Specified in the header connection (8,230 g, crude) obtained as an orange solid using the compound obtained in the same manner as in the example of obtaining 30b.

1H-NMR (CDCl3)(M. D.): 0,81 (3H, t, J=7.4 Hz), is 1.31 (3H, t, J=7.2 Hz), 1,40 (N, C) of 1.55 (1H, m), by 1.68 (1H, m), 2.63 in (1H, m), 3,14 (1H, DDD, J=4,8, 8,8, to 13.6 Hz), 3,52 (1H, m), 4,22 (2N, K, J=7,2 Hz), to 4.38 (1H, CL), 6,63 (1H, CL), 6,87 (1H, m), 7.23 percent (3H, m).

Example of getting 64b

6 Ethoxycarbonyl-4-ethyl-1,2,3,4-tetrahydroisoquinoline

Specified in the title compound obtained as a brown oil, using 1-tert-butoxycarbonylamino-2-(3-ethoxycarbonylphenyl)butane (8,230 g, crude, example of getting 63b), in the same manner as in examples get 38b-39b.

Example of getting 65b

6 Ethoxycarbonyl-4 is the nolin (3.0 g) in the same way, as in the example of a 40b. The crude crystals are washed with a mixture of ethanol/diethyl ether and dried, obtaining mentioned in the title compound as orange crystals.

1H-NMR (DMSO-d6)(M. D.): of 1.27 (3H, t, J=7.2 Hz), of 1.28 (3H, t, J=7.2 Hz), 2.91 in (2N, K, J=7,2 Hz), 4,18 (2N, K, J=7,2 Hz), to 7.64 (1H, d, J=8,8 Hz), 8,00 (1H, d, J=8,8 Hz), of 8.25 (1H, s), of 8.27 (1H, s), 8,98 (1H, s), 10,12 (1H, s).

Example of getting 66b

6-Amino-4-utilizacion

The reaction is carried out using 6-ethoxycarbonyl-4-utilizacion in the same way as in the example of obtaining 30b. The resulting residue is purified by using a column with NH-silica gel and the obtained crude crystal was washed with diethyl ether and dried, obtaining specified in the header connection (0,637 g) as orange crystals.

1H-NMR (CDCl3)(M. D.): to 1.35 (3H, t, J=7,6 Hz), 2,92 (2N, K, J=7,6 Hz), 4,17 (2H, CL), of 6.99 (1H, d, J=8,4 Hz), 7,00 (1H, s), to 7.77 (1H, d, J=8,4 Hz), 8,21 (1H, s), 8,86 (1H, s).

Example of getting 67b

Diethyl methyl-(3-nitrobenzyl)malonate

Sodium (0.7 g) is dissolved in ethanol (45 ml) and to this solution is then added diethylmalonate (5,26 ml) and 3-nitrobenzanthrone (5 g) and then heated at the boil under reflux for 2 hours. Sesamiae saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound (9,724 g) as a pale yellow oil.

1H-NMR (CDCl3)(M. D.): 1,27 (6N, t, J=7.2 Hz), of 1.37 (3H, s), 3,32 (2H, s), is 4.21 (4H, K, J=7,2 Hz), 7,44 (1H, d, J=7,6 Hz), of 7.48 (1H, DD, J=7,6, 7,6 Hz), 8,03 (1H, s), 8,11 (1H, d, J=7,6 Hz).

Example of getting 68b

Ethyl 1-methyl-2-(3-nitrophenyl)propionate

The resulting diethyl methyl-(3-nitrobenzyl)malonate (9,724 g) dissolved in dimethyl sulfoxide (30 ml) and then to this solution was added water (0.54 ml) and lithium chloride (2,54 g), followed by stirring under heating at 190°C for 3.5 hours. After cooling, add water and then extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated, getting mentioned in the title compound (5,071 g, 73,35% over 2 stages) as a brown oil.

1H-NMR (CDCl3)(M. D.): of 1.20 (3H, t, J=7.2 Hz), to 1.21 (3H, d, J=7,2 Hz), and 2.79 (2H, m), 3,10 (1H, m), 4,10 (2H, K, J=7,2 Hz), was 7.45 (1H, DD, J=7,6, 8.0 Hz), 7,52 (1H, d, J=7,6 Hz), of 8.06 (1H, s), 8,08 (1H, d, J=8.0 Hz).

Example of getting 69b

1-Methyl-2-(3-nitrophenyl)propionic acid

Ethyl 1-methyl-2-(3-nitrophenyl)propionate (5,071 g, an example of obtaining 68b) is dissolved in ethanol (50 ml) and to this under reflux for 2.5 hours. After cooling, add diethyl ether and water and the aqueous layer was separated. The organic layer is extracted with aqueous saturated sodium bicarbonate. The aqueous layers are combined acidified with dilute hydrochloric acid and then extracted with diethyl ether. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and the resulting residue is purified by using a column with silica gel, receiving specified in the header connection (2,918 g, 65,27%) as a red oil.

1H-NMR (CDCl3)(M. D.); to 1.24 (3H, d, J=6.0 Hz), and 2.83 (2H, s), and 3.16 (1H, m), 7,47 (1H, DD, J=7,2, 8.0 Hz), 7,54 (1H, d, J=7,2 Hz), 8,08 (1H, s), 8,10 (1H, d, J=8.0 Hz).

Example of getting 70b

N-BOC-1-methyl-2-(3-nitrophenyl)ethylamine

1-Methyl-2-(3-nitrophenyl)propionic acid (2,918 g, an example of obtaining 69b) is dissolved in tert-butanol (36 ml) and to this solution is then added triethylamine (4.09 to ml) and diphenylphosphoryl followed by heating at boiling under reflux for 2.5 hours. After cooling, the solvent is evaporated. Add aqueous saturated sodium bicarbonate and then extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous sulfat the title compound (2,117 g, 54,14%) as yellow crystals.

1H-NMR (CDCl3)(M. D.): of 1.13 (3H, d, J=6.8 Hz), 2,82 (1H, m), of 2.92 (1H, m), of 3.94 (1H, CL), 7,47 (1H, DD, J=7,2, 8.0 Hz), 7,54 (1H, d, J=7,2 Hz), with 8.05 (1H, s), of 8.09 (1H, d, J=8.0 Hz).

Example of getting 71b

N-BOC-2-(3-AMINOPHENYL)-1-methylethylamine

The reaction is carried out using N-BOC-1-methyl-2-(3-nitrophenyl)ethylamine (2,117 g, an example of obtaining 70b) in the same way as in the example of obtaining 29b. After extraction, the obtained residue is purified on a column of silica gel, receiving specified in the header connection (0,976 g, 51,63%) as a yellow oil.

Example of getting 72b

N-BOC-1-methyl-2-(3-ethoxycarbonylphenyl)ethylamine

Specified in the header connection (1,173 g, crude) obtained as a yellow oil using N-BOC-2-(3-AMINOPHENYL)-1-methylethylamine (0,976 g), in the same way as in the example of obtaining 30b. The compound obtained is used in the subsequent reaction without performing additional cleanup.

1H-NMR (CDCl3)(M. D.): 1,09 (3H, d, J=6.4 Hz), is 1.31 (3H, t, J=7.2 Hz), 1,43 (N, C), 2,62 (1H, DD, J=6,8 Hz to 13.2 Hz), 2,82 (1H, m), 3,88 (1H, m), 4,22 (2N, K, J=7,2 Hz), to 4.38 (1H, m), 6,56 (1H, m), 6.89 in (1H, d, J=6.8 Hz), 7,18 (1H, s), 7,22 (1H, DD, J=6,8, 8.0 Hz), 7.23 percent (1H, d, J=8.0 Hz).

Example of getting 73b

2-(3-Ethoxycarbonylphenyl)-1-meth in ethanol (5.0 ml) and to this solution is then added hydrochloric acid (5 ml) followed by stirring at room temperature for 1.5 hours. Then to this add hydrochloric acid (2.5 ml) and stirred at room temperature for 2 hours. The solvent is evaporated, getting mentioned in the title compound (1,148 g, crude) as a yellow oil. The compound obtained is used in subsequent reactions without additional purification.

1H-NMR (DMSO-d6)(M. D.): of 1.03 (3H, d, J=6,8 Hz) to 1.22 (3H, t, J=7.2 Hz), to 2.55 (1H, m), 2,95 (1H, m), 3,32 (1H, m), 4,10 (2H, K, J=7,2 Hz), at 6.84 (1H, d, J=7,2 Hz), 7,21 (1H, DD, J=7,2, 7,2 Hz), 7,29 (1H, d, J=7,2 Hz), to 7.35 (1H, s), 8,00 (1H, CL), a 9.60 (1H, s).

Example of getting 74b

6 Ethoxycarbonyl-3-methyl-1,2,3,4-tetrahydroisoquinoline

The reaction is carried out using 2-(3-ethoxycarbonylphenyl)-1-methylethylamine hydrochloride (1,148 g, an example of obtaining 73b) in accordance with the method Chem. Pharm. Bull. 42 (8), 1676 (1994). The product was then purified using a column with NH-silica gel, receiving specified in the header connection (0,441 g).

1H-NMR (CDCl3)(M. D.): 1,24 (3H, d, J=6.4 Hz), of 1.30 (3H, t, J=7.2 Hz), 2,48 (1H, DD, J=10.0 Hz, and 16.4 Hz), a 2.75 (1H, DD, J=3,6 Hz, and 16.4 Hz), 3,01 (1H, m), a 4.03 (2H, SHK), is 4.21 (2H, K, J=7,2 Hz), of 6.66 (1H, s), to 6.95 (1H, d, J=8,4 Hz), to 7.09 (1H, d, J=8,4 Hz), 7,14 (1H, s).

Example of getting 75b

6 Ethoxycarbonyl-3-methylisoquinoline

Specified in the header is (0,441 g), in the same way as in the example of obtaining 39b.

1H-NMR (CDCl3)(M. D.): of 1.34 (3H, t, J=7.2 Hz), to 2.67 (3H, s), 4,28 (2N, K, J=7,2 Hz), was 7.08 (1H, CL), 7,39 (1H, DD, J=2.0 a, 8,8 Hz), 7,40 (1H, s), a 7.85 (1H, d, J=8,8 Hz), 7,94 (1H, CL), 9,05 (1H, s).

Example of getting 76b

6-Amino-3-methylisoquinoline

The crude crystals (of 0.182 g), obtained using the obtained 6-ethoxycarbonyl-3-methylisoquinoline (0,356 g), in the same way as in the example of obtaining 33b, washed with diethyl ether and dried, obtaining mentioned in the title compound (93 g) as pale yellow crystals.

1H-NMR (CDCl3)(M. D.): 2,63 (3H, s), 4,14 (2H, CL), 6,77 (1H, d, J=2.0 Hz), 6,93 (1H, DD, J=2.0 a, 8,8 Hz), 7,18 (1H, s), 7,72 (1H, d, J=8,8 Hz), 8,9.

Synthetic example 1b

N-(8-Bronchioles-3-yl)-3-pyridinesulfonamide

3-Amino-8-bromohydrin (300 mg, example of obtaining 5b) is dissolved in pyridine (5 ml) and to this then add 3-pyridinesulfonamide (254 mg), followed by stirring at room temperature for 30 minutes. After completion of the reaction, the reaction solution was poured in a saturated salt solution and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and then concentrated. The crude crystals are washed 48.gif" border="0">(M. D.): 7,47 (1H, t, J=8.0 Hz), 7,52-of 7.60 (1H, m), 7,99-8,03 (2H, m), 8,10 (1H, d, J=2.4 Hz), 8,18 is 8.22 (1H, m), 8,71 (1H, d, J=2.4 Hz), 8,78 (1H, DD, J=1.6 Hz, 4.8 Hz), 8,98 (1H, d, J=2.4 Hz), 11,23 (1H, SHS).

Synthetic example 2b

N- (5-Bronchioles-2-yl)-5-methyl-3-pyridinesulfonamide

Specified in the title compound is obtained from 2-amino-5-brainline (example obtaining 1b) and 5-methyl-3-pyridinesulfonamide in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): is 2.37 (3H, s), 7,58-7,72 (4H, m), 8,11 (1H, CL), of 8.37 (1H, d, J=9.6 Hz, 8,59 (1H, d, J=1.2 Hz), 8,86 (1H, CL).

Synthetic example 3b

6-Amino-N-(8-bronchioles-3-yl)-3-pyridinesulfonamide

Specified in the title compound is obtained from 3-amino-8-brainline (example obtaining 5b) and 6-amino-3-pyridinesulfonamide in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 6,40 (1H, d, J was 8.8 Hz), 6,93 (2H, CL), 7,44 (1H, t, J=8.0 Hz), the 7.65 (1H, DD, J=2,4 Hz and 8.8 Hz), of 7.96-to 7.99 (2H, m), 8,01 (1H, d, J=2.4 Hz), 8,31 (1H, d, J=2.4 Hz), to 8.70 (1H, d, J=2.4 Hz), of 10.73 (1H, SHS).

Synthetic example 4b

N-(8-Bronchioles-3-yl)-4-cyanobenzenesulfonyl

Specified in the title compound is obtained from 3-amino-8-brainline (example obtaining 5b) and 4-cyanobenzenesulfonyl in the same way,0 Hz), of 7.96-8,07 (7H, m), to 8.70 (1H, d, J=2.4 Hz), 11,27 (1H, CL).

Synthetic example 5b

6-Chloro-N-(8-bronchioles-3-yl)-3-pyridinesulfonamide

Specified in the title compound is obtained from 3-amino-8-brainline (example obtaining 5b) and 6-chloro-3-pyridinesulfonamide in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 7,47 (1H, t, J=8.0 Hz), 7,71 (1H, d, J=8,4 Hz), 7,99-8,03 (2H, m), 8,10 (1H, d, J=2.4 Hz), to 8.20 (1H, DD, J=8,4 Hz), 8,71 (1H, d, J=2.4 Hz), 8,83 (1H, d, J=2.4 Hz), of 10.73 (1H, CL).

Synthetic example 6b

N-(8-Bronchioles-3-yl)-4-(N-ethylsulfonyl) benzene sulfonamide

Specified in the title compound is obtained from 3-amino-8-brainline (example obtaining 5b) and 4-(N-ethylsulfonyl) benzosulfimide in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): of 0.82 (3H, t, J=7.2 Hz), 2,69 was 2.76 (2H, m), 7,45 (1H, t, J=8,4 Hz), of 7.75 (1H, t, J=5.6 Hz), of 7.90-8,04 (7H, m), to 8.70 (1H, d, J=2,8 Hz), 11,18 (1H, CL).

Synthetic example 7b

N-(8-Bronchioles-3-yl)-5-cyano-2-pyridinesulfonamide

Specified in the title compound is obtained from 3-amino-8-brainline (example obtaining 5b) and 5-cyano-3-pyridinesulfonamide in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6) what C), to 8.57 (1H, DD, J=2.0 Hz, 8,4 Hz), 8,79 (1H, d, J=2.4 Hz), 9,14 (1H, d, J=2.0 Hz), 11,49 (1H, CL).

Synthetic example 8b

N-(8-Cyanohydrin-3-yl)-3-pyridinesulfonamide

Specified in the title compound is obtained from 3-amino-8-cyanohydrin (example obtaining 7b) and 3-pyridinesulfonamide in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): to 7.59 (1H, DD, J=4,8 Hz, 8.0 Hz), of 7.70 (1H, t, J=8.0 Hz), 8,21-of 8.25 (3H, m), with 8.33 (1H, d, J=8.0 Hz), 8,77-8,79 (2H, m), 9,01 (1H, d, J=2,8 Hz), 11,34 (1H, CL).

Synthetic example 9b

N-(8-Cyanohydrin-3-yl)-4-cyanobenzenesulfonyl

Specified in the title compound is obtained from 3-amino-8-cyanohydrin (example obtaining 7b) and 4-cyanobenzenesulfonyl in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 7,71 (1H, t, J=8.0 Hz), of 7.96-8,07 (4H, m), 8,18 (1H, d, J=2,8 Hz), 8,24 (1H, d, J=8.0 Hz), 8,31 (1H, d, J=8.0 Hz), 8,78 (1H, d, J=2,8 Hz), 11,37 (1H, CL).

Synthetic example 10b

N-(5-Bronchioles-2-yl)-3-pyridinesulfonamide

Specified in the title compound is obtained from 2-amino-5-brainline (example obtaining 1b) and 3-pyridinesulfonamide in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.)-(8-Bronchioles-3-yl)-5-endosulfane

Specified in the title compound is obtained from 3-amino-8-brainline (example obtaining 5b) and 5-indiancontrolled in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 1,92 is 2.01 (2H, m), 2,81-of 2.86 (4H, m), 7,34 (1H, d, J=8.0 Hz), 7,44 (1H, t, J=8.0 Hz), 7,60 (1H, DD, J=1.6 Hz, 8.0 Hz), of 7.70 (1H, d, J=1.6 Hz), 7,95 (1H, d, J=8.0 Hz), of 7.97 (1H, d, J=8.0 Hz), 8,03 (1H, d, J-2.4 Hz), 8,71 (1H, d, J=2.4 Hz), of 10.93 (1H, CL).

Synthetic example 12b

N-(8-eothinon-3-yl)-N-acetyl-5-indolinecarboxylic

Specified in the title compound is obtained from 3-amino-8-ichinomiya (example obtaining 6b) and N-acetyl-6-indolinecarboxylic in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 2,11 (3H, s), 3,11 (2H, t, J=8,4 Hz) 4,06 (2H, t, J=8,4 Hz), 7,28 (1H, t, J=8.0 Hz), 7,65-to 7.68 (2H, m), 7,93-of 7.96 (2H, m), with 8.05 (1H, d, J=9,2 Hz), by 8.22 (1H, DD, J=1.2 Hz and 7.6 Hz), 8,64 (1H, d, J=2.4 Hz), 10,87 (1H, CL).

Synthetic example 13b

N-(8-Bronchioles-3-yl)-3-chinaincorporated

Specified in the title compound is obtained from 3-amino-8-brainline (example obtaining 5b) and 3-chinaincorporated in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 7,38 (1H, t, J=8.0 Hz), 7,70-7,74 (1H, m), of 7.90-8,00 (3H, Synthetic example 14b

N-(8-Bronchioles-3-yl)-N*-acetyl-1,2,3,4-tetrahydroquinolin-6-sulfonamide

Specified in the title compound is obtained from 3-amino-8-brainline (example obtaining 5b) and N-acetyl-1,2,3,4-tetrahydroquinolin-6-sulphonylchloride in the same manner as in synthetic example 1b.

1H-NMR (CDCl3)(m d): 1,86 is 2.01 (2H, m), 2,77 (2H, t, J=6.4 Hz), 3,65 is 3.76 (2H, m).

Synthetic example 15b

N-(8-Eothinon-3-yl)-4-ethynodiolthinyl

Specified in the title compound is obtained from 3-amino-8-Yedinaya (example obtaining 6b) and 4-ethynodiolthinyl in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 7,26 (1H, t, J=8.0 Hz), 7,82-7,86 (1H, m), 7,93-of 7.95 (1H, m), 7,98 (1H, d, J=2.4 Hz), 8,02-of 8.06 (1H, m), 8,19 (1H, DD, J=1.2 Hz and 7.6 Hz), of 8.27 (1H, d, J=8,4 Hz), 8,59 (1H, d, J=2.4 Hz), 8,67 (1H, d, J=8,4 Hz), 9,12 (1H, s) 9,52 (1H, s), 11,57 (1H, CL).

Synthetic example 16b

4-Cyano-N-(8-eothinon-3-yl)benzosulfimide

Specified in the title compound is obtained from 3-amino-8-ichinomiya (example obtaining 6b) and 4-cyanobenzenesulfonyl in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 7,31 (1H, t, J=8.0 Hz), of 7.96-8,04 (6N, m), compared to 8.26 (1H, DD, J=1.2 Hz, 7.2 Hz), second in the title compound is obtained from 3-amino-8-ichinomiya (example obtaining 6b) and 3-pyridinesulfonamide in the same way, as in synthetic example 1b.

1H-NMR (DMSO-d6)(m d): 7,31 (1H, t, J=8.0 Hz), EUR 7.57-of 7.60 (1H, m), to 7.99 (1H, d, J=1.2 Hz, 8,4 Hz), of 8.04 (1H, d, J=2,8 Hz), 8,18-8,21 (1H, m), compared to 8.26 (1H, DD, 1.2 Hz, 7.2 Hz), 8,66 (1H, d, J=2,8 Hz), 8,77 (1H, DD, J=1.6 Hz, 4,8 Hz), 8,98 (1H, d, J=2,8 Hz), 11,20 (1H, CL).

Synthetic example 18b

N-(5-Bronchioles-2-yl)-4-cyanobenzenesulfonyl

Specified in the title compound is obtained from 2-amino-5-brainline (example obtaining 1b) and 4-cyanobenzenesulfonyl in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): EUR 7.57-7,73 (4H, m), 8,00-8,08 (4H, m), scored 8.38 (1H, d, J=8,8 Hz).

Synthetic example 19b

N-(8-Bronchioles-3-yl)-6-ethyl-3-pyridinesulfonamide

A solution of pyridine (0.5 ml) and methylene chloride (0.5 ml) containing 6-ethyl-3-pyridinesulfonamide (30 ml), added to 3-amino-8-brainline (18 mg, example of obtaining 5b) at 0°C. After stirring at room temperature for 30 minutes, water is added and the mixture extracted with ethyl acetate. The extract was purified preparative TLC (hexane-ethyl acetate=1:1), obtaining mentioned in the title compound (20 mg).

1H-NMR (DMSO-d6)(m d): a 1.25 (3H, t, J=7.5 Hz), 2,70 (2N, K, J=7,50 Hz), 7,34-7,98 (5H, m), 8,19 (nd

Pyridine (1 ml) and 4-chlorobenzenesulfonamide (255 mg) are added to 2-amino-6-chlorhydrin (119 mg, example of obtaining 2b) at room temperature, followed by stirring at room temperature for 3 days. Then add water and extracted with ethyl acetate. The ethyl acetate layer is dried over sodium sulfate and concentrated. Then the obtained solid is washed with methanol, getting mentioned in the title compound (20 mg).

1H-NMR (CDCl3)(M. D.): of 6.96 (1H, d, J=9.7 Hz), 7,34 (1H, d, J=8,4 Hz), 7,42-of 7.48 (3H, m), 7,54 (1H, t, J=8,4 Hz), 7,94 (2H, d, J=6.3 Hz), 8,29 (1H, d, J=9.7 Hz).

Synthetic example 21b

N-(8-Chlorhydrin-3-yl)-6-ethyl-3-pyridinesulfonamide

Specified in the title compound is obtained from 3-amino-8-chlorhydrin (example obtaining 9b) and 6-ethyl-3-pyridinesulfonamide in the same manner as in synthetic example 1b.

1H-NMR (CDCl3)(ppm,): of 1.28 (3H, t, J=8,3 Hz), 2,86 (2N, K, J=8,3 Hz), 7,24 (1H, d, J=8.0 Hz), 7,49 (1H, t, J=8.0 Hz), 7,73 (1H, d, J=8.0 Hz), 7,78 (1H, d, J=8.0 Hz), 7,95 (1H, DD, J=8.0 Hz, 2.1 Hz), 8,18 (1H, d, J=2.5 Hz), 8,67 (1H, d, J=2.5 Hz), 8,93 (1H, d, J=2.1 Hz).

Synthetic example 22b

N-(5-Chlorhydrin-2-yl)-6-ethyl-3-pyridinesulfonamide

Specified in the title compound is obtained from 2-amino-5-chlorhydrin>1H-NMR (CDCl3)(m d): to 1.32 (3H, t, J=8,3 Hz), 2,89 (2N, K, J=8,3 Hz), 6,97 (1H, d, J=9.4 Hz), 7,29 (1H, d, J=8.0 Hz), 7,35 (1H, d, J=8.0 Hz), 7,44 (1H, d, J=8.0 Hz), 7,56 (1H, t, J=8.0 Hz), 8,18 (1H, DD, J=8.0 Hz, 2.6 Hz), 8,30 (1H, d, J=9.4 Hz), 9,10 (1H, d, J=2,6 Hz).

Synthetic example 23b

N-(8-Chlorhydrin-3-yl)benzosulfimide

Specified in the title compound is obtained from 3-amino-8-chlorhydrin (example obtaining 9b) and benzosulfimide in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 7,30-of 7.48 (6N, m), to 7.84 (2H, d, J=7,4 Hz), 8,11 (1H, d, J=3.1 Hz), 8,66 (1H, d, J=3.1 Hz).

Synthetic example 24b

4-Cyano-N-(5-chlorhydrin-2-yl)benzosulfimide

Specified in the title compound is obtained from 3-amino-8-brainline (example obtaining 2b) and 4-cyanobenzenesulfonyl in the same manner as in synthetic example 1b.

1H-NMR (CDCl3)(M. D.): of 6.96 (1H, d, J=9.5 Hz), 7,35 (1H, d, J=8.7 Hz), was 7.45 (1H, d, J=8.7 Hz), EUR 7.57 (1H, t, J=8.7 Hz), 7,78 (2H, d, J=8,9 Hz), 8,10 (2H, d, J=8,9 Hz), with 8.33 (1H, d, J=9.5 Hz).

Synthetic example 25b

N-(5-Chlorhydrin-2-yl)-4-methylbenzenesulfonamide

Specified in the title compound is obtained from 2-amino-5-chlorhydrin (example obtaining 2b) and 4-toluensulfonate the M. D.): to 2.41 (3H, C) 6,98 (1H, d, J=9.3 Hz), 7,28 (2H, d, J=8,2 Hz), 7,35 (1H, d, J=7.9 Hz), 7,41 (1H, d, J=7.9 Hz), 7,53 (1H, t, J=7.9 Hz), 7,88 (2H, d, J=8,2 Hz), compared to 8.26 (1H, d, J=9,3 Hz).

Synthetic example 26b

N-(5-Chlorhydrin-2-yl)-4-sulfamoylanthranilic

Specified in the title compound is obtained from 2-amino-5-chlorhydrin (example obtaining 2b) and 4-sulfamoylanthranilic in the same manner as in synthetic example 1b.

1H-NMR (CDCl3)(m d): 7,42-7,49 (3H, m), 7,58 (1H, t, J=8.0 Hz), 8,00-to 8.12 (4H, m) 8,39 (1H, d, J=9,3 Hz).

Synthetic example 27b

N-(5-Bronchioles-2-yl)-4-(N-ethylsulfonyl)benzosulfimide

Specified in the title compound is obtained from 2-amino-5-chlorhydrin (example obtaining 2b) and 4-(N-ethylsulfonyl) benzosulfimide in the same manner as in synthetic example 1b.

1H-NMR (CDCl3)(M. D.): to 1.14 (3H, t, J=7.5 Hz), 3,01-to 3.09 (2H, m), was 7.08 (1H, d, J=9.5 Hz), 7,42 (1H, DD, J=7,6 Hz, 1.3 Hz), 7,49 (1H, t, J=7,6 Hz), the 7.65 (1H, DD, J=7,6 Hz, 1.3 Hz), of 7.96 (2H, d, J=8.7 Hz), 8,10 (2H, d, J=8.7 Hz), 8,31 (1H, d, J=9.5 Hz).

Synthetic example 28b

3-Cyano-N-(8-chlorhydrin-3-yl)benzosulfimide

Specified in the title compound is obtained from 3-amino-8-chlorhydrin (example obtaining 9b) and 3-cyanobenzenesulfonyl in the same way as in the, J=7.9 Hz), 7,72-7,86 (3H, m), of 8.00 (1H, d, J=7.9 Hz), 8,13 (1H, d, J=3.2 Hz), 8,16 (1H, s) 8,64 (1H, d, J=3.2 Hz).

Synthetic example 29b

N-(8-Chlorhydrin-3-yl)-3-methylbenzenesulfonamide

Specified in the title compound is obtained from 3-amino-8-chlorhydrin (example obtaining 9b) and 3-toluensulfonate in the same manner as in synthetic example 1b.

1H-NMR (CDCl3)(M. D.): 2,35 (3H, s), 7,16-7,79 (7H, m), of 8.09 (1H, d, J=2.7 Hz), 8,65 (1H, d, J=2.7 Hz).

Synthetic example 30b

N-(8-Chlorhydrin-3-yl)-3-sulfamoylanthranilic

Specified in the title compound is obtained from 3-amino-8-chlorhydrin (example obtaining 9b) and 3-sulfamoylanthranilic in the same manner as in synthetic example 1b.

1H-NMR (CDCl3)(M. D.): 7,46 (1H, t, J=7,6 Hz), 7,53 (1H, t, J=7,6 Hz), 7,58 for 7.78 (2H, m), of 8.00 (1H, d, J=7,6 Hz), of 8.04 (1H, d, J=7,6 Hz) to 8.14 (1H, d, J=2,8 Hz), of 8.47 (1H, s), 8,59 (1H, d, J=2,8 Hz).

Synthetic example 31b

N-(8-Methylinosine-3-yl)-3-pyridinesulfonamide

562 mg of white crystals get using 1,02 g (5.2 mmol, example of getting 16b) 7-amino-2-chloro-4-methylinosine and 0.9 g (5.2 mmol) of 3-pyridinesulfonamide, in the same manner as in synthetic example 1b. Methanol (4 ml), tetrahydrofuran (4 ml) and 10% palladium on plerou hydrogen. The reaction solution is filtered through celite and then evaporated. The residue is washed with ethyl acetate, receiving 65 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 2,82 (3H, s), of 7.64-7,66 (2H, m), 7,73 (1H, d, J=5,2 Hz), 8,03 (1H, s), 8.30 to-8,35 (2H, m), 8,82 (1H, DD, J=1,2, 4,8 Hz), of 9.00 (1H, d, J=5,2 Hz), 9,11 (1H, d, J=2.0 Hz).

Synthetic example 32b

N-(8-Methylinosine-3-yl)-4-cyanobenzenesulfonyl

358 mg of white crystals get using 305 mg (1,58 mmol, example of getting 16b) 7-amino-2-chloro-4-methylinosine and of 0.48 g (2.4 mmol) of 4-cyanobenzenesulfonyl, in the same manner as in synthetic example 1b. To 140 mg (0.38 mmol) of white crystals add acetic acid (6 ml), water (2 ml) and zinc (122 mg), followed by stirring at 60°C for 15 minutes. After filtering the reaction solution through celite add aqueous saturated solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated. Then the resulting residue is purified by chromatography on silica gel, receiving 82 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 2,60 (3H, s), 7,26 (1H, DD, J=1,2, 4,4 Hz), 7,41 (1H, DD example 33b

N-(6-Chloro-8-cyanohydrin-3-yl)-3-pyridinesulfonamide

764 mg of white crystals get using 3.0 mg (13 mmol, example of getting 13b) ethyl-7-amino-2-chlorhydrin-4-carboxylate and 2,3 g (13 mmol) of 3-pyridinesulfonamide in the same manner as in synthetic example 1b. To an ethanol solution (6 ml) 108 mg (0.28 mmol) of white crystals add 1 N. aqueous solution (0.5 ml) of sodium hydroxide, followed by stirring over night. To the reaction solution was added 1 N. aqueous solution of hydrochloric acid followed by extraction twice with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated, obtaining the remainder. Under ice cooling to tertrahydrofuran ring solution (10 ml) containing the residue, add oxalicacid (0.04 ml) and one drop of dimethylformamide, followed by stirring at room temperature for 30 minutes. After 30 minutes there is added aqueous saturated solution of ammonia (5 ml) followed by stirring for another 10 minutes. To the reaction solution was added a saturated salt solution and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated, obtaining the remainder. When hlaidentical acid (0.05 ml) followed by stirring at room temperature for 30 minutes. To the reaction solution was added a saturated salt solution and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica gel, receiving 37 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 7,62-7,66 (1H, m), 7.68 per-7,72 (2H, m), 8,08 (1H, d, J=8,8 Hz), 8,23 (1H, s), compared to 8.26-8,29 (1H, m), 8,81 (1H, DD, J=1,6, 4,8 Hz), 9,04 (1H, d, J=2,4 Hz).

Synthetic example 34b

N-(8-Chlorhydrin-3-yl)-4-cyanobenzenesulfonyl

58 mg specified in the connection header receive, using 38 mg (0.21 mmol) of 3-amino-8-chlorhydrin (0.21 mmol, example of getting 9b) and 43 mg (0.21 mmol) of 4-cyanobenzenesulfonyl, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): at 7.55 (1H, t, J=7,6 Hz), to 7.84 (1H, d, J=7,6 Hz), 7,95 (1H, t, J=7,6 Hz), to 7.99 (2H, d, J=8,8 Hz), of 8.04 (2H, d, J=8,8 Hz), of 8.09 (1H, d, J=2,8 Hz), 8,73 (1H, d, J=2,8 Hz), is 11.39 (1H, s).

Synthetic example 35b

N-(8-Chlorhydrin-3-yl)-4-(N-ethylsulfonyl)benzosulfimide

36 mg specified in the connection header receive, using 36 mg (0,19 mmol, example of getting 9b) 3-amino-8-chlorhydrin and 52 mg (0,19 mmol) of 4-(N-ethylsulfonyl) benzosulfimide, in the same way as in sintet, is), 7,54 (1H, t, J=7,6 Hz), to 7.77 (1H, t, J=6.0 Hz), 7,83 (1H, t, J=7,6 Hz), 7,92-of 7.95 (1H, m), to 7.93 (2H, d, J=8,8 Hz), 8,03 (2H, d, J=8,8 Hz), 8,07 (1H, d, J=2.4 Hz), 8,73 (1H, d, J=2.4 Hz), 11,20 (1H, C).

Synthetic example 36b

N-(8-Chlorhydrin-3-yl)-3-pyridinesulfonamide

29 mg specified in the connection header receive, using 33 mg (0,19 mmol, example of getting 9b) 3-amino-8-chlorhydrin and 33 mg (0,19 mmol) 3-pyridinesulfonamide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): rate of 7.54 (1H, t, J=7,6 Hz), 7,60 (1H, DD, J=4,8 and 7.6 Hz), 7,81 (1H, d, J=7,6 Hz), 7,94 (1H, d, J=7,6 Hz), of 8.09 (1H, d, J=2,8 Hz), 8,19 compared to 8.26 (1H, m), 8,72 (1H, d, J=2,8 Hz), 8,77 (1H, d, J=1,6, 4,8 Hz), of 9.00 (1H, d, J=2,8 Hz), 11,46 (1H, s).

Synthetic example 37b

N-(8-Chlorhydrin-3-yl)-5-ethylsulfonyl-2-pyridinesulfonamide

10 mg specified in the connection header receive, using 30 mg (0,17 mmol, example of getting 9b) 3-amino-8-chlorhydrin and 95 mg (0.34 mmol) of 5-ethylsulfonyl-2-chlorosulfonylphenyl, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): to 0.88 (3H, t, J=7,6 Hz), 2,79-of 2.86 (2H, m), 7,55 (1H, t, J=7,6 Hz), the 7.85 (1H, t, J=7,6 Hz), 7,94 (1H, d, J=7,6 Hz), 8,00 (1H, t, J=6.4 Hz), 8,16 (1H, d, J=2,8 Hz), of 8.27 (1H, d, J=8.0 Hz), to 8.41 (1H, d, J=2,4, 8.0 Hz), 8,84 (1H, d, J=2,8 Hz), 9,04 (1H, d, J=2.4 Hz), 11,47 (1H, s).

Synthetic poluchaut, using 35 mg (0,17 mmol, example of getting 10b) 3-amino-8-triptoreline and 37 mg (0.18 mmol) 4-cyanobenzenesulfonyl, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 7,71 (1H, t, J=7,6 Hz), 8,03-8,09 (5H, m), 8,19 (1H, d, J=2.4 Hz), 8,30 (1H, d, J=7,6 Hz), 8,78 (1H, d, J=2.4 Hz), 11,72 (1H, s).

Synthetic example 39b

N-(8-Trifloromethyl-3-yl)-4-(N-ethylsulfonyl)benzosulfimide

60 mg specified in the connection header receive, using 35 mg (0,17 mmol, example of getting 10b) 3-amino-8-triptoreline and 56 mg (0.20 mmol) 4-(N-ethylsulfonyl) benzosulfimide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): or 0.83 (3H, t, J=7.2 Hz), 2.71 to 2,78 (2H, m), of 7.69 (1H, t, J=8.0 Hz), 7,76 (1H, t, J=5.6 Hz), to 7.93 (1H, d, J=8,8 Hz), 8,04-8,07 (3H, m), 8,13 (1H, d, J=2,8 Hz), of 8.25 (1H, d, J=8.0 Hz), the rate of 8.75 (1H, d, J=2,8 Hz), to 11.28 (1H, s).

Synthetic example 40b

N-(8-Trifloromethyl-3-yl)-3-pyridinesulfonamide

71 mg specified in the connection header receive, using 45 mg (0.21 mmol, example of getting 10b) 3-amino-8-triptoreline and 45 mg (0.25 mmol) 3-pyridinesulfonamide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)

Synthetic example 41b

N-(8-Chlorhydrin-3-yl)-1,2,3,4-tetrahydro-6-naphthalenesulfonic

46 mg specified in the connection header receive, using 33 mg (0,19 mmol, example of getting 9b) 3-amino-8-chlorhydrin and 73 mg (0.22 mmol) of 6-chlorosulfonyl-1,2,3,4-tetrahydronaphthalene, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 1,68 (4H, s), 2,71 (4H, s), 7,20 (1H, t, J=8,4 Hz), 7,52 (1H, t, J=7,6 Hz), 7,53 (1H, DD, J=2.0 a, and 8.4 Hz), 7,58 (1H, d, J=2.0 Hz), 7,80 (1H, d, J=7,6 Hz), to 7.93 (1H, d, J=7,6 Hz), of 8.06 (1H, d, J=2.4 Hz), 8,73 (1H, d, J=2.4 Hz), 10,94 (1H, s).

Synthetic example 42b

N-(8-Chlorhydrin-3-yl)-2,3-dihydro-5-benzofuranol

57 mg specified in the connection header receive, using 30 mg (0,17 mmol, example of getting 9b) 3-amino-8-chlorhydrin and 44 mg (0.20 mmol) of 5-chlorosulfonyl-2,3-dihydrobenzofuran, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 3,19 (2H, t, J=8,8 Hz), 4,58 (2H, t, J=8,8 Hz) 6,86 (1H, d, J=8,8 Hz), 7.23 percent (1H, t, J=7,6 Hz), a 7.62 (1H, DD, J=1,6, 8,8 Hz), 7,72 (1H, d, J=1.6 Hz), 7,80 (1H, d, J=7,6 Hz), 7,92 (1H, d, J=7,6 Hz), 8,03 (1H, d, J=2.4 Hz), 8,73 (1H, d, J=2.4 Hz), 10,85 (1H, s).

Synthetic example 43b

N-(8-Chloro-4-vinylpyridin-3-yl)- 4-12b) 3-amino-4-vinyl-8-chlorhydrin and 36 mg (0.18 mmol) 4-cyanobenzenesulfonyl, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): from 5.29 (1H, d, J=17.6 Hz), 5,59 (1H, d, J=11,6 Hz), to 6.75 (1H, DD, J=11,6, 17.6 Hz), to 7.59 (1H, t, J=8.0 Hz), 7,80 (2H, DD, J=8,8 Hz), of 7.96 (1H, d, J=8.0 Hz), 8,00-of 8.04 (3H, m), a total of 8.74 (1H, s), of 10.58 (1H, C).

Synthetic example 44b

N-(8-Trifloromethyl-3-yl)-5-(N-acetylindole)sulfonamide

186 mg specified in the connection header receive, using 109 mg (0.51 mmol, example of getting I) 3-amino-8-triptoreline and 200 mg (0.77 mmol) of 5-chlorosulfonyl-N-acetylindole, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): a 2.13 (3H, s), 3,14 (2H, t, J=8.0 Hz), 4.09 to (2H, t, J=8,8 Hz), to 7.67 (1H, t, J=8,4 Hz), 7,69-7,73 (2H, m), 8,01 (1H, d, J=7,2 Hz), 8.07-a of 8.09 (2H, m), 8,24 (1H, d, J=8,4 Hz), 8,73 (1H, d, J=2,8 Hz), 10,98 (1H, s).

Synthetic example 45b

N-(8-Bronchioles-3-yl)-2-methylthio-5-pyridinesulfonamide

197 mg (0,556 mmol) of white crystals get, using 100 mg (0,56 mmol, example of obtaining 5b) 3-amino-8-brainline and 142 mg (0.67 mmol) of 2-chloro-5-pyridinesulfonamide, in the same manner as in synthetic example 1b. To 60 mg (0,17 mmol) of the crystals add dimethylformamide (1 ml), pyridine (1 ml) and 111 mg (1.6 mmol) of timelocked sodium, followed by stirring at to regrout with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated, obtaining the remainder. The residue is purified by chromatography on silica gel, receiving 62 mg specified in the connection header.

1H-NMR (DMSO-d6)(m d): to 3.33 (3H, s), 7,47 (1H, d, J=8,8 Hz), 7,55 (1H, t, J=8.0 Hz), to 7.84 (1H, d, J=6.8 Hz), of 7.97 (1H, d, J=8,8 Hz), 7,98 (1H, d, J=8,8 Hz), 8,13 (1H, d, J=2.0 Hz), a total of 8.74 (1H, d, J=2.4 Hz), 8,82 (1H, d, J=2.0 Hz), 11,16 (1H, s).

Synthetic example 46b

N-(8-Bronchioles-3-yl)-4-(2-methylsulfonylamino)benzosulfimide

55 mg specified in the connection header receive, using 30 mg (0.13 mmol, example of obtaining 5b) 3-amino-8-brainline and 57 mg (0.20 mmol) 4-(2-methylsulfonylamino) benzosulfimide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 2,92 (3H, s), 3.00 and was 3.05 (2H, m), 3,37-3,44 (2H, m), 7,46 (1H, t, J=7,6 Hz), of 7.48 (2H, d, J=8.0 Hz), 7,80 (2H, d, J=8.0 Hz), of 7.96 (1H, d, J=7,6 Hz), to 7.99 (1H, d, J=7,6 Hz), of 8.04 (1H, d, J=2.4 Hz), 8,71 (1H, d, J=2.4 Hz), 11,02 (1H, s).

Synthetic example 47b

N-(8-Bronchioles-3-yl)-4-oxa-7-benzothiazolesulfonamide

99 mg specified in the connection header receive, using 51 mg (0.23 mmol, example of obtaining 5b) 3-amino-8-brainline and 86 mg (0.34 mmol) of 7-chlorosulfonyl-4-hexabenzocoronene, in the same way is, =8,4 Hz), 4,39 (2H, t, J=8,4 Hz), 6,92 (1H, d, J=8,8 Hz), 7,42 (1H, DD, J-2,4, 8,8 Hz), 7,46 (1H, t, J=7,6 Hz), to 7.59 (1H, d, J=2.4 Hz), to 7.99 (1H, d, J=7,6 Hz), 8,02 (1H, d, J=7,6 Hz), with 8.05 (1H, sh), 8,71 (1H, d, J=2.4 Hz), 10,92 (1H, s).

Synthetic example 48b

N-(8-Bronchioles-3-yl)-4-(2-acetamidomethyl)benzosulfimide

56 mg specified in the connection header receive, using 30 mg (0.13 mmol, example of obtaining 5b) 3-amino-8-brainline and 201 mg (0.77 mmol) of N-(4-chlorosulfonylphenyl) ndimethylacetamide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): a 2.71 (2H, t, J=7.2 Hz), 3.25 to 3,20 (2H, m), 7,37 (2H, d, J=8,4 Hz), 7,46 (1H, t, J=8.0 Hz), 7,78 (2H, d, J=8,4 Hz), 7,86 (1H, sh), of 7.97 (1H, d, J=8.0 Hz), 8,00 (1H, d, J=8.0 Hz), of 8.04 (1H, d, J=2,8 Hz), 8,72 (1H, d, J=2,8 Hz), 10,99 (1H, s).

Synthetic example 49b

N-(8-Bronchioles-3-yl)-1,2,3,4-tetrahydro-N-acetyl-7-ethynodiolthinyl

180 mg of white crystals get, using 145 mg (of 0.65 mmol, example of obtaining 5b) 3-amino-8-brainline and 277 mg (0.85 mmol) of 1,2,3,4-tetrahydro-2-(TRIFLUOROACETYL)isoquinoline-7-sulphonylchloride, in the same manner as in synthetic example 1b. The crystals add ethanol (20 ml) and 1 N. aqueous sodium hydroxide solution (0.5 ml) followed by stirring at room temperature for 30 minutes. To the reaction solution add washed with a saturated solution of salt, dried over magnesium sulfate and concentrated, obtaining the remainder. To the residue add pyridine (0.5 ml) and acetic anhydride (0,014 ml) followed by stirring at room temperature for one hour. To this add a saturated salt solution and then extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated. Then the resulting residue is purified by chromatography on silica gel, getting 113 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): 1,19 of 1.28 (2H, m), is 2.05 (3H, s), 2,97 (1H, t, J=6.4 Hz), 3,03 (1H, t, J=6,4 Hz in), 3.75 (1H, t, J=6.4 Hz), to 4.73 (1H, s), 7,37 (1H, t, J=8,8 Hz), 7,53-7,58 (1H, m), 7,75-7,87 (2H, m), to $ 7.91 (1H, d, J=8.0 Hz), 8,19-of 8.27 (2H, m), 8,76-8,78 (1H, m).

Synthetic example 50b

N-(8-Bronchioles-3-yl)-1,1-dioxido-6-benzothiazolesulfonamide

White crystals get, using 71 mg (0.32 mmol, example of obtaining 5b) 3-amino-8-brainline and 119 mg (0.48 mmol) of 6-chlorosulfonylisocyanate. Under ice cooling to crystals when cooled with ice add chloroform (10 ml) and metallocarborane acid (145 mg), followed by stirring at room temperature for one hour. Add aqueous saturated sodium thiosulfate solution and then extracted with ethyl acetate. the residue is purified by chromatography on silica gel, getting 113 mg specified in the connection header.

1H-NMR (DMSO-d6)(M. D.): and 2.26-to 2.29 (2H, m), 3,05 (2H, t, J=6.0 Hz), 3,53 of 3.56 (2H, m), of 7.48 (1H, t, J=7,6 Hz), 7,86-of 7.90 (2H, m), of 7.96-of 8.04 (3H, m), 8,10 (1H, d, J=2.4 Hz), the rate of 8.75 (1H, d, J=2.4 Hz), 11,24 (1H, s).

Synthetic example 51b

N-(8-Bronchioles-3-yl)-4-(3-methylsulfinylpropyl)benzosulfimide

62 mg specified in the connection header receive, using 33 mg (0.14 mmol, example of obtaining 5b) 3-amino-8-brainline and 66 mg (0.22 mmol) of 4-(3-methylsulfinylpropyl) benzosulfimide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(m d): 1,90-to 1.98 (2H, m), of 2.72 (2H, t, J=8.0 Hz), with 2.93 (3H, s), 3,06 (2H, t, J=8.0 Hz), 7,42 (2H, d, J=8.0 Hz), 7,46 (1H, d, J=7,6 Hz), of 7.97 (2H, d, J=7,6 Hz), 8,00 (1H, d, J=7,6 Hz), with 8.05 (1H, d, J=2.4 Hz), 8,72 (1H, d, J=2.4 Hz), br11.01 (1H, s).

Synthetic example 52b

N-(8-Bronchioles-3-yl)-4-forbindelsesfaneblad

50 mg specified in the connection header receive, using 33 mg (0.14 mmol, example of obtaining 5b) 3-amino-8-brainline and 39 mg (0.20 mmol) 4-forbindelsesfaneblad, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 7,40 (1H, t, J=8,8 Hz), 7,47 (1H, t, J=7,6 Hz), 7,89-to 7.93 (2H, m), 9,78 (1H, DD, J=0,9, 7.6 G is-yl)-4-methoxy-2-pyridinesulfonamide

Under ice cooling to a solution (8 ml) of concentrated hydrochloric acid containing 0,86 g (3.7 mmol, example of getting 14b) 2 benzylthio-5-methoxypyridazine injected gas chlorine for one hour and then stirred. After that, the reaction solution is added a mixture of ice - water and then extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrated receiving 700 mg (2.1 mmol) of the residue. 93 mg specified in the connection header get using 180 mg (0.54 mmol) of the residue and 60 mg (0.27 mmol, example of obtaining 5b) 3-amino-8-brainline, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 4,07 (3H, s), 7,44 (1H, d, J=9,2 Hz), 7,47 (1H, t, J=7,6 Hz), of 7.96 (1H, t, J=7,6 Hz), 8,02 (1H, t, J=7,6 Hz), 8,13 (1H, d, J=2.4 Hz), 8,17 (1H, d, J=9,2 Hz), 8,82 (1H, d, J=2.4 Hz), 11,54 (1H, C).

Synthetic example 54b

N-(8-Bronchioles-3-yl)benzosulfimide

49 mg specified in the connection header receive, using 30 mg (0.13 mmol, example of obtaining 5b) 3-amino-8-brainline and 35 mg (0.20 mmol) of benzosulfimide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(who, of 1.02 (1H, s).

Synthetic example 55b

N-(8-Bronchioles-3-yl)-4-carboxamido-2-pyridinesulfonamide

In solution (16 ml) of concentrated hydrochloric acid containing 1.1 g (4.3 mmol, example of getting 15b) 2 benzylthio-4-carboxamidine, while cooling with ice introducing gaseous chlorine for one hour and then stirred. After the reaction solution is added to a mixture of ice - water and then extracted with ethyl acetate. The organic layer is successively washed with water and saturated salt solution, dried over magnesium sulfate and concentrate.

37 mg specified in the connection header receive, using 140 mg (0.40 mmol) of the residue and 45 mg (0.20 mmol) of 3-amino-8-brainline, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 7,46 (1H, d, J=8.0 Hz), 7,94-of 7.96 (2H, m), 8,00-8,02 (2H, m) to 8.12 (1H, d, J=2.4 Hz), 8,44 (1H, sh), 8,49 (1H, sh), 8,83 cent to 8.85 (2H, m), 11,35 (1H, s).

Synthetic example 56b

N-(8-Bronchioles-3-yl)-3-methoxybenzenesulfonamide

70 mg specified in the connection header receive, using 40 mg (0.18 mmol, example of obtaining 5b) 3-amino-8-brainline and 56 mg (0.27 mmol) of 3-methoxybenzenesulfonamide, in the same manner as in synthetic example 1b.

1 Hz), 7,46 (1H, t, J=7,6 Hz), to 7.99 (2H, t, J=7,6 Hz), 8,07 (1H, d, J=2.4 Hz), 8,72 (2H, m), 11,35 (1H, d, J=2,4 Hz).

Synthetic example 57b

N-(8-Bronchioles-3-yl)-3-hydroxybenzenesulfonate

73 mg specified in the connection header receive, using 45 mg (0.20 mmol, example of obtaining 5b) 3-amino-8-brainline and 117 mg (0.61 mmol) of 3-hydroxybenzenesulfonate, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 6,97 (1H, d, J=8.0 Hz), 7,18 (1H, sh), 7,25 (1H, d, J=8.0 Hz), 7,34 (1H, t, J=8.0 Hz), 7,47 (1H, t, J=8.0 Hz), of 7.97 (1H, d, J=8.0 Hz), 8,01 (1H, d, J=8.0 Hz), of 8.04 (1H, d, J=2.4 Hz), 8,73 (1H, d, J=2.4 Hz), 10,15 (1H, s), 10,96 (1H, s).

Synthetic example 58b

N-(4-Bronchioles-7-yl)-4-chlorobenzenesulfonamide

20 mg (0.09 mmol, example of getting 20b) 7-amino-4-bromoisoquinoline dissolved in 1.5 ml of pyridine and to this solution is then added 23 mg of 4-chlorobenzenesulfonamide, followed by stirring at room temperature over night. To the reaction solution was added water and the mixture extracted with ethyl acetate. The extract is dried over magnesium sulfate and concentrated. Then the obtained residue is purified by thin-layer chromatography on silica gel, receiving 13 mg specified in the connection header.

Melting point: gradually decomposes the, ,66 (1H, DD, J=2 Hz and 9.2 Hz), 7,82-to 7.84 (3H, m), to 7.99 (1H, d, J=9,2 Hz), at 8.60 (1H, s).

Synthetic example 59b

N-(4-Bromoisoquinoline-7-yl)-6-chloro-3-pyridinesulfonamide

Specified in the header of the get connection using 7-amino-4-isoquinoline (example obtaining 20b) and 6-chloro-3-pyridinesulfonamide, in the same manner as in synthetic example 57b.

1H-NMR (DMSO-d6)(M. D.): 7,66 (1H, DD, J=2,4 Hz and 9.2 Hz), of 7.70 (1H, d, J=8,4 Hz), 7,89 (1H, d, J=2.4 Hz), 8,02 (1H, d, J=9,2 Hz), to 8.20 (1H, DD, J=2,4 Hz and 8.4 Hz), 8,64 (1H, s), 8,84 (1H, d, J=2.4 Hz), 9,26 (1H, s).

Synthetic example 60b

2-(4-Chlorobenzenesulfonamide)-1,6-naphthiridine

2-Amino-1,6-naphthiridine (200 mg, example of getting 25b) is dissolved in dichloromethane (6.0 ml) and to this solution is then added triethylamine (0,20 ml) and 4-chlorobenzenesulfonamide (0.31 g), followed by stirring at 40°C for 1.5 hours. Add aqueous saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. The solvent is evaporated and the residue purified through column with silica gel, getting mentioned in the title compound (84 mg, 21,44%) as pale yellow crystals.

1H-NMR (CDCl3)�).

Synthetic example 61b

1-Chloro-6-(4-cyanobenzenesulfonyl)isoquinoline

Specified in the header of the get connection using 6-amino-1-chloroisoquinoline (example obtaining 23b) and 4-cyanobenzenesulfonyl, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 7,52 (1H, DD, J=2.0 a, 8,8 Hz), to 7.68 (1H, d, J=2.0 Hz), 7,79 (1H, d, J=5.6 Hz), 8,03 (4H, m), 8,18 (1H, d, J=5.6 Hz), 8,21 (1H, d, J=8,8 Hz), 11,36 (1H, s).

Synthetic example 62b

1-Chloro-6-(4-chlorobenzenesulfonamide)isoquinoline

Specified in the header of the get connection using 6-amino-1-chloroisoquinoline (example obtaining 23b) and 4-chlorobenzenesulfonamide, in the same manner as in synthetic example 1b.

1H-NMR (CDCl3)(M. D.): 7,33 (1H, CL), 7,39 (1H, DD, J=2.0 a, 8,8 Hz), 7,44 (2H, d, J=8,8 Hz) to 7.50 (1H, d, J=5.6 Hz), 7,58 (1H, d, J=2.0 Hz), 7,81 (2H, d, J=8,8 Hz), 8,24 (1H, d, J=5.6 Hz), of 8.25 (1H, d, J=8,8 Hz).

The Belarusian library Association-MS (FAB-MS; mass spectrometry with fast atom bombardment): 353.

Synthetic example 63b

1-Chloro-6-(4-pyrrolidin-1-ylsulphonyl)benzosulfimide)isoquinoline

Connection required gain, using 6-amino-1-chloroisoquinoline (example obtaining 23b) and 4-(pyrrolidin-1-ylsulphonyl)benzosulphochloride, same with m), 3,20 (4H, t, J=7.0 Hz), 7,46 (1H, d, J=5.4 Hz), 7,49 (1H, DD, J=2.0 a, 9,2 Hz), to 7.61 (1H, d, J=2.0 Hz), 7,87 (2H, d, J=8,8 Hz), 8,02 (2H, d, J=8,8 Hz), 8,19 (1H, d, J=9,2 Hz) to 8.20 (1H, d, J=5.4 Hz), 9,72 (1H, s).

Synthetic example 64b

1-Chloro-6-(4-(N-ethylsulfonyl)benzosulfimide)isoquinoline

Specified in the header of the get connection using 6-amino-1-chloroisoquinoline (example obtaining 23b) and 4-(N-ethylsulfonyl)benzosulphochloride, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 0,81 (3H, t, J=7.2 Hz), 2,73 (2H, m), 7,53 (1H, d, J=9,2 Hz), to 7.67 (1H, s), of 7.75 (1H, d, J=6.0 Hz), 7,78 (1H, d, J=6.0 Hz), 7,92 (2H, d, J=8.0 Hz).

Synthetic example 65b

1-Methoxy-6-(pyridine-3-ylsulphonyl)isoquinoline

Specified in the header of the get connection using 6-amino-1-methoxyethanol (example obtaining 43b) and 3-pyridinesulfonamide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 4.09 to (3H, s), to 7.09 (1H, d, J=6.0 Hz), 7,25 (1H, DD, J=2.0 a, 8,8 Hz), 7,37 (1H, d, J=8.0 a, 8,8 Hz), of 7.48 (1H, d, J=2.0 Hz), of 7.96 (1H, d, J=6.0 Hz), 8,07 (1H, DDD, J=1,6, of 2.0, 8.0 Hz), 8,14 (1H, d, J=8,8 Hz), a total of 8.74 (1H, DD, J=1,6, 8,8 Hz), the remaining 9.08 (1H, d, J=2.0 Hz).

ERIE-MS (ESI-MS; mass spectrometry with electrospray ionization): 316,0.

Synthetic example 66b

6-(4-Cyanobenzoyl isohedron (example obtaining 43b) and 4-cyanobenzenesulfonyl, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): of 3.97 (3H, s), 7,25 (1H, d, J=5.6 Hz), 7,32 (1H, d, J=8,8 Hz), 7,51 (1H, s), of 7.90 (1H, d, J=5.6 Hz), of 7.97 (2H, d, J=7,6 Hz), 8,01 (2H, d, J=7,6 Hz), 8,03 (1H, d, J=8,8 Hz).

Synthetic example 67b

6-(4-Carbamoyltransferase)-1-methoxyethanol

Specified in the header connection receive, using 6-(4-cyanobenzenesulfonyl)-1-methoxyethanol (example obtaining 65b) according to the method described in Synthesis, 949 (1989).

1H-NMR (DMSO-d6)(M. D.): 3,96 (3H, s), 7,24 (1H, d, J=6.4 Hz), 7,33 (1H, d, J=9,2 Hz), 7,51 (1H, s), 7,55 (1H, CL), 7,88 (1H, d, J=6.4 Hz), 7,89 (2H, d, J=8.0 Hz), to 7.93 (2H, d, J=8.0 Hz), 8,01 (1H, d, J=9,2 Hz), of 8.06 (1H, CL), 10,95 (1H, s).

THE BELARUSIAN LIBRARY ASSOCIATION-MS: 358.

Synthetic example 68b

6-(4-(N-Ethylsulfonyl)benzosulfimide)-1-methoxyethanol

Specified in the header of the get connection using 6-amino-1-methoxyethanol (example obtaining 43b) and 4-(N-ethylsulfonyl)benzosulphochloride, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 0,81 (3H, t, J=6.8 Hz), 2,71 (2H, m), of 3.96 (3H, s), 7.23 percent (1H, d, J=6.4 Hz), 7,32 (1H, d, J=8,8 Hz), of 7.48 (1H, s), 7,73 (1H, CL), 7,89 (2H, d, J=8.0 Hz), of 7.90 (1H, d, J=6.4 Hz), 8,01 (3H, m), 11,03 (1H, CL).

ERIE-MS (ESI-MS): the title compound get using 6-amino-1-methoxyethanol (example obtaining 43b) and 6-amino-3-pyridinesulfonamide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 3,96 (3H, s), to 6.39 (1H, d, J=8,8 Hz), 6.89 in (2N, C), 7,25 (1H, d, J=4, 2 Hz), 7,32 (1H, d, J=9,2 Hz), 7,47 (1H, s), to 7.64 (1H, d, J=9,2 Hz), 7,89 (1H, d, J=4, 2 Hz), 8,01 (1H, d, J=8,8 Hz), 8,31 (1H, s), 10,95 (1H, s).

ERIE-MS: 331,0.

Synthetic example 70b

1-Methoxy-6-(4-methylbenzenesulfonamide)isoquinoline

Specified in the header of the get connection using 6-amino-1-methoxyethanol (example obtaining 43b) and 4-toluensulfonate, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 2,28 (3H, s), of 3.96 (3H, s), 7,22 (1H, d, J=6.0 Hz), 7,32 (3H, m), of 7.48 (1H, s), 7,71 (2H, d, J=8,4 Hz), 7,88 (1H, d, J=6.0 Hz), 8,00 (1H, d, J=9,2 Hz), 10,79 (1H, s).

ERIE-MS: 329,0.

Synthetic example 71b

6-(4-Acetamidobenzenesulfonyl)-1-methoxyethanol

Specified in the header of the get connection using 6-amino-1-methoxyethanol (example obtaining 43b) and 4-acetamidobenzenesulfonyl, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): a 2.01 (3H, s), of 3.96 (3H, s), 7.23 percent (1H, d, J=6.0 Hz), 7,32 (1H, d, J.

Synthetic example 72b

6-(4-Methanesulfonylaminoethyl)-1-methoxyethanol

The compound was synthesized using 6-amino-1-methoxyethanol (example obtaining 43b) and 4-nitrobenzenesulfonamide, in the same manner as in synthetic example 1b, was processed in the same manner as in the example of obtaining 170b, to restore the nitrogroup. The compound obtained is dissolved in pyridine and cooled to this solution add methanesulfonate, followed by stirring for 4 hours. Add a saturated salt solution and then extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. After evaporation of the solvent the residue is purified on a column of silica gel and the obtained crystals are recrystallized from ethanol, getting listed at the beginning of the connection.

1H-NMR (DMSO-d6)(M. D.): a 3.06 (3H, s), of 3.97 (3H, s), from 7.24 (3H, m), 7,33 (1H, d, J=9.0 Hz), 7,49 (1H, s), 7,79 (2H, d, J=8,8 Hz), 7,89 (1H, d, J=6.0 Hz), 8,01 (1H, d, J=9.0 Hz), accounted for 10.39 (1H, s) 10,80 (1H, s).

ERIE-MS: 372,1.

Synthetic example 73b

6-(2-Chloropyridin-5-ylsulphonyl)-1-methoxyethanol

Specified in the header connection receive, and the as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): and 3.31 (3H, s) to 3.99 (3H, s), 7,30 (1H, d, J=6.0 Hz), 7,34 (1H, d, J=8,8 Hz), 7,56 (1H, s), 7,71 (1H, d, J=8,8 Hz), 7,92 (1H, d, J=6.0 Hz), of 8.06 (1H, d, J=8,8 Hz), 8,19 (1H, d, J=8,8 Hz), 11,13 (1H, s).

ERIE-MS: 350,1.

Synthetic example 74b

1-Methoxy-6-(3-methylbenzenesulfonamide)isoquinoline

Specified in the header of the get connection using 6-amino-1-methoxyethanol (example obtaining 43b) and 3-toluensulfonate, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 2,31 (3H, s), of 3.96 (3H, s), 7,22 (1H, d, J=6.0 Hz), 7,32 (1H, DD, J=2.0 a, 8,8 Hz), 7,39 (2H, m), 7,47 (1H, d, J=2.0 Hz), a 7.62 (1H, m), to 7.67 (1H, s), 7,87 (1H, d, J=6.0 Hz), 8,00 (1H, d, J=8,8 Hz), 10,84 (1H, s).

Synthetic example 75b

6 Benzylmethylamine-1-methoxyethanol

Specified in the header of the get connection using 6-amino-1-methoxyethanol (example obtaining 43b) and benzolsulfonate, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 4,13 (3H, s), 4,42 (2H, s), 6,69 (1H, CL), 7,13 (2H, m), 7,22 (2H, m), 7,30-7,37 (3H, m) to 7.50 (1H, d, J=2.4 Hz), to 7.99 (1H, d, J=6.0 Hz), to 8.20 (1H, d, J=8,8 Hz).

Synthetic example 76b

6-(3-Cyanobenzenesulfonyl)-1-methoxyethanol

Specified in sanischare, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 3,98 (3H, s), 7,28 (1H, d, J=6.0 Hz), 7,34 (1H, DD, J=2.0 a, 8,8 Hz), 7,53 (1H, d, J=2.0 Hz), of 7.75 (1H, DD, J=8,0, 8.0 Hz), to $ 7.91 (1H, d, J=6.0 Hz), of 8.04 (1H, d, J=8,8 Hz), of 8.09 (2H, m), 9,29 (1H, m) 11,05 (1H, s).

Synthetic example 77b

1-Methoxy-6-(4-thiazol-2-albenzaalbenza)isoquinoline

The compound (40 mg), obtained using 6-amino-1-methoxyethanol (example obtaining 43b) and 4-iodobenzonitrile, in the same manner as in synthetic example 1b, 2-tri-n-butylstannane (136 mg) and tetrakis(triphenylphosphine)palladium (0) (11 mg) is heated with boiling under reflux for one hour in toluene in a nitrogen atmosphere. After evaporation of the solvent the residue is purified on a column of silica gel. The obtained crystals are recrystallized from methanol, getting mentioned in the title compound (20 mg).

1H-NMR (CDCl3)(M. D.): 4,08 (3H, s) 6,94 (1H, CL), to 7.09 (1H, d, J=6.0 Hz), 7.23 percent (1H, DD, J=2.0 a, 8,8 Hz), 7,41 (1H, d, J=3.6 Hz), was 7.45 (1H, d, J=2.0 Hz), 7,89 (2H, d, J=8,4 Hz), of 7.90 (1H, d, J=8.6 Hz), 7,95 (1H, d, J=6, Hz) of 7.82 (2H, d, J=8,4 Hz), 8,13 (1H, d, J=8,8 Hz).

Synthetic example 78b

6-(4-Chlorobenzenesulfonamide)-1-methoxyethanol

Specified in the header with the mayor the same way, as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 4,00 (3H, s), 7,27 (1H, d, J=5.6 Hz), was 7.45 (1H, DD, J=2.0 a, 8,8 Hz), 7,53 (1H, d, J=2.0 Hz), 7,63 (2H, d, J=8,8 Hz), the 7.85 (1H, d, J=8,8 Hz), 7,92 (1H, d, J=5.6 Hz), of 8.06 (1H, J=8,8 Hz), 10,97 (1H, C).

Synthetic example 79b

6-(4-Chlorobenzenesulfonamide)-1-methylisoquinoline

Specified in the header of the get connection using 6-amino-1-methylisoquinoline (example obtaining 33b) and 4-chlorobenzene suphavilai, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): was 2.76 (3H, s), 7,56 (1H, d, J=6.0 Hz), 7,52 (2H, m), 7,60 (2H, d, J=8,8 Hz), 7,82 (2H, d, J=8,8 Hz), 8,08 (1H, d, J=9,2 Hz), to 8.20 (1H, d, J=6.0 Hz).

ERIE-MS: 333,0.

Synthetic example 80b

6-(4-Chlorobenzenesulfonamide)-1-utilizacion

Specified in the header of the get connection using 6-amino-1-utilizacion (example obtaining 48b) and 4-chlorobenzenesulfonamide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): of 1.39 (3H, t, J=7,6 Hz) at 3.25 (2H, K, J=7,6 Hz), 7,35 (1H, DD, J=2,4, 9,2 Hz), 7,38 (1H, d, J=5.6 Hz), 7,41 (2H, d, J=8,8 Hz), 7,53 (1H, d, J=2.4 Hz), 7,81 (2H, d, J=8,8 Hz), with 8.05 (1H, d, J=9,2 Hz), of 8.37 (1H, d, J=5.6 Hz).

ERIE-MS: 347,0.

Synthetic example 81b

6-(4-Chlorbenzyl the (sample receiving 66b) and 4-chlorobenzenesulfonamide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.}: of 1.18 (3H, t, J=7.2 Hz), 2,85 (2N, K, J=7,2 Hz), 7,38 (1H, d, J=8,8 Hz), 7,60 (1H, s), a 7.62 (2H, d, J=8.0 Hz), 7,82 (2H, d, J=8.0 Hz), 8,00 (1H, d, J=8,8 Hz), compared to 8.26 (1H, s), 8,99 (1H, s).

Synthetic example 82b

6-(4-Chlorobenzenesulfonamide)-4-methylisoquinoline

Specified in the header of the get connection using 6-amino-4-methylisoquinoline (example obtaining 58b) and 4-chlorobenzenesulfonamide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 2,43 (3H, s), 7,41 (1H, d, J=8,8 Hz), 7,56 (1H, s), a 7.62 (2H, d, J=8,8 Hz), the 7.85 (2H, d, J=8,8 Hz), to 7.99 (1H, d, J=8,8 Hz), compared to 8.26 (1H, s), 8,98 (1H, s), 11,09 (1H, CL).

Synthetic example 83b

6-(4-Chlorobenzenesulfonamide)-3-methylisoquinoline

Specified in the header of the get connection using 6-amino-3-methylisoquinoline (example obtaining 76b) and 4-chlorobenzenesulfonamide, in the same manner as in synthetic example 1b.

1H-NMR (DMSO-d6)(M. D.): 2,53 (3H, s), 7,30 (1H, d, J=8,8 Hz), 7,45 (1H, s) to 7.50 (1H, s), a 7.62 (2H, d, J=8,4 Hz), to 7.84 (2H, d, J=8,4 Hz), to 7.93 (1H, d, J=8,8 Hz), 9,03 (1H, s).

Synthetic example 84b

6-(4-Chlorobenzenesulfonamide)-1-cyanoethylene

Connection, p is m, as in synthetic example 1b, was dissolved in chloroform (150 ml). Under ice cooling to this solution was added m-chloroperbenzoic acid (0.9 g), followed by stirring at room temperature over night. The solvent is evaporated and the resulting crystals are washed with diethyl ether, collected by filtration and dried, obtaining 6-(4-chlorobenzenesulfonamide)isoquinoline-N-oxide (1,072 g). In acetonitrile (1.5 ml) dissolve 50 mg of the obtained product and to this solution is then added trimethylsilane (0,08 ml) and triethylamine (0.04 ml) followed by heating at boiling under reflux for 3.5 hours. After evaporation of the solvent the residue is purified on a column of silica gel, getting mentioned in the title compound (23 mg, 64%) as yellow crystals.

1H-NMR (DMSO-d6)(M. D.): 7,66 (2H, d, J=8,8 Hz), to 7.67 (1H, DD, J=2.0 a, 9,2 Hz), 7,80 (1H, d, J=2.0 Hz), to 7.93 (2H, d, J=8,8 Hz), 8,17 (1H, d, J=9,2 Hz), 8,18 (1H, d, J=5.6 Hz), 8,59 (1H, d, J=5.6 Hz).

ERIE-MS: 344,1.

Synthetic example 85b

1-Carbarnoyl-6-(4-chlorobenzenesulfonamide)isoquinoline

The crystals obtained from 6-(4-chlorobenzenesulfonamide)-1-cyanoethylene (30 mg, synthetic example 83b) according to the method described in Synthesis, 949 (1989), washed with di is-NMR (CDCl3)(M. D.): of 6.25 (1H, CL), 7,35 (2H, d, J=8,8 Hz), the 7.43 (1H, DD, J=2.0 a, 9,2 Hz), a 7.62 (1H, d, J=2.0 Hz), 7,66 (1H, d, J=6.8 Hz), 7,81 (2H, d, J=8,8 Hz), of 8.04 (1H, CL), of 8.37 (1H, CL), to 9.32 (1H, d, J=9,2 Hz), 9,76 (1H, CL).

Synthetic example 86b

6-(4-Chlorobenzenesulfonamide)-1-methylaminoethanol

1-Chloro-6-(4-chlorobenzenesulfonamide)isoquinoline (50 mg, synthetic example 61b) and 40% solution of methylamine in methanol (5.0 ml) is heated at 130°C in a sealed vessel for 18 hours. After cooling to content add aqueous saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. After evaporation of the solvent the residue is purified on a column of silica gel, getting mentioned in the title compound (28 mg, 52%) as a pale yellow solid.

1H-NMR (DMSO-d6)(M. D.): 3,14 (3H, s), with 5.22 (1H, CL), 6,89 (1H, d, J=6.0 Hz), 7,19 (1H, DD, J=2,4 Hz and 9.2 Hz), 7,31 (1H, d, J=2.4 Hz), 7,40 (2H, d, J=8,8 Hz), to 7.64 (1H, d, J=9,2 Hz), 7,73 (2H, d, J=8,8 Hz), 7,98 (1H, d, J=6.0 Hz).

Synthetic example 87b

1-Amino-6-(4-chlorobenzenesulfonamide)isoquinoline

The crystals obtained using 6-(4-chlorobenzenesulfonamide) isoquinoline-N-oxide (intermediate joint is m ether and dried, getting listed in the title compound (2 mg) as pale brown crystals.

1H-NMR (DMSO-d6)(M. D.): 7,76 (1H, d, J=6.0 Hz), 6,93 (2H, CL), to 7.15 (1H, DD, J=2.0 a, 8,8 Hz), 7,27 (1H, d, J=2.0 Hz), to 7.59 (2H, d, J=8,8 Hz), 7,63 (1H, d, J=6.0 Hz), 7,80 (2H, d, J=8,8 Hz), 9,05 (1H, d, J=6.0 Hz).

ERIE-MS: 334,1.

Synthetic example 88b

6-(4-Chlorobenzenesulfonamide)-1-dimethylaminoethanol

1-Chloro-6-(4-chlorobenzenesulfonamide)isoquinoline (synthetic example 61b, 60 mg) was dissolved in dimethyl sulfoxide (1 ml), to this solution is then added a 50% solution (0.04 ml) of dimethylamine in methanol followed by heating under stirring at 80°C for 10 hours. After cooling to content add water and then extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. After evaporation of the solvent the residue is purified preparative TLC and utverjdayut using isopropyl ether, getting mentioned in the title compound (17 mg).

1H-NMR (DMSO-d6)(M. D.): 2,96 (6N, (C), 7,12 (1H, d, J=6.0 Hz), 7,27 (1H, DD, J=2.0 a, 9,2 Hz), was 7.45 (1H, d, J=2.0 Hz), to 7.64 (2H, d, J=8,8 Hz), the 7.85 (2H, d, J=8,8 Hz), to 7.93 (1H, d, J=6.0 Hz), 8,01 (1H, d, J=9,2 Hz), 10,91 (1H, CL).

Synthetic example 89b

omegaton connection in synthetic example 83b, 50 mg) is dissolved in acetic anhydride (0.75 ml) followed by heating under stirring at 80°C for 16 hours. The mixture is then refluxed for 2 hours. After cooling, add aqueous saturated sodium bicarbonate and then extracted with ethyl acetate. The extract is washed with saturated salt solution and dried over anhydrous magnesium sulfate. After evaporation of the solvent the residue is dissolved in ethanol (2.0 ml) and water (0.5 ml) and then heated to boiling under reflux for 0.5 hours. After evaporation of the solvent the residue is purified on a column of silica gel, getting mentioned in the title compound (20 mg) as a pale red solid.

1H-NMR (CDCl3)(M. D.): to 6.58 (1H, d, J=7,2 Hz), 7,22 (1H, d, J=7,2 Hz), 7,31 (1H, DD, J=2.0 a, and 8.4 Hz), 7,54 (1H, d, J=2.0 Hz), 7,56 (2H, d, J=8,8 Hz), 8,01 (2H, d, J=8,8 Hz), 8,53 (1H, d, J=8,4 Hz), 10,36 (1H, CL).

ERIE-MS: 335,1.

Synthetic example 90b

6-(4-Chlorobenzenesulfonamide)-1-ethoxyethanol

1-Chloro-6-(4-chlorobenzenesulfonamide)isoquinoline (synthetic example 61b, 57 mg) was dissolved in dimethyl sulfoxide (1 ml). Add ethanol (0.1 ml) and 60% sodium hydride (14 mg) and then heated under stirring at 80°C for 9 tworoom salt and dried over anhydrous magnesium sulfate. After evaporation of the solvent the residue is purified preparative TLC and utverjdayut using isopropyl ether, getting mentioned in the title compound (21 mg).

1H-NMR (DMSO-d6)(M. D.): to 1.38 (3H, t, J=7.2 Hz), 4,46 (2N, K, J=7,2 Hz), 7,24 (1H, d, J=6.0 Hz), 7,35 (1H, DD, J=2.0 a, 9,2 Hz), to 7.50 (1H, d, J=2.0 Hz), 7,63 (2H, d, J=8,8 Hz), of 7.90 (1H, d, J=6.0 Hz), of 8.04 (1H, d, J=9,2 Hz), 10,94 (1H, CL).

Synthetic example 91b

N-(5-Vinylpyridin-2-yl)-3-pyridinesulfonamide

A solution containing 2-amino-5-bromohydrin (510 mg, example of obtaining 1b), vinyltrimethylsilane (0,94 ml), toluene (4 ml), tetranitropentaerithrite (0 valence) (20 mg) and 2,6-di-tert-butyl/p-cresol (about 0.1 mg) was stirred at 120°C for 4 hours. After the reaction mixture reaches room temperature, add water and then extracted with ethyl acetate. An ethyl acetate layer is dried over sodium sulfate and concentrated. Then the obtained solid is washed with hexane, getting 282 mg of solid substances, including vinylacetate substance. The solid is dissolved in 2 ml of pyridine and to this add 412 mg of 3-pyridinesulfonamide, followed by stirring at room temperature over night. Add water and then extracted is washed with methanol, getting listed in the title compound (235 mg).

1H-NMR (CDCl3)(M. D.): 5,59 (1H, DD, J=10,8 Hz, 1.5 Hz), of 5.82 (1H, DD, J=16.9 and Hz, 1.5 Hz), to 6.95 (1H, d, J=10.3 Hz), 7,20 (1H, DD, J=10,8 Hz and 16.9 Hz), was 7.36 (1H, d, J=8.5 Hz), the 7.43 (1H, m) to 7.50 (1H, d, J=8.5 Hz), a 7.62 (1H, t, J=8.5 Hz), 8,24 (1H, d, J=10.3 Hz), 8,29 (1H, m), a total of 8.74 (1H, m), which 9.22 (1H, m).

Synthetic example 92b

N-(4-Triptorelin-7-yl)-4-chlorobenzenesulfonamide

203 mg (0.96 mmol) of 4-chlorobenzenesulfonamide added to a solution (3 ml) of pyridine containing 200 mg (0.87 mmol) of 7-amino-4-triptorelin and 1 mg of 4-dimethylaminopyridine, followed by stirring at 70°C for 50 minutes. Add 2 N. aqueous hydrochloric acid and then extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution, dried over magnesium sulfate and evaporated. The resulting residue is crystallized from a mixture of ethyl acetate-diisopropyl ether, getting 253 mg specified in the title compounds as a pale yellow solid.

1H-NMR (DMSO-d6)(M. D.): 6,87 (1H, s), 7,12 (1H, d, J=2.4 Hz), 7,17 (1H, DD, J=2,6, and 8.4 Hz), 7,60 (1H, d, J=8,4 Hz), to 7.67 (2H, d, J=6.8 Hz), 7,87 (2H, d, J=6.8 Hz), of 11.29 (1H, s).

Claims

1. The inhibitor of the expression of interest>, pharmacologically acceptable its salt or hydrate:

where in the formula the ring Andarepresents a monocyclic or bicyclic aromatic ring which may have a Deputy; ringais optionally substituted 6-membered cyclic unsaturated hydrocarbon or unsaturated 6-membered heterocycle containing one nitrogen atom as heteroatom; ringarepresents an optionally substituted 5-membered heterocycle containing 1 or 2 nitrogen atom; R1arepresents a hydrogen atom or C1-C6 alkyl group; Wandrepresents a single bond or-CH=CH-; Yarepresents a carbon atom or a nitrogen atom; Zarepresents-N(R2a)-, where R2adenotes a hydrogen atom or a lower alkyl group, or a nitrogen atom, respectively.

2. The inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida under item 1, pharmacologically acceptable its salt, or a hydrate, where Wadenotes a single bond.

3. The inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida under item 1, pharmacologically acceptable its salt, or both is Yes.

4. The inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida under item 1, pharmacologically acceptable its salt, or a hydrate, where the ring Inarepresents an optionally substituted benzene or pyridine.

5. The inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida according to any one of paragraphs.1-4, pharmacologically acceptable its salt, or a hydrate, where the ring Withais optionally substituted pyrrole.

6. The inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida under item 1, pharmacologically acceptable its salt, or a hydrate, where the ring Andarepresents a benzene or pyridine which may have a Deputy; ringarepresents benzene which may have a Deputy; ringais pyrrole which may have a Deputy; Waindicates a single bond; Zais-NH-.

7. The inhibitor of expression of integrin containing as an active ingredient sulfonamides heterocyclic compound represented by formula (Ib), a pharmacologically acceptable its salt or hydrate:

where the ring Qbmeans an aromatic ring which may have one or two nitrogen atom; ring Mbdenotes a C5-C12 unsaturated monocycle or a heterocycle having a double bond, in common with the ring Qbthe ring may have from 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, the ring Qband the ring Mbmay have a common nitrogen atom, the ring Qband the ring Mbmay have a Deputy, selected from the following group a;bdenotes a single the other and each means hydrogen atom or a C1-C4 alkyl group; mbdenotes an integer of 1 or 2; Tb, WbXband Ybare the same or different from each other and each means =C(Db)-, where Dbrepresents a hydrogen atom, halogen atom, hydroxyl group, C1-C4 alkyl or alkoxygroup, which may be substituted by halogen atom, cyano, -(CO)bnNR6bR7bwhere R6band R7bare the same or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted by a halogen atom; nbmeans 0 or 1, or C2-C4 alkenylphenol or alkenylphenol group which may have a Deputy, respectively, or a nitrogen atom; Uband Vbare the same or different from each other and each means =C(Db)-, where Dbhas the same meaning as described above, a nitrogen atom, -CH2-, an oxygen atom or-CO-; Zbdenotes a single bond or-CO-NH-; R1bdenotes a hydrogen atom or a C1-C4 alkyl group; anddenotes a single bond or a double bond;

group a: a halogen atom, hydroxyl group, C1-C4 alkyl or alkoxygroup, which may be substituted by a halogen atom, C is from each other and each means hydrogen atom or a C1-C4 alkyl group, which may be substituted by a halogen atom; and Rbis 0 or 1; or R8band R9bmay form a 5 - or 6-membered ring together with the nitrogen atom to which they relate, and the ring may optionally contain a nitrogen atom, oxygen atom or sulfur atom and, in addition, may have a Deputy), aminosulfonyl group which may be substituted mono - or di-C1-C4 alkyl group, C1-C8 acyl group which may have a Deputy, C1-C4 alkyl-S(O)bs-C1-C4 Allenova group, where sbmeans the integer 0, 1 or 2, phenylcarbonylamino, which may have a C1-C4 alkyl or Deputy, - (CO)bqNR10bR11bwhere R10band R11bare the same or different from each other and each means hydrogen atom or a C1-C4 alkyl group which may be substituted amino group which may be substituted by halogen atom or C1-C4 alkyl group; and qbmeans 0 or 1, or aryl group or heteroaryl group which may have a Deputy.

8. The inhibitor of expression of integrin containing as an active ingredient sulfonamides heterocyclic compound under item 7, pharmacologically acceptable its salt or their guy is, or a nitrogen atom.

9. The inhibitor of expression of integrin containing as an active ingredient sulfonamides heterocyclic compound under item 7, pharmacologically acceptable its salt, or a hydrate, where Zbrepresents a single bond.

10. The inhibitor of expression of integrin containing as an active ingredient sulfonamides heterocyclic compound according to any one of paragraphs.7-9, pharmacologically acceptable its salt, or a hydrate, where at least one of the TbUb, VbWbXband Ybrepresents a nitrogen atom.

11. The inhibitor of expression of integrin containing as an active ingredient sulfonamides heterocyclic compound according to p. 10, pharmacologically acceptable its salt, or a hydrate, where abrepresents a halogen atom, C1-C4 alkyl group, or alkoxygroup, which can be substituted by a halogen atom, a cyano, (CO)brNR12bR13bwhere R12band R13bare the same or different from each other and each represents a hydrogen atom or a C1-C4 alkyl group which may be substituted by a halogen atom; and rbis 0 or 1, or C2-C4 alkenylphenol or alkenylphenol group, to the enta sulfonamides heterocyclic connection on p. 11, pharmacologically it acceptable salt or hydrate, where only one of the TbUb, Vb, WbXband Ybrepresents a nitrogen atom.

13. The inhibitor of expression of integrin containing as an active ingredient sulfonamides heterocyclic compound according to p. 12, pharmacologically acceptable its salt, or a hydrate, where only one of the Tb, Wband Ybrepresents a nitrogen atom.

14. The inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida on p. 13, pharmacologically acceptable its salt, or a hydrate, where the integrin is2,3,5,6,v,1,3,4 or5 integrin.

15. The inhibitor of expression of integrin containing as an active ingredient the compound sulfonamida on p. 13, pharmacologically acceptable its salt, or a hydrate, where the integrin is21,361,v1,v3 orv5 integrin.

16. For the treatment of a disease selected from arteriosclerosis, psoriasis, osteoporosis, angiogenesis, retinal angiogenesis, diabetic retinopathy, inflammatory diseases or diseases associated with increased blood clotting by inhibiting the expression of integrin containing compound sulfonamida defined in any of paragraphs.1-13, pharmacologically acceptable its salt or hydrate.

17. Means on p. 16, where the disease is arteriosclerosis, psoriasis, osteoporosis or disease associated with hypercoagulability.

18. The way to prevent, cure or alleviate disease, which is an effective inhibition of the expression of integrin, with the exception of cancer and cancer metastasis, by introducing the patient a pharmacologically effective dose of the compounds sulfonamida represented by any of formulas (Iaor (Ib) defined in paragraph 1 or 7, pharmacologically acceptable the military in paragraph 1 or 7, pharmacologically acceptable salts thereof or their hydrate to obtain funds for the prevention, cure or relief of the disease, which is an effective inhibition of the expression of integrin, except funds for cancer treatment or cancer metastasis.



 

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