Method of producing pyridazineamines or pharmaceutically acceptable salts of acids thereof,or stereo

专利摘要:
Pyridazinamines of the formula and their pharmaceutically acceptable acid addition salts and/or possible stereochemically isomeric forms and/or tautomeric forms for use as medicines in particular for use as anti-viral agents; pharmaceutical compositions containing such compounds as an active ingredient and a method of preparing such compositions; novel pyridazinamines of the fnrmula and a method of preparing said compounds
公开号:SU1384198A3
申请号:SU853867689
申请日:1985-03-22
公开日:1988-03-23
发明作者:Антуан Стокброекс Раймонд；Йозеф Мария Ван Дер АА Марсель；Иозефус Мария Виллемс Йоаннес；Геребернус Мария Люикс Марсель
申请人:Жансен Фармасетика,Н.В. (Фирма)；
IPC主号:

专利说明:

(21) 3867689 / 23-04
(22) 03.22.85
(31) 593444; 702772
(32) 03/26/84; 02/15/85
(33) US
(46) 03/23/88. Bul № 11
(71) Zhansen Pharmasetika, N.V. (BE)
(72) Raymond Antoine Stockbroex, Marcel Joseph Marie van der Aa, Johannes Josephus Marie Willems
and Marcel Hereburnus Marie Luiks
(53) 547.852.2.07 (088.8)
(56) Weigand-Hilgetag. Experimental methods in organic chemistry, -M .: Chemistry, 1968, p. 427.
(54) A METHOD FOR OBTAINING PYRIDAZINAMINS OR THEIR. PHARMACEUTICALLY ACCEPTABLE FROM THE ACCESSION OF ACIDS, OR THEIR STEREOCHEMICAL ISOMERS, OR THEIR TAUTOMERS.
(57) The invention relates to heterocyclic compounds, in particular to the preparation of the pyridazinamine formula.
  NN CRN.
- CR
CR,
or their pharmaceutically acceptable acid addition salts, or their sterearchic isomers, or their tautomers, where R is hydrogen, halogen, lower alkyl, 1H-imidazol-1-yl, lower alkoxy, aryloxy, lower alkylthioarylthio, hydroxy, mercapto , lower alkylsulfonyl, lower alkylsulfonyl, cyano, lower alkoxycarbonyl, lower alkylcarbonyl; R "j and R, independently of each other, hydrogen and lower alkyl, or R and Rj form a bivalent radical of the formula —CH — CH — CH CH —J A — bivalent SC, —C„ H ,, - (d),
hydrogen in the radical ,, „, S.,
ny radical of formula (a),
- with H2 "- (krsn" n, - (b), - with 2mC (Rj) R6 - (s) or C, H5., R, C where one of the atoms
H,
or C „H, 2, may be substituted by lower alkyl; type is independently from each other integers from 1 to 4 inclusive, and the sum of the type is 3.4 or 5; R4- is aryl, pyrimidinyl, quino (BE) LIN, lower alkylcarbonyl, aryl-lower alkyl, pyridinyl, unsubstituted or substituted with cyano or lower alkyl, cyclohexyl, unsubstituted or substituted with cyano or aryl; RS is hydrogen, aryl, hydroxy, aryloxy, lower alkyl, lower alkoxy, substituted by morpholine, pyrrolidine, or piperidine — arylamino, (aryl) - (lower alkyl) -amino, phenylcarbonyloxy, aryl — lower alkyl amino ; RC — hydrogen, lower alkyl, aryl, aryl — lower alkyl, arylcarbonyl — lower alkyl, arylcarbonyl, aryl — lower alkylcarbonyl, aminocarbonyl, indolyl; R-, and Rg - independently of each other; H, lower alkyl, aryl, aryl - lower alkyl, where arylphenyl, unsubstituted or substituted by up to 3 substituents, each of which may be halogen, lower alkyl, trifluoromethyl, nitro, amino, lower alkoxy, hydroxy, lower alkoxycarbonyl, thienol, and naphthalenyl, provided that i) if A is a radical of formula (c) and RJ is hydrogen, then RJ is different from H, hydroxy - groups or lower alkyl, ii) if, RJ and R g are hydrogen, and A is a radical
SC, -С „Н ,, - (d),
hydrogen in the radical ,, „, S.,
C (Rj) R6 - (c) or C, H5., R, C where one of the atoms
H,
or C „H, 2, may be substituted by lower alkyl; type is independently from each other integers from 1 to 4 inclusive, and the sum of the type is 3.4 or 5; R4- is aryl, pyrimidinyl, quinoLIN, lower alkylcarbonyl, aryl-lower alkyl, pyridinyl, unsubstituted or substituted by cyano or lower alkyl, cyclohexyl, unsubstituted or substituted by cyano or aryl; RS is hydrogen, aryl, hydroxy, aryloxy, lower alkyl, lower alkoxy, substituted by morpholine, pyrrolidine, or piperidine — arylamino, (aryl) - (lower alkyl) -amino, phenylcarbonyloxy, aryl — lower alkyl amino ; RC — hydrogen, lower alkyl, aryl, aryl — lower alkyl, arylcarbonyl — lower alkyl, arylcarbonyl, aryl — lower alkylcarbonyl, aminocarbonyl, indolyl; R-, and Rg - independently of each other; H, lower alkyl, aryl, aryl - lower alkyl, where arylphenyl, unsubstituted or substituted by up to 3 substituents, each of which may be halogen, lower alkyl, trifluoromethyl, nitrogrupp
from 00
four
WITH
oo

cm
of formula (b), then R differs from 3,3-diphenylpropyl, iii) if R and R ,, are hydrogen, and A is a radical of formula (a), then Ry differs from halide, iv) if R ,, is C1 , R and R, is hydrogen, and A is a radical of formula (b), then R differs from 2-methoxy phenyl} v) if R i is C, and A is a radical of formula (b), then R is different from di - methoxyphenylmethyl, dimethoxyphenylethyl, c-methylphenylethyl or (2-Me84198
Tylphenyl) methyl. The goal is to develop a method for obtaining new compounds of the indicated class, which possess antiviral activity. Their preparation is carried out by alkylation of the corresponding amine with halogen-containing pyridazine with isolation of the target product in free form or in the form of the indicated salts, isomer or in the form of tautomer. 5 tab.
. .one
This invention relates to a process for the preparation of new pyridazinamines, which have antiviral activity and can be used in medicine.
The purpose of the invention is a method for producing new pyridazinamines having antiviral activity that is not. Beta is known in the pyridazinamine range.
Example 1. A mixture of 3.1 parts of 3,6-α-dichloropyridazine, 3 hours, 1- (2-fluorophenyl) piperazine 5, 3.2 hours of sodium carbonate, .0.1 parts of potassium iodide and 72 hours K, K-dimethylformamide is stirred and heated for 2 days at 60 ° C. The reaction mixture is drunk in water. The precipitated product is filtered off and dissolved in trichloromethane. The organic layer is dried, filtered and evaporated. The residue is clear; Filtration is carried out on silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as solvent. The pure fractions are collected and the eluent is distilled off. The residue was crystallized from a mixture of 2-propanol and 2,2-oxnibispropane, to obtain 4.5 parts (77%) of 3-chloro-6- 4- (2- fluorobenyl phenyl) -1 -piperazinyl 2-pyridazine, t .pl. 148, (compound 9).
In tab. 1 shows the designations of the radicals R ,. R and A in compounds 1, prepared according to the procedure described in example 1, and the melting points of the obtained compounds 1.
Example 2, Mixture of 2.7 parts of 3,6-difluoropyridazine, 4.6 parts of 1,3- (trifluoromethyl) fensch1 piperazine, 3.2 parts of sodium carbonate and 90 parts of H, M-dimethylformamide stirred for
12 hours, at. The reaction mixture is poured into water. The product is filtered, washed with water and crystallized from 2-propanol to give 3 h. (46Х) 3-fluoro-6- 4- (3-trifluoromethyl) phenyl-1-piperazinylpyridazine, m.p. 131.5 ° C (compound 24). Analogously, the following are obtained: (2,3-dimethylphenyl) -1-pipera-0 zinyl-6-fluoropyridazine, mp. 144, (compound 25);
 3-fluoro-6- 4- (3-methylphenyl) -1-piperazinyl pyridazine; m.p. 128, (building 26);
 , 6-dihydro-4- (3-methylphenyl) -1 -1 (2H) -nridinyl} -6-fluoropyridazine, m.p. 105.2 ° C (compound 27).
Example 3. A mixture of 4.5 parts of 3,6-d-ichloropyridazine, 5.2 parts of 1,2,3,6-0-tetrahydro-4- (3-methylphenyl) pyridine, 5.3 parts of sodium carbonate and 72 hours; N, N-dimethylformamide is stirred and heated for .12 hours at 70 ° C. The reaction mixture is evaporated and water is added to the residue; The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by filtration on silica gel using a mixture of trichloromethane and methanol (98: 2 by volume) as eluent. The pure fractions are collected and the eluent is distilled off. The residue is crystallized from 2-propanol. The product is filtered off and dried, yielding 2.1 h (24%) of 5 3-chloro-6- 3,6-dihydro-4- (3-methylphenyl) -1 (2H) -pyridinyl pyridazine; m.p. 122.2 ° C (compound 28).
In tab. 2 shows the designations - radicals R, l A in the compounds, semi5
0
according to the procedure described in Figure 3 and the melting point of the compounds obtained.
Analogously to Example 3, 4- (6-chloro-5-methyl-3-pyridazinyl) -1-piperazinecarboxylic acid ethyl ester is obtained, mp, 132, (compound 135) .10
Example 4. A mixture of 5 parts of 1- (3-. -Methylphenyl) piperazine dihydrochloride, 10.6 parts of sodium carbonate and 180 hours of N, N-dimethylformamide was stirred for 1 hour at 65 ° C. Then 7.2 parts 15 of 3,6-dibrampyridazine are added and the whole is stirred for 12 hours at 65 ° C. The reaction mixture was poured into ice water. The product is filtered and dissolved in dichloromethane. Solution 20 is washed twice with water, dried, ilted and evaporated. The residue is crystallized from ethanol. The product is filtered off and dried, yielding 4.1 parts (61.5%) of 3-bromo-6-4- (3-methylphenyl) -25 -1-piperazinyl} pyridazine m.p. 145.7 ° C (compound 136).
Analogously to example 4 receive:
3-bromo-6- 4- (2,3-dimech ylphenyl; -1- piperazinyl pyridazine, mp.166.7 ° C. Q (compound 137)
3-bromo-6-14- (3-chlorophenyl) -1-piperazinyl} pyridazine, m.p. 158.7 ° C (“Compound 118);
3-bromo-6-p-t3- (triphosphoromethyl) phenyl3-1-piperazinyl} pyridazine, mp. 154.3 ° C (compound 139);
3-bromo-6- 4- (2-methoxyphenyl) -1-piperazinyl pyridazine, m.p. 164.8 ° C (compound 140)
3-bromo-6- 4- 3- (trifluoromethyl) phenyl -1-piperidinyl pyridazine monohydrochloride, m.p. 222.5 ° C (compound 141) J
3-bromo-6- {3, b-dihydro-4- 3- (triormethyl) phenyl -1 (2H) -pyridinyl - -pyridazine, t. Pl. 130.6 ° C (compound 142);
1- (6-bromo-3-pyridazinyl) -4- (3-chlorophenyl) -hexahydro-1H-1,4-diazepine, m.p. 148.8 C (compound 143), 50
3-bromo-6- 4- (3-bromophenyl) -1-pipazazalpyridazine, m.p. 179.8 ° C (compound 144);
3-bromo-6-3, b-dihydro-4- (3-methyl-phenyl) - (2H) -pyridinyl pyridazine, 55 mp, 127, (compound 145),
Example 5. A mixture of 4.5 parts of 3,6-dichloropyridazine, 4.9 h, H-13- (three
45

Q
0
five
five
five
fluoromethyl) phenyl-3-piperidinamine, 6.4 parts of sodium carbonate and 1aO parts of N, N-dimethylformamide are stirred for 12 hours at 65 ° C. The reaction mixture is drunk in ice water and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by chromatography on a column of silica gel, using a mixture of three chloromethane and methanol (99: 1 by volume) as
: eluent. The pure fractions are collected and the eluent is distilled off. Crystalline residue
: are made from 2-propanol. The product was filtered off (the filtrate was saved) and dried, yielding 1.2 parts (16.8%) of 1- (6-chloro-3-pyridazinyl) (trifluoromethyl) phenyl j-3-piperidinamine, m.p. 92.6 ° C. (compound 146).
The stored filtrate is converted to the hydrochloride salt in 2-propanol. The salt was filtered off and dried, yielding 2.6 parts (32.9%) of 1- (6-chloro-3-pipidazinyl) (trifluoromethyl) -phenyl-3-piperidinamine monohydrochloride, m.p. 173.5 C (compound 147).
Example 6. A mixture of 3 parts of 3,6-dichloropyridazine, 6.1 parts of (trifluoromethyl) phenyl-4-piperidinamine d hydrobromine-, 6.4 parts of sodium carbonate and 180 parts of N, K-dimethylac etamide stirred. 24 h at 60 ° C. After cooling to room temperature, the reaction mixture is poured onto water. The product is extracted with methyl benzene. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column chromatography on silica gel and using a mixture of three chloromethane and methanol (97: 3 by volume) as eluent. The pure fractions are collected and the solvent is distilled off. The residue is crystallized from 2,2-oxy-bispropane. The product is filtered off and dried, yielding 2.5 parts (47%) of 1- (6-chloro-3-pyridazinyl) -N-13- (trifluoromethyl) phenyl} -4-piperidinamine, m.p. 117, ( connection 148).
In accordance with the described procedure and using equivalent amounts of suitable starting materials, also compounds 1 are obtained, the melting point of which and the designations of the radicals are given in table. 3
Example 7. A mixture of 5.2 parts of 3,6-diiodo-pyridazine, 3.5 parts of 1- 3- (three
fluoromethyl) phenyl piperazine, 3.2 parts of sodium carbonate and 90 hours N, K-dimethylacetamide is stirred and heated for 12 hours at 70 ° C. Pour the reaction mixture into water. The precipitated product is filtered off and crystallized from 2-propanol, yielding 3.2 parts (48%) of 3-iodo-6-4-H3- (trifluoromethyl) phenyl -1-piperazinyl pyridazine, m.p. 144.6 ° C. (compound 202).
Analogously to example 7 receive:
H-iodo-6- 4- (3-methylphenyl) -1-piperazinyl pyridazine, m.p. 163, (compound 203) j
(3-chlorophenyl) - 1-piperazinyl, -6-iodopyridazin, t. Pl. 165.0 C (compound 204), 3-t4- (2,3-dimethylphenyl) -1-pipetrazinyl-6-iodopyridazine, mp.179.4 (compound 205)
H-iodo-6- 4- 3- (trifluoromethyl) phenylJ-1-piperidinyl pyridazine, m.p. 106.8 ° C (compound 206).
Example 8. A mixture of 4.6 parts of 1- -f3- (trifluoromethyl) phenyl J piperazine, 6.4 parts of sodium carbonate and 160 hours, 4- -methyl-2-pentanone is subjected to azeotropic distillation for drying. 3.3 parts of 3,6-dichloropyridazine are added and the whole is stirred and refluxed for 48 hours using a water separator. After cooling, water is added and the product is extracted with dichloromethane. The organic layer is dried, filtered and evaporated. The residue is purified by chromatography on a column of silica using a mixture of trichloromethane and methanol (99: 1 by volume) as eluent. Collect the pure fractions and eluent is distilled off. The residue is crystallized from 2-propanol to obtain 2.6 parts of (37.9) 3- -chloro-6-4-13- (trifluoromethyl) phenyl -1 -1 piperazinyl} pyridazine t „pl. 149.4 C (compound 207).
Example 9 To a stirred solution of 7.5 parts of 3,6-dichloropyridazine in 75 parts of N, N-dimethylformamide, a solution of 8 parts of ethyl ester of 1-piperazinecarboxylic acid and 5.6 parts of N are added dropwise. , N-diethylethanamide in 25 h. N, N-dimethylformade. After the addition is complete, it is stirred for 12 hours at a temperture of about 50 ° C. After cooling, the reaction mixture is poured onto water and the product is extracted with trichloromethane.
five
0
50
five
five
0
986
The organic layer was dried, filtered and evaporated. The residue was crystallized from 2-propanol to give 3.6 parts of 4- (6-chloro-3-pyridazinyl) -1-piperazinecarboxylic acid ethyl ester, m.p. 123.8 ° C. (compound 208).
Example 10. A mixture of 3.2 h, 3- -chloro-6- (methylsulfonyl) pyridazine, i 3 parts of 1- (3-methylphenyl) piperazine, 2 parts of N, N-diethylethanamine and 180 parts of benzene is stirred for 24 hours when boiling under reflux. The reaction mixture is evaporated. Water was added to the residue. The precipitated product is filtered off, washed with water and dissolved in trichloromethane. The solution is dried, filtered and evaporated. The residue is crystallized from methanol .. The product is filtered and dried to give 5 parts (89%) of 3-14- (3-mets1-phenyl) -1-piperazinyl-6- (methylsulfonyl) pyridazine, mp. 20l c (compound 209).
Analogously to example 10 receive:
(3-Methylphenyl) -1-piperazinyl-6- (methylsulfonne 1) pyridazine, mp, 146, (compound 210);
, 6-dihydro-4- (3-methylphenyl) -1 -1 (2H) -pyridines -1-6- (methylsulfone) - pyridazine, m.p. 179, (compound 211) 5
3- (3, b-dihydro-4- (3-methylphenyl) -g-1 (2H) -pyridinsh1 -b- (methylsulfonyl) -pyridazine, mp. 131.0 ° C (compound 212).
-Example 11. A mixture of 3.3 parts of 3,6-dichlorpyridine, 3.3 parts of 1- (2-pyridinyl) piperazine, 1.5 parts of sodium bicarbonate and 120 hours, ethanol permutated and boil it under reflux for 48 hours. The reaction mixture is evaporated. Water is added to the residue and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column using a mixture of trichloromethane and methanol (99: 1 by volume) as eluent. The pure fractions are collected and the eluent is distilled off. The residue is crystallized from a mixture of 2-propanol and tetrahydrofuran to give 2.5 parts (54.3%) of 3-chloro-6- 4- (2-pyridine: yl) -1- piperazinyl, m.p. 194.7 ° C (compound 213).
Example 12. A mixture of 3.2 parts of 3- chloro-b- (methylthio) pyridazine, 3.14 parts of 1,2,3,6-tetrahydro-4- (3-methylphenyl)
7
pyridine hydrochloride, 5.3 parts of sodium carbonate and 80 parts of 1-butanol are stirred for D8 hours at reflux temperature. The reaction mixture is evaporated. Water is added. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is purified by chromatography on a column of silica gel using a mixture of trichloromethane and methanol (98: 2 vol.) As eluent. The pure fractions are collected and the eluent is distilled off. The residue is crystallized from 2-propanol. The product is filtered and dried to give 0.8 parts (18%), 6-dihydro-4- (3-methylphenyl) -1 (2H) -pyridinyl-6- (methylthio) pyrid, zine, t. square 129.8 C (compound 214),
Example 13. To a stirred solution of 300 parts of hexahydro-1H-1,4-diazepine in 900 parts of methylbenzene, 75 parts of 3,6-dichloropyridazine were added. All this is stirred and boiled under reflux for 4 hours. The reaction mixture is evaporated. Water was added to the residue. The product is extracted with trichloromethane. The extract is dried, the filter


rut and evaporated. The residue is converted., And the filtrate is purified by chromatography
to hydrochloride salt in 2-propanol and ethanol. The salt is filtered off and dried, yielding 28 parts (22%) of 1- - (b-chloro-3-pyridazinyl) -hexahydro-1H-1,4-diazepine monohydrochloride (compound 215).
Example 14. A mixture of 3.9 parts of 3,6-dichlo-4,5-dimethylpyridazine, 4.2 hours, 1- (2,3-dimethylphenyl) piperazine and 2.94 tf. potassium carbonate is stirred and heated for 4 hours in an oil bath at 190 ° C. After cooling, the mixture is taken up in water and trichloromethane. The organic layer is separated, dried, filtered and evaporated. The residue is crystallized from 2-propanol. The product is filtered off and dried with a half ture of 2 parts (30%) of 3-chloro-6-14- (2,3-dimethylphenyl) -1-piperazinyl J-4,5-dimethylpyridazine, t. Pl. 194.5 seconds (compound 217).
. Analogously to Example 14, the following are obtained: H-chloro-4,5-dimesh-1-6-4- (Z-methylphenyl) -1-piperazinyl pyridazine, mp.
172, (compound 218)
4- (3-methylphenyl) -1- (6-methyl-3-pyridazinyl) -4-piperidinol, m.p.
131, (compound 219),
35
40
45
50
55
on a column of silica gel using a mixture of trichloromethane and methane la (95: 5 by volume) as eluent. The pure fractions are collected and the elite is distilled off. The residue is crystallized from 2,2-oxybispropane. The product is filtered and dried to give 1.7 parts (27%) of 3- (4-ethylphenoxy) -6- - (3-methylphenyl), -1-piperazinyl pyrizine, m.p. 106.6 ° C (compound 22
Analogously to example 16, Z-methyl-6-t4- (3-methylphenyl) -1-p perazinyl pyridazine is obtained, m.p. 152, (compound 222) -,
(3-methylphenyl) -1-piperazine-6- (methylthio) pyridazine, m.p. 145 (compound 223). Example 17. According to the method of any one of Examples 1-16, using the appropriate starting materials, they are:
3- (3,5-dimethylphenoxy) -6- (1H-im Dazol-1-yl) pyridazine, so pl. (compound 2)
3- (1H-imidazol-1-yl) -6- (4-methyl phenoxy) pyridazine, m.p. 146 ° С (compound 3);
0
4198
0
five
five
eight
Example 15. A mixture of 3.5 parts of N- - (6-chloro-3-pyridase ynyl) acetamide, 3.6 parts of 1- (3-methylphenyl) piperazine and 2.8 parts of potassium carbonate is stirred for 7 hours per oil Noah bath at 16 0 ° C. After cooling, trichloromethane and water are added. The layers are separated. The organic layer is dried, filtered and evaporated. The residue is purified by chromatography on a silica gel column using a mixture of trichloromethane and methanol (97: 3 by volume) as eluent. A second fraction is collected and the eluent is distilled off. The residue is converted to the hydrochloride salt in 2-propanol and 2-propanol. The salt is filtered and dried to give 0.5 h (6.6%) of 6- - 4- (3-methylphenyl) -1-piperazinylJ-3-pyridazinamine and dihydrochloride, m.p. 178, (Compound 220).
Example 16 A mixture of 4 hours, 6-chloro-3- (4-ethylphenoxy) pyridazine and 6 parts 1 (3-methylphenyl) piperazine is stirred and heated for 3 hours in an oil bath at 110 C. This is left to stand. over 12 hours. Concentrated ammonium hydroxide and trichloromethane are added. The precipitate is filtered off
five
0
five
0
five
on a column of silica gel using a mixture of trichloromethane and methanol (95: 5 by volume) as eluent. The pure fractions are collected and the elution is distilled off. The residue is crystallized from 2,2-oxybispropane. The product is filtered and dried to give 1.7 parts (27%) of 3- (4-ethylphenoxy) - (3-methylphenyl), -1-piperazinyl pyridazine, m.p. 106.6 ° C. (compound 221).
Analogously to example 16, receive: Z-methyl-6-t4- (3-methylphenyl) -1-piperazinyl pyridazine, so pl. 152, (compound 222) -,
(3-Methylphenyl) -1-piperazinyl-6- (methylthio) pyridazine, m.p. 145.0 ° C (compound 223). Example 17. By the method of any of examples 1-16, using the appropriate starting materials, receive:
3- (3,5-dimethylphenoxy) -6- (1H-imidazol-1-yl) pyridazine, m.p. (compound 2)
3- (1H-imidazol-1-yl) -6- (4-methylphenoxy) pyridazine, m.p. 146 ° C (compound 3);
3- (1H-imidazol-1-yl) -6- (3-nitrophenoxy) pyridazine, m.p. M2 ° C (compound 4);
3- (4-chlorophenoxy) -6- (1H-imidazol-1-yl) pyridazine, m.p. 165 ° C (compound 5) i
3- (4-bromophenoxy) -6- (1H-imidazol-1-yl) pyridazine, m.p. 169 ° C (compound 6)
1- (4-fluorophenyl) -4-14- (3-pyridazinyl) -1-piperaz ynyl-3-cyclohexane-carbonitrile (compound 7)
1- (4-fluorophenyl) (3-pyridazinyl) -1-piperazinyl cyclohexancarbonitrile, m.p., 189.5 C (compound 8),
3-chloro-4-methyl-6- (1-piperazinyl) - pyridazine (compound 224) -,
1- (6-chloro-3-pyridazinyl) -4-piperi dynamin, m.p. 260 ° C with decomposition (compound 225),
3-chloro-6- 4- (3-phenylpropyl) -1-piperazinyl pyridazine monohydrochloride, m.p. 206 ° C (compound 226),
3-chloro-4-methyl-6- 4- (3-phenylpropyl) -1-piperazinyl pyridazine monohydrochloride 1-butanol (1: 1) monohydrate, m.p. 186 ° C (compound 227);
3-methoxy-6- 4- (3-phenylpropyl) -1- piperazinyl pyridazine, t, pl. 78.C (compound 228))
3- 4- (3-phenylpropyl) -1-piperazinyl pyridazine dihydrochloride monohydrate, m.p. 209, (compound 229) -,
thirty
H-chloro-6- 3, b-dihydr lenil) -1 (2H) -pyridinyl hydrochloride, so pl. 187,247);
H-chloro-6- 3- (3-methyl
rol-1 (5H) -yl pyridazine,
  J y and ./-1,Г1О HMG1L J y-
1-acetyl-4- (6-chloro-3-pyridazinyl) -35 (compound 248) i
piperazine, mp 155 C (compound 231);
3- (4-butyl-1-piperaz ynyl) -6-chloropyridazine (E) -2-butandioate (1: 1), so pl. (compound 232) -;
H-chloro-6- (4-cyclohexyl-1-piperazinyl) pyridazine, m.p. (Compound 233) j
1- (6-chloro-3-pyridazinyl) -1-phenylmethyl) -4-piperidinamine, m.p. (compound 234);
H-chloro-6- 3, b-dihydro-4- (3-methoxy-xphenyl) -1 (2H) -pyridinyl pyridazine ,. m.p. 125, 5 ° C (compound 235) -,
H-chloro-6- 3,4-dihydro-5-phenyl--1 (2H) -pyridinyl pyridazine, m.p. (compound 237) -,
3-chloro-6- 4- (3-chlorophenyl) -3, b-dihydro-1 (2H) -pyridinyl, pyridazine, so pl. 135 ° C (compound 236),
H-chloro-b-3,4-DIHIDRO-5- (3-methylphenyl) -1 (2H) -pyridiyl pyridazine, m.p. 160.5 ° C (compound 238),
H-chloro-6-W, b-dihydr ethyl) -1 (2H) -pyridinyl n so pl. 104 C (compound
40З-chloro-6-t2,3-dihydr
phenyl) - 1 H-pyrrol-1-yl. m.p. 194 ° C (compound
H-chloro-6- {5-t4-chlorothyl) phenyl 3,4-dihydro-1 45 nyl pyridazine, m.p. 1 dynamics 251);
H-chloro-6- 3- (3-fluoro GRSdro-1H-pyrrol-1-yl pi, mp 214 ° C (compounds
50 H-chloro-6- 3- (3-fluoro-hydro-1H-pyrrol-1-yl pi, mp 229 ° C (compounds
3-3, b-dihydro-4- (3-1 (2H) -pyridinyl J-6-met
55 t. Pl, (compounds
, b-dihydro-4- (3-1 (2H) -pyridinyl-6-met. m. pl. 115 ° C (connected
with
0
0
five
five
0
H-chloro-6-H 4- (3-fluorophenyl) -3,6-di-hydro-1 (2H) -pyridinyl pyridazine, m.p. 124 C (compound 239)
H-chloro-6- 4- (2,3-dimethylphenyl) -3, b-dihydro-1 (2H) -pyridinyl pyridazine, m.p. 145 C (compound 240);
3-chloro-6- 4- (3-chlorophenyl) -3, 6-dihydro-5-methyl-1 (2H) -pyridinyl} pyridazine, m.p. 89, (compound 24 G) -,
H-chloro-6-C3, 4-dihydro-5-3- (trifluoromethyl) phenyl} -1- (2H) -pyridinyl - pyridazine, t. Pl. 164 ° C. (compound 242) -,
H-chloro-6- 3.b-dihydro-5-t 3- (trifluoromethyl) phenyl -1 (2H) -pyridinyl 1 pyridazine, m.p. (Compound 243)
H-chloro-6-t 5- (3-fluorophenyl) -3,6-di-- hydro-1 (2H) -pyridinyl, pyridazine, t. Pl. 134 ° C (compound 244);
H-chloro-6- {3,4-DIHIDRO-5- (3-methoxyphenyl) - (2H) -pyridinyl pyridazine, t, pl. (compound 245) -,
H-chloro-6-HZ- (2,3-dimethylphenyl) -. 3,4-dihydro-1 (2H) -pyridinyl pyridazin, t, pl. 147.5 C (compound 246);
H-chloro-6- 3, b-dihydro-4- (2-naphthenyl) -1 (2H) -pyridinyl pyridazine mono-hydrochloride, m.p. 187 C (compound 247);
H-chloro-6- 3- (3-methylphenyl) -2H-pier. square 199 С
rol-1 (5H) -yl pyridazine,
-
(Compound 248) i
H-chloro-6-W, b-dihydro-4- (2-phenyl ethyl) -1 (2H) -pyridinyl, pyridazine, mp. 104 C (compound 250)
H-chloro-6-t2,3-dihydro-4- (3-methylphenyl) -1 H-pyrrol-1 -yl pyridazine, m.p. 194 ° C (compound 249);
H-chloro-6- {5-t4-chlorop3- (triptothermethyl) phenyl 3,4-dihydro-1 (2H) -pyridinyl pyridazine; 141, (compound 251);
H-chloro-6- 3- (3-fluorophenyl) -2,3-di-GRSdro-1H-pyrrol-1-yl pyridazine, m.p. 214 C (compound 252);
H-chloro-6- 3- (3-fluorophenyl) -2,5-di-hydro-1H-pyrrol-1-yl pyridazine, m.p. 229 ° C (compound 253) li
3-3, b-dihydro-4- (3methylphenyl) -1 -1 (2H) -pyridinyl J-6-methylpyridazine,
mp, (compound 254);
, b-dihydro-4- (3methylphenyl) -1 -1 (2H) -pyridinyl-6-methoxypyridazine, so pl. 115 ° C (compound 255);
,eleven
H-butoxy-6- 3,6-dihydro-4- (3-methylphenyl) - (2H) -pyridinyl} pyridazine, m.p. 97 C (compound 256);
3-butox. I-6-14- (3-methylphenyl) -1- piperazinyl pyridazine, m.p. 104.5 ° C (compound 257);
3-methoxy-6- 4- (3-methylphenyl) -1- piperazinyl pyridazine, m.p.-- TZb C (compound 258);
(3-fluorophenyl) -3,4-dihydro- -1 (2H) -pyridinyl-6-methoxypyridazine m.p. (Compound 259) i
3-13, b-dihydro-4- (2,3-dimethylphenyl) -1 (2H) -pyridinyl-6-methoxypyridazine, m.p. (Compound 260) J
1- (6-methoxy-3-pyridazinyl) -4- (3- -metx1phenyl) -4-piperidinol, m.p. 126 ° C (compound 261) -,
, 4-dihydro-4- (3-methylphenyl) -1 (2H) -pyridinyl 1-6-e toxipyridazine, m.p. 85 ° C (compound 262);
1- (6-butoxy-3-pyridazinyl) -4- (3- -methylphenyl) -4-piperidinol, m.p. 106 ° C (compound 263);
3-14- (3-methylphenyl) -1-piperazinyl1-6-phenoxypyridazine, m.p. 123 ° C (compound 264) i
3- 4-chlorophenoxy-6-l4- (3-methylphenyl) -1-piperazinyl | pyridazine, mp. 131 ° C (compound 265) j
3- 4- (3-metshphenyl) -1-piperazinyl-6- (phenylthio) pyridazine, mp 135 C (compound 266);
(3-methylphenyl) -1-piperazinyl3-6- (phenylmethoxy) pyridazine, m.p. 158.5 ° C (compound 267);
4- (3-methylphenyl) (phenylmethoxy) -3-pyridazinyl-4 - piperidine, m.p. 125 ° C (compound 268) ;,
6- 4-OXY-4- (3-metalphenyl) -1-pipe ridinyl-3-pyridazinol, m.p. 264 ° C (compound 269),
6-13.b-dihydro-4- (3-methylphenyl) -1 -1 (2H) -pyridinyl-3-pyridazinol,
m.p. 178 ° C (compound 270) i
(3-methylphenyl) -1-piperazinyl, 1-3 (2H) -pyridazinone, m.p. 210 ° C (compound 271) j
(4-methoxyphenyl) -1-piperazinyl pyridazine, mp (compound 272) J
(3-methylphenyl) -1-piperazinyl-3-pyridazintiol, m.p. (Compound 273)
1-I6- 4- (3-methylphenyl) -1-piperazinyl-3-pyridazinyl ethanone5. m.p. (compound 274) and
one

g
ten
,
15
20
25
thirty
-
 dd
-
45
WITH .
 50 55
38419812
1- {6-is, b-dihydro-4- (3-methylphenyl) - (2H) -pyridinyl-3-pyridazinyl ethanone, m.p. 114, (compound 275).
In tab. 4 shows the elemental analysis data of the synthesized compounds. ,
To illustrate the beneficial antiviral properties, a number of such compounds have been tested to determine the cytopathic effect of rhinoviruses. The compounds have an acceptably low degree of cell toxicity in combination with the necessary antiviral activity at low dosage.
Test method for determining the cytopathic effect of rhinovirus. Sensitive to rhinovirus Hela-; cells are sown in minimal nutrient medium (MPS) with the addition of 5% inactivated serum of bovine fruit and minor amino acids. The seed cells are incubated overnight at 37 ° C in an atmosphere of 5% COj. After 24 hours, the cells are treated with solutions of the tested compounds in a solvent containing 1 vol.h. DMSO and 7 vol. h, MPS, with the addition of 10% inactivated serum or the indicated solvent. The cells treated with the solvent and the preparation are incubated for 3 hours at which time the standardized rhinovirus standard is added. During the subsequent incubation period at 33 ° C, the rhinovirus is allowed to grow in Hela cells. Exposure of the result is delayed until the full (100%) cytopathic effect in the virus control (cells treated with solvent and virus) is reached. Anti-virus activity is assessed as the lowest concentration of the test drug, inhibiting at least 75% of the cytopathic effect observed in the viral control.
In tab. 5 shows the results of testing the antiviral activity of the compounds.
Thus, the proposed compounds with sufficiently low toxicity showed high antiviral activity, previously unknown in the range of pyridazine derivatives, and can be used in medicine.
35

权利要求:
Claims (1)
[1]
13 claims
The method of producing pyridazinamines of the general formula
Nn xn
"2" 3
13
R, is hydrogen, halo, lower alkyl, 1H-imidazol-1-yl, is lower alkoxy, aryloxy, lower alkylthio, arylthio, oxy, mercapto, lower alkylsul- finil, lower alkylsulfonyl, cyano, lower alkoxycarbonyl, lower alkylcarboyl,
independently of each other, hydrogen and lower alkyl, or R and R, together form a two-valent radical of the formula —CH — CH — CH — CH—; divalent radical of formula
(but)
(B)
may be substituted alky
scrap,
regardless of the number from 1 with m +
aryl, pyrimidinyl, a quinhyd radical from a friend up to 4 inclusive, n 3, 4 or 5j
R.
NIL, lower alk skarbonyl, aryl-lower alkyl, pyridine-NIL, unsubstituted or substituted by cyano or lower alkyl, cyclohexe, unsubstituted or substituted by cyano or aryl; hydrogen, arcl, hydroxy, aryloxy, lower alkyl, lower al
|
8419814
coxy substituted by morpholine, pyrrolidone or piperidine, arylamino, (aryl) - (lower alk1) amino, phenylcarbonyloxy, aryl-lower alkylamino R - hydrogen, lower alkyl, aryl, aryl-lower alkyl, arylcarbonyl-lower alkyl, arylcar - bonyl, aryl-lower alkylcarbonyl, aminocarbonyl, indolyl;
ten
RJ is independently of each other hydrogen, lower alkyl, aryl, aryl-lower alkyl, where aryl is phenyl substituted or substituted with up to 3 substituents each of which may be halogen, lower alkyl, trifluoromethyl, nitro, amino, lower alkoxy group, hydroxy group, lower alkoxycarbonyl, thienyl and naphthalenyl, provided that
i) if A is a radical of the formula with,. and R is hydrogen, then Ry is different from hydrogen, hydroxy or lower alkyl;
A.) if R ,, R,
and
R is hydrogen, and
5 iii)
iv)
0
A is a radical of the formula b, then R is different from 3,3-diphenyl-propyl}
if R and Rj are hydrogen, and A is a radical of formula a, then R is different from halogen, if it is hydrogen.
R. chlorine, R and R - BOA A is a radical of the formula
five
bv then Ry is different from 2-methoxyphenyl
v) if R, is chlorine and A is a radical of the formula b 1, then R 4 is different from dimethoxyphenylmethyl, dimethoxyphenylethyl, o-methylphenyl ethyl or (2-methylphenyl) methyl, or their pharmaceutically acceptable acid addition compounds, or stereochemical
isomers, or about tl and taschu and amine of general formula
their tuatomer so that
where A has the indicated meanings, is subjected to alkylation with pyridazine of the general formula
15
Nn
 Vw
-U
Ro R.
where is r,
and R ,,
J W is halo,
with the selection of the desired product in free form, either as a pharmaceutically acceptable acid addition salt, or as a stereometric grit isomer, or as a toatomer. Priority signs:: 03.26.84 when R is hydrogen, halogen, 1Nimidazo-1-yl, lower alkoxy, arylOKCHji
R and R, - is hydrogen, lower alkyl or —CH GH — CH CH — i
V mHjri -CnH n
R5 - 1 2n
R: RS
m and n are from 1 to A, with m + n 3, 4 or 5; Cd - aryl, pyrimidi
NN // VN
ten
C1H
(CNG 2- - 2-С2Н5-СБН / (eng
Q
(CH2 2 S Z-SbIO
(
1384198
sixteen
nile, lower alkylcarbonyl, aryl-lower alkyl, pyridinyl, unsubstituted or substituted with cyano or lower alkyl, cyclohexyl, unsubstituted or substituted with cyano or aryl, RJ - hydrogen, aryl, hydroxy, lower alkyl, lower alkoxy-substituted morpholine, pyrrolidine or piperidine, arylamino, (aryl) - (lower alkyl) -amino, phenylcarbonyloxy, aryl-lower alkshtamino, R - hydrogen, lower alkyl, aryl, aryl-lower alkyl, aminocarbonyl, R and Rj - hydrogen, lower alkyl, aryl where aryl is phenyl, unsubstituted or substituted by substituent up to 3, each of which can be halogen, lower alkyl, trifluoromethyl, nitro, amino, lower, alkoxy, oxy, lower alkoxycarbonyl.
02.15.85 with R., - lower alkylthio, arylthio, hydroxy, mercapto, lower alkyl sulfinyl, lower alkylsulfonyl, cyano, lower alkoxycarbonyl, lower alkylcarbonyl, lower alkyl, R4 - quinolinyl, RS aryloxy, R - arylcarbonyl lower alkyl, arylcarbonyl, aryl-lower alkylcarbonyl, indolyl, RT and RJ, independently of each other, aryl-lower alkyl, aryl is thienyl or naphthalenyl.
Table 1
107, 9
177.7
one
17138419818
Continued table.
iL: in:;: i ::::::::::::::::::: ir
12С1Н (СН2) Г - {3-С2Н5-СБН 119.8
.l
13C1H (CH2) 2-CH5-CH3-2-PYRIDINIL 226.2
(CH2) 2
14C1 sn (sn2) - - {3-СНз-СБН), 7
(
15C1H (CH2) 2-ljI-t2A, 64CHo, VC6H2l
(CH2) 2
16С1СНз (СН212- - 3-С1-СБН)
(
17С1Н ((t) 191
(CH2h
18ClH (CH2) 2-CH-W- (
(
19С1Н (СН2) (-С12-СБНз 1 °
(CH2) 2
20C1CH3 (CH2) 2-N - (- CF3-C6H / jV176.6
(CH2) 2
21G1. H (CH2VC 1 C6W5 22.7
(6H2) 2
22C1H (CH2) 2-CH- (3-CH3-SbN (4) 107.5
(
23 C1H (CH2) 2-CH- (3-CF3-C5Hi 69.8
(
 hh
29
Cl
(СН2) 2-у НЗО-СБН4) Reason
 (CH2) 2
thirty
ClСН2-СНССНз) - Ь} Г- (4-СНзО-СБН / -
(CH2
31
C1 (CH2) 2-N- (2-THA30AHA)
(CH2) 2
32
C1
(CH2) 2-N- (3Cl-C6Hit (CH2) 2
C1
C1
C1
(CH2) 2-T 1-SbH5 (CH2) 2
(СН2) 2-1} 1- (2-СНзО-СБН /) (СН2) 2
(CH2) 2- N- (4-CHg-C6Hzt) (
36С1
(CH2) 2- N-3, MCHS) 2-SbNz Foundation (
37С1
(CH2) (2-PYRIMIDYNIL) (
38C1 (, 3- (eHjV-C6H3l
(CH2) 2
table 2
183.3
133.5
221.9
-
146.6
 II
172.0
144.5
188.6
162,6
207.7
164.6
21138419822
Continued table. 2
:: i: i: ii ::::::: E :: i :: iz ::; n
39Cl (CH2) 2- N- (3-nH3-CgHf) -140.1
(
40ClСН2-СН (СНзЬК- (2-С1-СесЩ | .- -118,2
(CH2) 2
41Cl (W2 2 2H50C (0) -SbNc - -200.6
(CH:, 2
42Cl (CH - - And b-SeNz - -155.8
(CH2)
43ClCH2-CH (CH3) -N - (- CH3-C6H / V -124.4
(CH2) 2
44Cl (, S-CF-CgHjV -160.0
2
45Cl (CH V - CHIC HS - -156.4
(Ch.
46ClСН2-СН (СНз) - Н- 37СНз-СБН1 Г Grounding 114.8
(CH2h
7Cl (cH V tjI-t -f-CeH / t). - -153.1
{Cll2
48Cl1CH2) (3-CH-2-PIR11DINIL) - -177.3
(CH)
49Cl (CH2V C6H "r (ObC -Cl-C6Hit - -262.5
(CH2) 2
50ClCH2 -CHtCHjbTsM t-Cl-G HO- -161.3
(# 2) 2
23138419824
Continued table. 2
niZZIZZIZIIZZZIZilir.
51Cl (СН2) 2-КЧЗЛ- (СНзО) 2-СБНз - -149.5
((
". .
52С1CH-CHCCHjVN-CeHs- -115.9
VD:
53C1 ((-OH-C6HO 203.5
(
54C1 (CH2) g-CH-5H-SbN5- - 149.6
(
55Cl (, 5-С12-СБНз) - 167.2
(CH2) 2
56С1 (СН2) 2- Н-, 5- (СНз) 2 С5Нз1 Basis 164.7
(CH2) 2
7 c1cn2-sn-1 n- g, s- (dbp) 2-SbN HCI213.0
(CHiH
58Cl CH2-CH-Tyan- (3-CH3-CeNg) Basis 161.9
 (
59С1 СНг-СН-1 Н-СБН5НС1 142.2
(CH2) s
60C1 (CH2V 3-C1-C6HOBASE123.0
(CH212
61С1СН2-СН-Ь1Н- (3-СНз-СН) НС1Ьб, 5
(W
2Cl (CH2) 2-i- (2, 1-C1 bN3) Base 185.2
(CH2) 2
25138419826
Continued table. 2
(CH2l2
I
64Cl (CH2), - -, 174.9
(CH
SbH5
65Cl (CH2) 2-C-C (0) -T H-SbH5-224.4
(CH2) 2
66С1 (СН2) 2-рН-К () (E-SNzSbN / Basis136,5
{CH2b
HE
67C1 (CH2V9 2- -Cl-C6Hft) - -172.9
(CH)
DOS
68, C1 (CH2) 2-C-SbH5- -147.6
(CH2) s
HE
69C1 (CH VC-C -CF-CgHiflH1194.5
(CH-g
(0) - € Ns
70C1 (CH2) 2 i CH2J-C6H Base221.8
(CH2
SNS
71C1 (CH2) 2-CH-N-CH2-CH CH-C6H5 - -95.2
(CH2) 2
OH 72 C1 (CH2V (Bf- -Cl-C6H - -199.6
(
74С1 (СЙ2) 2-СН-0-С (01-СБН5Основание120,9
(SNg
CH
75С1 (.-80,4
(CH)
C (0) -OCH
76C1 (CHaV - H-CS-CF-CgHft; - -119.0
77C1CH2-CH C- (5-CF3-C6Hit - -120.8
(SNGCH
SbH5
78C1 (CH2VC-C6H5- -178.7
(SS
 HE
79C1 (CH VC-CS-CHg-CeH / j - -140.4
CCH2
80 C1CH2-CH-W-2,) gSbNz4- -163.2
(cng
81 C1 (CH2V N- (2-CH3-C6Hit) - .0
(CH2-) 2
C (0)
82 C1 ()
(CH2) 2
29
(CHg) - CH-CO- (3-CgH jj) (CHj)
Cl
Cl
No. 2)) (CH)
(CH2) 2-CH- (-CHj-C H / j (CH2) 2
Cl
Cl
Cl
Cl
Cl
H
ch2-ch (snz) -c- {s-sgz-SeN / 4
(CH2) 2 (} H
(cH2) 2-c- (2-thienyl)
(CH2) g
CH-CH-TyAN-S S-CF -CfiHit (CH2) 2
(CH2) 2-N- (g-quinolinyl)
(
((2-thienyl)
g and ii
CH-CH2
C1
WITH
C1
C1
CH2-CH - (- C1-SbNO
(sn) he /
(CH V j -CS-Cl-CgHO
(Ng
No. 2) (-F- CgHitl
No. 2) 2
(CH2) 2-C- {-C1,) CH-CH2
thirty
Continued table. 2
zziiz :::
Base 126.0
HCl
173.8
127.9
163,8
162.7 152.0
207.7 156.4
118.9
206.0 .47.0
137.5
95С1 (CH VC-Cs-CHjO-CgHft - -134.7
(CH2) 2
96C1 (CH2) 2-N-CH2- (2-CH3-C6H /). - -134.7
(CH)
HE
97 С1СН2-СН (СНзУС- (3-СНз-СБН / 4) - -154.0
(CH
98 C1- (CH2) 2-CH-NH- (3-Cl-C6HO- -153.3
(CH2) 2
HE
99 С1СН2-СН (СНз) -С- (3-Р-СБН - 160,5
(CHj)
HE
100 C1 CH2-CH (CH3) -C- (2-TENIL base 148.1
(CH2) 2
 101 C1 (CH2) 2-CH- (1H-INDOL-3-IL) 7
(CH2) 2-
.HE
102 с1 (cH, i (3-F-ceHO-, 8
(
he
103 C1 (CH2VC- 2,3- (CH3VC6H33-. - 1750
CSN) d,
he
104С1 (СН2) 2-С- (1-NAPTALEN L) - -201.8
(CH2) 2
C} H
105C1CH2-CH (CH3) -C- (3-C1-SbH1 HC1200
(CH2) 2
33
i ::; i
12
106 Cl
V
(W-SRZ-SbIz) (
Cl
Cl
Cl
Cl
Cl
Cl
§
SNZO-S
Cl
Cl
HE
(cH2) 2.-c- (t-Br-CeHii) No. 2) 2
he
(CH2-) 5-SbH5 (CH2) 2
HE
(CH-2) 2-C- (t-Cl-C6Hit) (CH2) 2
HE.
(CH2) 2-С - (- СНз-СБНг) (СН) 2
CJH (
(cng
(CH2) 2-c- (1-NAPHTHALENE) CH-CH2
(cH2) 2-Y- -cHrC6H "t)
(W2
OH (CH2V9 t t-CH (CH3) rC6Hitl
No. 2) 2
he
(Shch2) 2-С- (СН2) -СеН5
CCH)
1384198
34 Continued table. 2
I
Foundation 208.4
Foundation 169.4
105.1
161.5
Foundation 123.1
156.6
138.4
185.5
136.5
Foundation 106.2
35
in
Cl
Cl
OH
(CH2) 2-C- (CH2-) 2-SbH5 (CH2) 2
OH (CHo), - C- (2-NAFTALENYL)
(CH2) 2
118 Cl
(CH2) 2-If- (-N0 2- CORR (Sh2) 2
OH
Cl (СН2) 2- - СНзО-СБН1
(CH2)
NC (CH2) 2-ff-i3-CH -C6H /
(CH2) 2
Cl (CH2) 2-C - (- Cl-C6H / t)
CH-CH2
122 ClCH2-CH (CH3) -CH- {3-OCH3-SbH / 1HCl
(CHo)
22
123 Cl
OH
(CH2) 2-C-CH3 (CH2) 2
124 CHgOOC, (CH2) 2-C- (3-CH3-C6Htt)
CH-CH2
"25 (CH2ViJ - 3-CH3-C6H)
CH-CH
126 Cl
(CH2) (l-NAFTALENYL) (iH2) 2
1384198
36
Continued table. 2
......
147.3
196.1
HCl-1 / 2HjO 266.7
Base
173.7
179.8
204.5
196.1
125.1 159.6
164.8
156.6
CHjOOC (CH2) 2-7- 3-CH3-SbH / 1
(CH2
ClСН2-С- (2-ТИЕНИМ
nsn nn
Cl (СН2) 2 3 3-CLEAR
CH.CH2
CN (CH2) 2-С- (3-СНз-СНО)
nsn nn
C1 (CH2) 2-CH 2-PYRIDINIL
C1 (CH2) 2-C- (2-PYRIDINIL
CH-CH2
C1 (CH2) 2-C-CH
CH CH 2
C1 (CH2V5f 2b 3
CH SNO
149С1Н
150С1Н
H ((t-Cl- 6Htt) Base 209.7
(CH2) 2
H (W2 y- - bNO- -l
(CH2) 2
210.7
145.4
 n
138.0
 II
Base
39138419840
Continued table. 3
(W2
152 C1HH (CH2V (F-C6H) - -197.4
153ClNN ((3, -С12-СБНз) Basis
(CH212
154С1НН (СН2), 6- (СНз) 2-СБНз1 - -124.4
 (
155С1-СН Н-СН СН- (СН2)) 2-СБНз1 - -209.2
(CH2) 2
156С1-СН СН-СН СН- (СН2) (2-СНзО-СБН /) - -178.6
(.
157С1-СН CH-СН CH- (CH2l2 C: gH5- -170.2
(CH2-) 2
158C1-CH CH-CH CH- (CH: 2) 2-1J- (3-CF3-C6Hij.) - Tb7.2
{CH2) 2
159С1-СН СН-СН СН- (СН2) 2- (3-С1-СБН 4.) - -167.0
(CH2) 2
160C1 -sn overs, over-over- () (3-СНз-СБН1) - -135.6
(CH2) 2
161С1 -CH СН-СН СН- (СН2) (3,5-С12-СБНз1-225,
(CH2) 2
. HE
162С1 НН (CH2VC- 3, HCHaJfC6Hj, 196.3
(CH2) 2
Al138419842
Continued table. 3
ZIEII IZ Zn ZZ- I ZIZIZ ZEI
C (0) 0-CH2CH3
: 163С1НН (CH2V9 6HO Basis 155.5
(
C (0)
164 C1 HH (CH2VV-H- (34: H3-CeHitV - - 195.1
(CH2b
165С1Н, Н (СН2) (3-ВГ-СБН) V 157.1
(CH2) 2
0- (cH2) s- (piperidinyl
166С1НН (еН2) 2-С-СБН5- -137.1
(CH2) 2
(CH2) 2-CH3
167С1НН (СН2) 2-С-СеН5- -136.8
(CH2) 2
168С1НСН -CH-О-СРз-СБН;) 1/2 (COOH) 155.2
(CH2)
169С1-СН СН - СН-СН- (СН2) (2 С12 СbНз) Basis 218.5
(CH2) 2.
170С1НН (СН21з- -СбН5- -, 132.7
(SNg) 2
171С1НН (CH2VC CO-CH2-C6H5- -130.2
(
172С1НН (СН2) з-СН- {3-СГз-СБН Base 121,7
SNG
173С1НН (СН2) 2-СН-СН2-СО- (3-Р-СБН (У --156.2
{CH2) 2
HE
174С1НН (CH2)), 4
CH2
43. 138419844
 Continued table. 3
 T T riEIIZZZZZ II IZII I
ACE C1H (CH2V 3 3-C6H) - -144.7
(CH2) 2
(JH 176 С1ННСН2-С-СБН5- -138.0
(Cll2 HE
177 С1ННСН2-С- (3-СРз-СБН 1 - -95.0
(CH2) s
H
17S C1.NH (CH2) s-C-SbH5- -107.5
CH2
H I
179 С1НН (СН2) з-ф-СЗ-СНз-СБН / 1.) НВг193.0
CH21 / 2CHN-SNON-CH,
180 C1 H H (CH2) (3-CH.y-C5H.ij.) Base 104.4
-s- (ONON
181, С1НН (СН2) s-С- (2-ТИЕШЛ Basis 154,0
CH2
HE
182С1НН (
CH2
183С1НН (CH2b- - 3-P-SbNO- -91.5
CH2
9
184С1НН (СН2) з-С- (3-Р-СБН4.) 119.3
CH2
185 ВгНН (СН2)) з-СБН5НС UN 197.3
VESOO CH
(
-s- (OH45138419846
 Continued table. 3
i.niIIIEIIZI ZIIIIIIZIZZIIII
he
186 С1НН (СН2), 3- (СНз) 2-СБНз1 Base 183.7
CH2
V .187 C1NH (CH2), 5- (CH3) 2-SatN31 - - 115.7
CH2
HE
188С1НН (CH2V9 3 3 C6H i) - - 164.4
CH2. :
189С1НН (CH2) (3-CHs-C6Hii. Base 94.6
6H2
190C1HN (CH2) 2-CH- (2-TENYL - -127.0
(CH2) 2
HE
191С1НН (CH2VC -O-OCHy-CgHf) HC1193.8.
CH2
192С1НН (СН2) з-9Н -СЗ-ОСНз-СБН) Basis 102.1
0%
HE
193С1НН (CH2V9 - (- С1.3-СГз-СБНз) - -129.8
BUT
.
194С1НН (СН2) (3-Р-СБН /) - -121.5
CH.
Cfh
195С1НН (CH2V9- 3-p-C6H), - .V 138.4
CH2
196С1НН (СН2) 2-СН- (3-СНз-СБН () - -74.7
SNP
47
(CH2) 2 201 C1HH (CH2) (2-tHeHHA)
1384198
48
Continued Table 3
119.3
51
138419852
Table 5

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同族专利:

---

公开号 | 公开日

---

ZW5485A1|1986-10-22|

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DK166277C|1993-08-30|

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DE3581819D1|1991-04-04|

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CA1238321A|1988-06-21|

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AU576563B2|1988-09-01|

---

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---

EP0156433B1|1991-02-27|

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EP0156433A3|1986-07-23|

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AT61050T|1991-03-15|

---

EP0156433A2|1985-10-02|

---

DK134185D0|1985-03-25|

---

IL74707D0|1985-06-30|

---

BG43690A3|1988-07-15|

---

GR850714B|1985-06-14|

---

AU4034885A|1985-10-03|

---

FI85373C|1992-04-10|

---

US5157035A|1992-10-20|

---

FI851177A0|1985-03-25|

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FI85373B|1991-12-31|

---

HU198010B|1989-07-28|

---

IL74707A|1988-05-31|

---

KR870001158B1|1987-06-13|

---

RO91197B|1987-07-01|

---

CS195285A3|1992-11-18|

---

ES541521A0|1986-04-16|

---

NO161257C|1989-07-26|

---

DK134185A|1985-09-27|

---

PT80157A|1985-04-01|

---

NZ211494A|1988-05-30|

---

US5001125A|1991-03-19|

---

RO91197A|1987-06-30|

---

FI851177L|1985-09-27|

---

CZ277730B6|1993-04-14|

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DK166277B|1993-03-29|

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PH22495A|1988-09-12|

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NO851167L|1985-09-27|

---

ES8606289A1|1986-04-16|

---

KR850006401A|1985-10-05|

---

HUT37614A|1986-01-23|

---

NO161257B|1989-04-17|

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法律状态:

优先权:

---

申请号 | 申请日 | 专利标题

---

US59344484A| true| 1984-03-26|1984-03-26|

---

US06/702,772|US5001125A|1984-03-26|1985-02-15|Anti-virally active pyridazinamines|

---