CN1069272A - The method for preparing benzo pyrrole or thiapyran and pyrazoles - Google Patents

The method for preparing benzo pyrrole or thiapyran and pyrazoles Download PDF

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CN1069272A
CN1069272A CN 91105264 CN91105264A CN1069272A CN 1069272 A CN1069272 A CN 1069272A CN 91105264 CN91105264 CN 91105264 CN 91105264 A CN91105264 A CN 91105264A CN 1069272 A CN1069272 A CN 1069272A
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represent
formula
phenyl
pyrazoles
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R·B·蒂特曼
M·H·霍克利
O·S·吉尔
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Boots Co PLC
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Boots Co PLC
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Abstract

The method of preparation I compound or its pharmacologically acceptable salt.Among the formula I described in the definition such as specification sheets of each group.Formula I compound and pharmacologically acceptable salt thereof can be used as immunomodulator.

Description

The method for preparing benzo pyrrole or thiapyran and pyrazoles
The present invention relates to new therapeutical agent, specifically, (1) chromene also (4,3-c) pyrazoles or (1) chromene also the preparation method of (4,3-c) pyrazole compound and these compounds as the therapeutic activity of immunomodulator.
The present invention relates to have the formula I compound of immunoregulatory activity,
Figure 91105264X_IMG16
X represents oxygen or sulphur in the formula;
When X represents oxygen or sulphur, R 1Represent hydrogen or and R 2Represent a key together; R 2With R 1And R 3In one represent a key together; R 3With R 2And R 4In one represent a key together; R 4Represent hydrogen or and R 3Represent a key together;
Perhaps, when X represents sulphur, R 1And R 2Represent a key, R 3Represent methylidene, and R 4And R 5Represent hydrogen;
When X represents oxygen, Z representative-CH=or-N=;
When X represents sulphur, Z representative-CH=;
Work as R 3During represent methylidene, R 5Represent hydrogen;
Perhaps work as R 3With R 2And R 4In one when representing a key together, R 5Representative
Figure 91105264X_IMG17
;
R 6Represent hydrogen, halogen, S(O) nY 1, carboxyl, carbamyl, acyl group, esterification carboxyl or CONR 12R 13;
R 6' represent hydrogen or methyl;
Perhaps, R 6And R 6' represent cyclopropyl with the carbon atom that they connected;
R 7Represent hydrogen, halogen, trifluoromethyl, C 1-6Alkyl, methoxyl group or S(O) mY 1;
R 8Represent hydrogen, halogen or trifluoromethyl;
R 8' represent hydrogen, halogen or trifluoromethyl;
R 9And R 10Can be identical or different, represent halogen; Perhaps R 9Represent hydrogen, and R 10Represent hydrogen, halogen, trifluoromethyl, nitro, C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl or acyloxy;
R 12Represent methylidene, ethyl or C 3-8Cycloalkyl, R 13Representative can be by cyano group, phenyl, 3～8 Yuans non-aromatic heterocycles, 5 or 6 element heterocycle aryl or C 3-8The C that cycloalkyl replaces arbitrarily 1-6Alkyl; Perhaps R 13Representative can be by C 2-6The phenyl that carbalkoxy or halogen replace arbitrarily; Perhaps
R 12And R 13Representing with the nitrogen-atoms that they connected can be by C 2-6Acyloxy (C 1-6) 3-8 person's non-aromatic heterocycle of replacing of alkyl;
Y 1Represent C 1-6Alkyl;
N is 0,1 or 2; And m is 0 or 1.
In our common pending application application (PCT number of patent application PCT/GB 89/00859 and PCT/GB 89/00860), some formula A and formula B compound have been described,
Figure 91105264X_IMG18
Above-mentioned first PCT patent application also discloses as midbody compound, without any the 2-(4-chloro-phenyl-of therapeutic activity)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-acetate 4-methoxy-benzyl ester also.
These compounds are got rid of in scope of the present invention.
Therefore, method of the present invention provides the new compound of formula I,
X represents oxygen or sulphur in the formula;
When X represents oxygen or sulphur, R 1Represent hydrogen or and R 2Represent a key together; R 2With R 1And R 3In one represent a key together; R 3With R 2And R 4In one represent a key together; R 4Represent hydrogen or and R 3Represent a key together;
Perhaps, when X represents sulphur, R 1And R 2Represent a key, R 3Represent methylidene, R 4And R 5Represent hydrogen;
When X represents oxygen, Z representative-CH=or-NH=;
When X represents sulphur, Z representative-CH=;
Work as R 3During represent methylidene, R 5Represent hydrogen;
Perhaps work as R 3With R 2And R 4In one when representing a key together, R 5Representative
Figure 91105264X_IMG20
;
R 6Represent hydrogen, halogen, S(O) nY 1, carboxyl, carbamyl, acyl group, esterification carboxyl or CONR 12R 13;
R 6' represent hydrogen or methyl;
Perhaps, R 6And R 6' represent cyclopropyl with the carbon atom that they connected;
R 7Represent hydrogen, halogen, trifluoromethyl, C 1-6Alkyl, methoxyl group or S(O) mY 1;
R 8Represent hydrogen, halogen or trifluoromethyl;
R 8' represent hydrogen, halogen or trifluoromethyl;
R 9And R 10Can be identical or different, represent halogen; Perhaps R 9Represent hydrogen, and R 10Represent hydrogen, halogen, trifluoromethyl, nitro, C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl or acyloxy;
R 12Represent methylidene, ethyl or C 3-8Cycloalkyl, R 13Representative can be by cyano group, phenyl, 3～8 Yuans non-aromatic heterocycles, 5 or 6 element heterocycle aryl or C 3-8The C that cycloalkyl replaces arbitrarily 1-6Alkyl; Perhaps R 13Representative can be by C 2-6The phenyl that carbalkoxy or halogen replace arbitrarily; Perhaps
R 12And R 13Representing with the nitrogen-atoms that they connected can be by C 2-6Acyloxy (C 1-6) 3-8 person's non-aromatic heterocycle of replacing of alkyl;
Y 1Represent C 1-6Alkyl;
N is 0,1 or 2; And m is 0 or 1,
Condition is:
I) represents oxygen as X; During Z representative-CH=, and
A) work as R 6Represent C 1-6During the dialkyl amino formyl radical, R then 10The acyloxy of representative except that acetoxyl group; Perhaps,
B) work as R 6Represent hydrogen, halogen, S(O) nY 1, carbamyl, carboxyl, C 2-6Carbalkoxy, C 2-6During alkanoyl, perhaps work as R 6And R 6' when forming cyclopropyl with the carbon atom that they connected, R then 10Representative removes C 2-6Acyloxy beyond the alkanoyloxy; Perhaps,
C) work as R 1And R 2Form a key, R 3And R 4Form a key, R 6', R 8, R 8', R 9And R 10Each represents hydrogen, R 7When representing chlorine, R then 6Do not represent 4-methoxyl group benzyloxy carbonyl;
II) represent sulphur as X, and a) R 3Represent methylidene; Perhaps b) R 6Represent hydrogen, carboxyl, S(O) nY 1, C 2-6Carbalkoxy, carbamyl or C 1-6During the dialkyl amino formyl radical, R then 10The acyloxy of representative except that acetoxyl group.
Should be appreciated that the group that contains the chain of 3 or more a plurality of carbon atoms can be a straight or branched, for example, propyl group comprises n-propyl and sec.-propyl, and butyl comprises normal-butyl, sec-butyl, isobutyl-and the tertiary butyl.Term " halogen " comprises fluorine, chlorine or bromine.
In a class formula I compound, R 1And R 2Form a key, and R 3And R 4Form a key, this compounds is suc as formula shown in the II:
R in the formula 6, R 6', R 7, R 8, R 8', R 9And R 10As defined above.In another kind of formula I compound, R 1Represent hydrogen, R 2And R 3Form a key, and R 4Represent hydrogen, this compounds is suc as formula shown in the III:
R in the formula 6, R 6', R 7, R 8, R 8', R 9And R 10As defined above.
In another kind of formula I compound, R 1And R 2Form a key, and R 4And R 5Represent hydrogen, this compounds is suc as formula shown in the IV:
R in the formula 7, R 8, R 8', R 9And R 10As defined herein.Preferred substituted is as described below.More preferably, R 7Represent halogen or trifluoromethyl, R 8Represent hydrogen or halogen, R 8' represent hydrogen or halogen, and R 9Represent hydrogen.
In formula I compound, R preferably 6' represent hydrogen.
In some formula I compound, radicals R 6Can be carboxyl, acyl group or some uncle's carbonylamino group of esterification.These groups can be used formula-COR 14Expression, wherein R 14Representation alkoxy (C for example 1-6); Alkenyloxy (C for example 2-6); Cycloalkyloxy (C for example 3-10); The Sauerstoffatom that is connected with non-aromatic heterocycle; The carbocyclic ring aryloxy; The heterocycle aryloxy; Alkyl (C for example 1-6); Alkenyl (C for example 2-6); Cycloalkyl (C for example 3-10); Non-aromatic heterocycle; Isocyclic aryl; Or heterocyclic aryl; In these groups each all can be optionally substituted.The ester of facile hydrolysis defined herein and acid amides and those ester and the acid amides of hydrolysis not too easily all comprise within the scope of the invention.The present invention also comprises some uncle's carbonylamino group.Some formula I compounds are at 4 ethanoyl that can contain replacement of member ring systems.In some preferred formula I compound, radicals R 6Can have following various structure:
a） -CO.OR 15
b） -CO.R 16
c） -CO.NR 12R 13
R in the formula 12Represent methylidene, ethyl or C 3-8Cycloalkyl, R 13Representative can be by cyano group, phenyl, 3-8 person's non-aromatic heterocycle, any C that replaces of 5 or 6 element heterocycle aryl 1-6Alkyl, perhaps R 13Representative can be by C 2-6The phenyl that carbalkoxy or halogen replace arbitrarily; Perhaps R 12And R 13Representing with the nitrogen-atoms that they connected can be by C 2-6Acyloxy (C 1-6) 3-8 person's non-aromatic heterocycle of replacing of alkyl; R 15And R 16Represent C 1-6Alkyl, C 2-6Alkenyl, C 3-10Cycloalkyl, 3-8 person's non-aromatic heterocycle, phenyl or 5 or 6 element heterocycle aryl, radicals R 15, R 16In each all can be replaced arbitrarily by Z.
Z represents Z 1, Z 2, phenyl, 3-8 person's non-aromatic heterocycle (preferably containing 1 or 2 heteroatoms that is selected from oxygen, sulphur or nitrogen), 5-6 element heterocycle aryl (preferably containing 1-3 heteroatoms that is selected from oxygen, sulphur or nitrogen), each group all can be by Z 1Or Z 2Replace arbitrarily;
Z 1Represent halogen, trifluoromethyl, hydroxyl, carboxyl or cyano group;
Z 2Represent C 1-6Alkyl, C 3-10Cycloalkyl, S(O) mY 1, CONR 18R 19, C 1-6Alkoxyl group, C 2-6Carbalkoxy, C 2-6Alkanoyl, C 2-6Alkanoyloxy, phenoxy group, NY 2Y 2', NHCOY 2Or NHSO 2Y 2, and each group all can further be replaced by Z.
Y 2And Y 2' can be identical or different, represent hydrogen, C separately 1-6Alkyl or phenyl;
R 18And R 19Can be identical or different, represent hydrogen separately; C 1-6Alkyl; C 3-10Cycloalkyl; C 2-6Alkenyl; Isocyclic aryl; 3-8 person's non-aromatic heterocycle; 5 or 6 element heterocycle aryl; Perhaps R 18And R 19Form 3-8 person's non-aromatic heterocycle with the nitrogen-atoms that they connected.
In formula I compound, suitable substituents R 6Comprise following groups: hydrogen; Halogen (fluorine, chlorine or bromine), preferably fluorine or chlorine, most preferably chlorine; Carboxyl; Carbamyl; S(O) nY 1, Y wherein 1Be preferably C 1-4Alkyl, n represent 0,1 or 2(for example methylthio group, ethylmercapto group, rosickyite base, methyl sulfinyl, ethylsulfinyl-1 base, sulfonyl propyl base), more preferably, Y 1Be C 1-2Alkyl, most preferably, Y 1It is methyl; Suitable is, n is 0 or 1, and n is preferably 0.Most preferably, R 6Be hydrogen or C 2-6Carbalkoxy.
In formula I compound, R 6With R 6' and their carbon atoms of being connected can form cyclopropyl together.
Preferably, R 6Also comprise CONR 12R 13, R wherein 12Represent methylidene or ethyl, R 13Representative can be by cyano group, phenyl, contain 1 or 2 heteroatomic 3-8 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen, contain the C that 1-3 the heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen replace arbitrarily 1-6Alkyl; Perhaps R 13Representative can be by C 2-6The phenyl that carbalkoxy (for example methoxycarbonyl) or halogen (for example chlorine) replace arbitrarily; Perhaps R 12And R 13Form with the nitrogen-atoms that they connected and can contain the other heteroatomic 3-8 person's non-aromatic heterocyclic group that is selected from oxygen, sulphur or nitrogen, this group can be by C 2-6Acyloxy (C 1-6) alkyl (for example propionyloxy ethyl) replacement.
Preferably, R 6Also comprise the carboxylate group, this group is preferably by formula-COOR 15Expression, R in the formula 15Represent C 1-6Alkyl; C 2-6Alkenyl; C 3-10Cycloalkyl; Contain 1 or 2 heteroatomic 3-8 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen; Isocyclic aryl; Contain 1-3 the heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen; Each group all can be replaced arbitrarily by Z.Preferably, R 15Represent C 1-6Alkyl; C 3-8Cycloalkyl; Contain 1 or 2 heteroatomic 5-7 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen; Phenyl; Contain 1 or 2 heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen; Each group all can be replaced arbitrarily by Z.
Preferably, R 6Also representative is preferably by formula-COR 16The acyl group of expression, R in the formula 16Represent C 1-6Alkyl; C 2-6Alkenyl; C 3-10Cycloalkyl; Contain 1 or 2 heteroatomic 3-8 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen; Isocyclic aryl; Contain 1-3 the heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen; Each group all can be replaced arbitrarily by Z.Preferably, R 16Represent C 1-6Alkyl; C 3-8Cycloalkyl; Contain 1 or 2 heteroatomic 5-7 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen; Phenyl; Contain 1 or 2 heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen; Each group all can be replaced arbitrarily by Z.
Preferably, Z represents Z 1Or Z 2
Preferably, Z 1Represent halogen (fluorine, chlorine or bromine), more preferably fluorine or chlorine, most preferably chlorine; Hydroxyl or cyano group;
Preferably, Z 2Represent following groups: C 1-6Alkyl, preferably C 1-4Alkyl (for example methyl, ethyl or propyl group), more preferably methyl or ethyl, and methyl most preferably; C 3-7Cycloalkyl, preferably C 3-5Cycloalkyl; C 1-6Alkoxyl group, preferably C 1-4Alkoxyl group (for example methoxyl group, oxyethyl group or propoxy-), methoxy or ethoxy more preferably, and methoxyl group most preferably; S(O) mY 1, Y wherein 1Be preferably C 1-4Alkyl, m represent 0,1 or 2(for example methylthio group, ethylmercapto group, rosickyite base, methyl sulfinyl, ethylsulfinyl-1 base, propyl group sulfinyl, methylsulfonyl, ethylsulfonyl, third alkylsulfonyl), more preferably, Y 1Be C 1-2Alkyl, methyl most preferably, suitable m is 0 or 1, is preferably 0; C 2-5Carbalkoxy (for example methoxycarbonyl or ethoxycarbonyl); C 2-5Alkanoyl (for example ethanoyl or propionyl); Or C 2-5Alkanoyloxy (for example acetoxyl group or propionyloxy); CONR 18R 19, R wherein 18And R 19Preferred hydrogen, the C of representing 1-6Alkyl, C 2-6Alkenyl, C 3-8Cycloalkyl, contain 1 or 2 heteroatomic 3-8 person's non-aromatic heterocycle, phenyl that is selected from oxygen, sulphur or nitrogen, contain 1-3 the heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen; Perhaps R 18And R 19Form with the nitrogen-atoms that they connected and to contain the other heteroatomic 3-8 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen, substituent R 18, R 19In each all can be replaced arbitrarily by Z.
In formula I compound, particularly preferred substituent R 6Comprise hydrogen, carboxyl or R wherein 14As defined above-COR 14
Preferred esterifying carboxyl group R 6Comprise: C 2-6Carbalkoxy (for example methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, butoxy carbonyl or penta oxygen carbonyl); C 3-8Cyclo alkoxy carbonyl (for example cyclobutoxy group carbonyl, cyclopentyloxy carbonyl, cyclohexyloxy carbonyl) or tetrahydrochysene-2H-pyrans-4-base oxygen base carbonyl, each of these groups can be replaced by following substituting group: C 1-6Alkyl (for example methyl); C 3-8Cycloalkyl (for example cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl); Phenyl; Contain 1 or 2 heteroatomic 3-8 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen (for example tetrahydrofuran base, THP trtrahydropyranyl, morpholino, piperidino-(1-position only), thiomorpholine generation, 1-piperazinyl); Contain 1-3 the heteroatomic 5 or 6 Yuans aromatic heterocyclic radicals (for example pyridyl, thiazolyl, thienyl) that are selected from oxygen, sulphur or nitrogen; C 2-6Carbalkoxy (for example ethoxycarbonyl); C 2-6Alkanoyl (for example ethanoyl); C 1-6Alkoxyl group (for example methoxy or ethoxy); S(O) mY 1(for example methylthio group); C 2-6Alkanoyloxy (for example acetoxyl group); Cyano group; Hydroxyl; Acetoxyl group; Trifluoromethyl; Halogen.Optional C 1-6Alkoxy substituent can be by C 1-6Alkoxyl group (for example methoxyl group) or C 2-6Alkanoyloxy (for example acetoxyl group) further replaces.Optional phenyl, non-aromatic heterocycle or aromatic heterocyclic radical substituting group can be by C 1-6Alkyl (for example methyl), C 1-6Alkoxyl group (for example methoxyl group), halogen (for example chlorine) further replace.
In particularly preferred compound, R 6Represent CO 2(CH 2) PJ, wherein p represents 0-3, and J represents cyano group, hydroxyl, C 3-8Cycloalkyl, C 2-6Alkanoyloxy, C 2-6Carbalkoxy, C 1-6Alkoxyl group, C 1-6Alkoxyl group (C 1-6) alkoxyl group, C 1-6Alkylthio, or the J representative contains 1 or 2 heteroatomic 5 or 6 Yuans aromatic heterocyclic radical that are selected from oxygen, sulphur or nitrogen; Contain 1 or 2 heteroatomic 5 or 6 Yuans non-aromatic heterocycle that are selected from oxygen, sulphur or nitrogen; Or phenyl.In these groups each all can be by C 1-6Alkyl, C 1-6Alkoxy or halogen replaces arbitrarily.Preferably, p is 1 or 2.
Particularly preferred substituent R 6Also comprise it to be C 3-8The acyl group of naphthene base carbonyl (for example cyclopropyl carbonyl, cyclohexyl-carbonyl); Or can be by the C of phenyl or phenoxy group replacement 2-6Alkanoyl (for example ethanoyl, propionyl, butyryl radicals, pentanoyl, caproyl), phenyl wherein or phenoxy group can be by halogen, C 1-4Alkyl or C 1-4Alkoxyl group replaces arbitrarily; Perhaps C 2-6Alkanoyl can be replaced by following radicals: C 2-6Carbalkoxy (for example methoxycarbonyl), C 2-6Alkoxyl group (for example methoxyl group), C 1-4Alkylthio (for example methylthio group), C 3-8Cycloalkyl (for example cyclopentyl).
In particularly preferred compound, R 6Represent COCH 2K, wherein K represents C 1-4Alkoxyl group or phenoxy group.
Particularly preferred substituent R 6Also can comprise group CONR 12R 13, R wherein 12Represent methylidene or ethyl, preferable methyl, R 13Comprise phenyl or the C that is replaced by phenyl 1-4Alkyl (even more preferably methyl or ethyl, most preferably methyl).Most preferably, R 12Represent ethyl, and R 13Represent phenyl.
Especially preferred substituent R 6Comprise hydrogen; The cyclopropyl methoxycarbonyl; 2-methoxyl group benzyloxy carbonyl; 4-benzyloxycarbonylchloride base; 2-methyl carbobenzoxy-(Cbz); 3-methyl carbobenzoxy-(Cbz); 2-kharophen ethoxycarbonyl; 2-(2-methyl piperidine subbase) ethoxycarbonyl; 3-(2-propionyloxy ethyl)-3-azepine pentamethylene carbamyl; Methyl (2-aminomethyl phenyl) carbamyl; Methyl (3-aminomethyl phenyl) carbamyl; Methyl (4-aminomethyl phenyl) carbamyl; Methyl (1,3-two oxa-s penta ring-2-ylmethyl) carbamyl; Chlorine; Bromine; Methylthio group; Ethylmercapto group; Methyl sulfinyl; Methylsulfonyl; Carboxyl; Methoxycarbonyl; Ethoxycarbonyl; The third oxygen carbonyl; Butoxy carbonyl; Penta oxygen carbonyl; The ring butoxy carbonyl; Encircle penta oxygen carbonyl; Hexamethylene oxygen carbonyl; Tetrahydrochysene-2H-pyrans-4-base oxygen base carbonyl; Cyclobutyl methoxy carbonyl; Tetrahydrofurfuryl oxygen base carbonyl; Carbobenzoxy-(Cbz); 4-methoxyl group benzyloxy carbonyl; 3-methoxyl group benzyloxy carbonyl; 4-methyl carbobenzoxy-(Cbz); 2-benzyloxycarbonylchloride base; 3-benzyloxycarbonylchloride base; The 2-(phenyl) ethoxycarbonyl; The 2-(4-p-methoxy-phenyl) ethoxycarbonyl; The 2-(4-chloro-phenyl-) ethoxycarbonyl; The 2-(2-pyridyl) ethoxycarbonyl; 2-(4-methyl-5-thienyl) ethoxycarbonyl; The 2-(2-thienyl) ethoxycarbonyl; 2-cyclohexyl ethoxycarbonyl; 2-methoxyl group ethoxycarbonyl; The 2-(methylthio group) ethoxycarbonyl; 2-'-hydroxyethoxy carbonyl; 2-acetoxyl group ethoxycarbonyl; 2-cyano group ethoxycarbonyl; The 2-(ethoxycarbonyl) ethoxycarbonyl; The 2-(2-methoxy ethoxy) ethoxycarbonyl; 3-oxo butoxy carbonyl; The 2-(2-chloro-phenyl-) ethoxycarbonyl; The 2-(3-aminomethyl phenyl) ethoxycarbonyl; 4,4,4-trifluoro butoxy carbonyl; 2-morpholino ethoxycarbonyl; 2-piperidino-(1-position only) ethoxycarbonyl; The 2-thiomorpholine is for ethoxycarbonyl; 1-methyl-2-morpholino ethoxycarbonyl; The 3-morpholino third oxygen carbonyl; 3-(4-methyl isophthalic acid-piperazinyl) the third oxygen carbonyl; 1-methyl-2-piperidyl methoxy carbonyl; Ethanoyl; Propionyl; Butyryl radicals; Pentanoyl; Caproyl; Cyclopropyl carbonyl; Cyclohexyl-carbonyl; The phenoxy group ethanoyl; Phenyl acetyl; 3-methoxycarbonyl propionyl; Carbamyl; 3-oxa-pentamethylene carbamyl; 3-(2-acetoxyl group ethyl)-3-azepine pentamethylene carbamyl; Methyl (2-morpholino ethyl) carbamyl; Benzyl (methyl) carbamyl; Methyl (3-pyridylmethyl) carbamyl; Toluene (2-phenyl) ethyl carbamyl; 2-cyano ethyl (methyl) carbamyl; Methyl (phenyl) carbamyl; Ethyl (phenyl) carbamyl; 2-phenoxy group ethoxycarbonyl; 1-benzyl ethoxycarbonyl; The 3-(3-pyridyl) the third oxygen carbonyl; 2-(4-(N, N-dimethylamino) phenyl) ethoxycarbonyl; The 2-phenyl third oxygen carbonyl; The 3-acetoxyl group third oxygen carbonyl; The 3-hydroxyl third oxygen carbonyl; 4-chloro-phenyl-(methyl) carbamyl; 4-(2-acetoxyl group ethyl) piperazinyl carbonyl; 4-(2-propionyloxy ethyl) piperazinyl carbonyl; 4-methoxycarbonyl phenyl (methyl) carbamyl; The 2-(4-p-methoxy-phenyl) propionyl; 4-chlorophenoxy ethanoyl; The cyclopentyl ethanoyl; The 2-(3-aminomethyl phenyl) propionyl; 2-methylphenoxy ethanoyl; 2-methylthio group propionyl; The methoxyl group ethanoyl.
In formula I compound, suitable substituents R 7Comprise hydrogen; Halogen (fluorine, chlorine, bromine), preferred fluorine or chlorine, more preferably chlorine; Trifluoromethyl; C 1-6Alkyl, preferred C 1-4Alkyl (for example methyl, ethyl or propyl group), more preferably methyl or ethyl, most preferably methyl; Methoxyl group; S(O) mY 1, Y wherein 1Be preferably C 1-4Alkyl and m represents 0 or 1, (for example methylthio group, ethylmercapto group, rosickyite base, methyl sulfinyl, ethylsulfinyl-1 base, propyl group sulfinyl), m is preferably 0, more preferably, Y 1Be C 1-2Alkyl, most preferably methyl.
In preferred formula I compound, R 8Represent hydrogen, fluorine, chlorine or trifluoromethyl, even more preferably hydrogen or chlorine, and hydrogen most preferably.
In preferred formula I compound, R 8' represent hydrogen or chlorine, especially hydrogen.
Substituent R 9And R 10Can be positioned at any position of benzo ring, promptly be positioned on 6,7,8 and/or 9 of benzo ring.Therefore, substituent R given here 9And R 10In each all be considered to be on each position in these positions.In one group of compound, R 10Be positioned on 6 or 7 of benzo ring, particularly on 6.In one group of preferred compound, R 10Be positioned on 8 or 9 of benzo ring, particularly on 8.
In preferred formula I compound, R 9Represent hydrogen, fluorine or chlorine, even more preferably hydrogen or fluorine, most preferably hydrogen.
In some formula I compound, radicals R 10Can represent acyloxy, and can have the following formula structure:
R in the formula 17Represent alkyl (C for example 1-6); Alkenyl (C for example 2-6); Cycloalkyl (C for example 3-11); Non-aromatic heterocycle; Isocyclic aryl or heterocyclic aryl; In these groups each can be optionally substituted.In preferred formula I compound, R 17Represent C 1-6Alkyl; C 2-6Alkenyl; C 3-11Cycloalkyl; 3-8 person's non-aromatic heterocycle; Isocyclic aryl; Or 5 or 6 element heterocycle aryl; In these groups each all can be replaced arbitrarily by Z.Preferably, R 17Represent C 1-6Alkyl; C 2-6Alkenyl; C 3-10Cycloalkyl; Contain 1 or 2 heteroatomic 5-7 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen; Phenyl; Contain 1 or 2 heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen; Each substituent R 17All can be by Z 1Or Z 2Replace arbitrarily.Comprise the ester of facile hydrolysis and the ester of those more difficult hydrolysis in the scope of the present invention.Preferably, R 10Represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl, hydroxyl, nitro, C 1-6Alkyl (preferred C 1-4Alkyl), C 1-6Alkoxyl group (preferred C 1-4Alkoxyl group) or the acyloxy of above-mentioned definition.More preferably, R 10Represent hydrogen, halogen (preferred fluorine or chlorine), hydroxyl, C 1-6Alkoxyl group (for example methoxyl group), C 1-6Alkyl (for example methyl), nitro or acyloxy.Most preferably, R 10Represent hydrogen, fluorine, hydroxyl or acyloxy.
In particularly preferred formula I compound, R 10Comprise hydrogen; Hydroxyl; C 3-10Cycloalkanes acyloxy (for example cyclopropyl carbonyl oxygen base), cyclobutyl carbonyl oxygen base or adamantyl carbonyl oxygen base); C 2-6Alkanoyloxy (for example acetoxyl group or propionyloxy) or C 2-6Chain ene acyloxy, this two group all can be selected from following substituting group and be replaced: C 2-6Alkanoyloxy (for example acetoxyl group), S(O) mY 1(for example methylthio group), C 1-6Alkoxyl group (for example methoxyl group), carboxyl, chloro-phenyl-, two (C 1-6Alkyl) amino or C 2-6Carbalkoxy (for example methoxycarbonyl or ethoxycarbonyl), and the phenyl that can be optionally substituted (for example 4-p-methoxy-phenyl, 4-aminomethyl phenyl, 4-chloro-phenyl-) further replaces; Perhaps R 10Represent aryl-carbonyl oxygen, wherein aryl suitably is phenyl, thienyl, furyl, (they itself can be by C for pyridyl 1-6Alkyl (for example methyl), C 1-6Alkoxyl group (for example methoxyl group) or halogen (for example chlorine) replace).
R wherein preferably 10Represent OCO(CH 2) pThose compounds of L, in the formula, p is 0-3, and L represents hydrogen; C 3-11Cycloalkyl; Two (C 1-6Alkyl) amino; C 2-6Alkanoyloxy; C 2-6Carbalkoxy; C 1-6Alkylthio; C 1-6Alkoxyl group; By C 1-6Alkyl, C 1-6Adamantyl or phenyl that alkoxy or halogen replaces arbitrarily.
Preferred substituted R 10Comprise the chloroethene acyloxy; 4-chlorobenzoyl oxygen base; Cyclopentylcarbonyl oxygen base; The cyclohexyl-carbonyl oxygen base; Hydrogen; Fluorine; Chlorine; Hydroxyl; Acetoxyl group; Propionyloxy; Butyryl acyloxy; Penta acyloxy; The methoxycarbonyl acetoxyl group; 3-methoxycarbonyl propionyloxy; The acetoxyl group acetoxyl group; The 3-(methylthio group) propionyloxy; Benzoyloxy; The methoxyl group acetoxyl group; 4-methoxyl group benzyloxy carbonyl acetoxyl group; The ethoxycarbonyl acetoxyl group; The but-2-ene acyloxy; 3-ethoxycarbonyl propionyloxy; The carboxyl acetoxyl group; Adamantyl ketonic oxygen base; 3-phenyl propionyl; The methylmercaptan ethyl acyloxy; The phenyl acetoxyl group; The dimethylamino acetoxyl group; Thenoyl oxygen base; Furoyl oxygen base; 2-toluyl oxygen base; 2-methoxybenzoyl oxygen base; 4-methoxybenzoyl oxygen base; Pyridyl ketonic oxygen base; Cyclopropyl carbonyl oxygen base; Cyclobutyl carbonyl oxygen base; 4-toluyl oxygen base; 3-toluyl oxygen base.
The preferred formula I of one class compound is those compounds of being represented by the formula V,
Figure 91105264X_IMG24
R in the formula 6', R 7, R 8, R 9, R 10And R 14And preferred substituted is as described in the above-mentioned formula I.More preferably, R 6' represent hydrogen, R 14Represent OR 15, R 16Or NR 12R 13, R wherein 12Represent methylidene or ethyl, R 13Representative can be by cyano group, phenyl, contain 1 or 2 heteroatomic 3-8 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen, contain the C that 1-3 the heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen replace arbitrarily 1-6Alkyl, perhaps R 13Representative can be by C 2-6The phenyl that alkoxy carbonyl or halogen replace arbitrarily; Perhaps R 12And R 13Form with the nitrogen-atoms that they connected and can contain the other heteroatomic 3-8 person's non-aromatic heterocyclic that is selected from oxygen, sulphur or nitrogen, this heterocycle can be by C 2-6Acyloxy (C 1-6) the alkyl replacement; R 15And R 16Can be identical or different, the group that representative can be optionally substituted, this group is selected from C 1-6Alkyl; C 2-6Alkenyl; C 3-10Cycloalkyl; Contain 1 or 2 heteroatomic 3-8 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen; Phenyl; Contain 1-3 the heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen; R 9Represent hydrogen, and R 10Represent hydrogen, hydroxyl, halogen, C 1-6Alkoxyl group or C 1-6Alkyl.
Another kind of preferred formula I compound is those compounds of being represented by the formula VI,
Figure 91105264X_IMG25
R in the formula 6', R 7, R 8, R 9, R 10And R 14And preferred substituted is as defining above-mentioned formula I.More preferably, R 6' represent hydrogen, R 14Represent OR 15, R 16Or NR 12R 13, R wherein 12Represent methylidene or ethyl, R 13Representative can be by cyano group, phenyl, contain 1 or 2 heteroatomic 3-8 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen, contain the C that 1-3 the heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen replace arbitrarily 1-6Alkyl, perhaps R 13Representative can be by C 2-6The phenyl that carbalkoxy or halogen replace arbitrarily; Perhaps R 12And R 13Form with the nitrogen-atoms that they connected and can contain the other heteroatomic 3-8 person's non-aromatic heterocyclic that is selected from oxygen, sulphur or nitrogen, this heterocycle can be by C 2-6Acyloxy (C 1-6) the alkyl replacement; R 15And R 16Can be identical or different, the group that representative can be optionally substituted, this group is selected from C 1-6Alkyl; C 2-6Alkenyl; C 3-10Cycloalkyl; Contain 1 or 2 heteroatomic 3-8 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen; Phenyl; Contain 1-3 the heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen; R 9Represent hydrogen, R 10Represent hydrogen, hydroxyl, halogen, C 1-6Alkoxyl group or C 1-6Alkyl.
Another kind of preferred formula I compound is those compounds of being represented by the formula VII,
Figure 91105264X_IMG26
R in the formula 6, R 6', R 7, R 8And R 17And preferred substituted such as above-mentioned the formula I is defined.Preferably, substituting group OCOR 17Be positioned at 8 or 9 of member ring systems, especially 8.More preferably, R 6' represent hydrogen, R 6Represent hydrogen, C 2-6Carbalkoxy or C 1-6Alkylthio, R 17Representative can the substituted arbitrarily group that is selected from following groups: C 1-6Alkyl; C 2-6Alkenyl; C 3-11Cycloalkyl; Contain 1 or 2 heteroatomic 3-8 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen; Phenyl; Contain 1 or 2 heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen.
Another kind of preferred formula I compound those compounds for representing by the formula VIII,
R in the formula 7, R 8And R 17And preferred substituted is as defining above-mentioned formula I.More preferably, R 17Representative can be optionally substituted group, and this group is selected from C 1-6Alkyl; C 2-6Alkenyl; C 3-11Cycloalkyl; Contain 1 or 2 heteroatomic 3-8 person's non-aromatic heterocycle that is selected from oxygen, sulphur or nitrogen; Phenyl; Contain 1 or 2 heteroatomic 5 or 6 element heterocycle aryl that are selected from oxygen, sulphur or nitrogen.
Another kind of preferred formula I compound is those compounds of being represented by the formula IX,
Figure 91105264X_IMG28
R in the formula 6, R 6', R 7, R 8, R 8', R 9And R 10And preferred substituted as above defines the formula I.More preferably, R 6' represent hydrogen or methyl; R 6Represent hydrogen, halogen, C 2-6Alkanoyl, C 2-6Carbalkoxy, S(O) nY 1, carbamyl, carboxyl, perhaps R 5And R 6Represent cyclopropyl with the carbon atom that they connected; R 7Represent hydrogen, halogen, trifluoromethyl, methoxyl group, C 1-6Alkyl, S(O) mY 1; R 8Represent hydrogen, halogen or trifluoromethyl; R 8' represent hydrogen, halogen or trifluoromethyl; R 9And R 10Can be identical or different, represent halogen respectively; Perhaps R 9Represent hydrogen, and R 10Represent hydrogen, halogen, trifluoromethyl, hydroxyl, nitro, C 2-6Alkanoyloxy, C 1-6Alkyl or C 1-6Alkoxyl group.
In one group of preferred compound, X represents O.Organize in the preferred compound R at another 6Represent COR 14, COOR especially 15, X preferably represents O, and Z preferably represents-CH=.Organize in the preferred compound R at another 10Represent OCOR 17, X preferably represents oxygen, and Z preferably represents-CH=.
Listed compound and the pharmaceutically useful salt thereof of Table A that concrete formula I compound is in specific embodiments of the invention to be provided comprises the free alkali of the compound that exemplifies as salt, hydrate or solvated compounds.
Formula I compound can contain one or more chiral centres, so optical activity form that can be different exists.When formula I compound contained a chiral centre, two kinds of enantiomers that they exist the present invention includes enantiomorph and mixture of enantiomers.Enantiomorph can split by the known method of the professional in present technique field, for example splits by following method: formation can be by for example salt or the title complex of the isolating diastereomer of crystallization process; Formation can be by for example derivative of crystallization process, solution-air or the isolating diastereomer of liquid chromatography; By with enantiomorph specificity reagent react, for example enzymatic oxidation or reduction reaction carry out selective derivatizationizations to a kind of enantiomorph; Perhaps in chiral environment for example chiral support as the silicon-dioxide of the chiral ligand that has bonding on or in the presence of chiral solvent, carry out solution-air or liquid chromatography (LC).In addition, special enantiomorph can prepare by using optically active reagent, substrate, catalyzer or solvent to carry out asymmetric synthesis, also can a kind of enantiomorph be changed into another kind of enantiomorph by asymmetric conversion reaction and prepare.
For example, all formula IV compounds all have chiral centre.Specifically, in the Table A (seeing below) each (1) benzo thiapyran of listed concrete 3a-methyl substituents also (4,3-c) pyrazoles therefore be named as R or S enantiomorph.In addition, the compound of naming below also can R or the S enantiomeric forms exist: the 2-(4-chloro-phenyl-)-3-oxo-1,2,3,4-tetrahydrochysene (1) chromene is (4,3-c) pyrazoles-4-acetate 2-morpholino ethyl ester also.
When formula I compound contained an above chiral centre, they can diastereomeric form exist.The present invention includes the mixture of each diastereomer and diastereomer.Diastereomer can be by for example crystallization process or the liquid chromatography separation of the known method of present technique field professional.
Some formula I compound can be different tautomeric form or exist as different rotamerism form.
Some formula I compounds are alkali, can with mineral acid or organic acid, for example hydrochloric acid, Hydrogen bromide, fumaric acid, tartrate and citric acid form acid salt.Should be appreciated that, if these salt are pharmaceutically useful, then available they replace during its corresponding formula I compound is used for the treatment of.Such salt can be routinely method for example by formula I compound and suitable acid-respons are prepared.
Some formula I compound can exist by more than one crystallized forms, the present invention includes each crystallized form and composition thereof.
The all right solvate of some the formula I compound for example form of hydrate exists, and the present invention includes each solvate and composition thereof.
The present invention also comprises and contains the formula I compound for the treatment of significant quantity and the pharmaceutical composition of pharmaceutically acceptable diluent or carrier.
As hereinafter used, (1) chromene that term " active compound " is meant the formula I is (4,3-c) pyrazoles or (1) chromene (4,3-c) pyrazoles also also.In treatment is used, can be with this active compound by oral, rectum, non-stomach and intestine or topical routes, preferred oral or topical.Like this, any pharmaceutical compositions that therapeutic composition of the present invention can be that known confession is oral, rectum, non-stomach and intestine or topical routes are used.The pharmaceutically acceptable carrier that is suitable for using in such composition is well-known in pharmaceutical field.Composition of the present invention can contain 0.1～90%(weight) active compound.Usually composition of the present invention is made unit dosage form.Used vehicle is a known vehicle in pharmaceutical field in these compositions of preparation.
In composition of the present invention, when needing, the compatible composition with pharmacologically active of active compound and other can be used in combination.
Formula I compound is specified as immunomodulator, and they are generally immunosuppressor, and still, under some morbid state, some compounds can present immunostimulatory activity.The compounds of this invention can be used for treating the disease that is caused by the abnormal immune reaction.Therefore, the pharmaceutical composition that contains the formula I compound for the treatment of significant quantity can be used for treatment and immune diseases associated for example tissue rejection such as kidney repels; Autoimmune disorders is rheumatoid arthritis and systemic lupus erythematosus for example; Tetter is contact allergy, eczema and psoriasis for example; And knurl melanoma for example.
In such treatment, the amount of the formula I compound of taking every day should be able to reach result of treatment, is generally 0.1-2000mg, preferred 1-500mg.
Therefore, on the other hand, the present invention also comprises the method for treatment and immune diseases associated, comprises the formula I compound of taking the treatment significant quantity.
The therapeutic activity of formula I compound confirms by many tests the ordinary test animal.Such test comprises, for example, makes BALB/c mouse oral and give test compound by non-stomach and intestine approach.Therefore, formula I compound can be used as immunomodulator.Though the definite consumption of the active compound of being taken depends on many factors, for example, patient's age, the severity of disease and medical history, and this amount always depends on doctor in charge's correct judgement, but, the suitable oral dosage of Mammals (comprising the people) was generally 0.01-40mg/kg/ days, was more typically 0.2-25mg/kg/ days, as single dosage or be divided into a plurality of divided dose administrations.For non-stomach intestine medicine-feeding, proper dosage was generally 0.001-4.0mg/kg/ days, was more typically 0.005-1mg/kg/ days, as single dosage or be divided into a plurality of divided dose administrations or by the continuous infusion administration.The suitable local administration preparation amount of contained activeconstituents usually is a 0.01-20%(weight), be more typically 0.05-5%(weight).The preferred oral administration.
The preparation method of formula I compound will be described below.
The formula I compound of being represented by the formula II can prepare by the formula I compound of for example being represented by the formula III with the chloranil oxidation.
The formula I compound of being represented by the formula II can react formula X compound or its tautomer and formula XI compound and prepare by for example 50-200 ℃ of heating down,
Figure 91105264X_IMG29
R in the formula 22Representative (OQ) 2, R 23Represent OQ or NQ ' 2; Perhaps R 22Representative (SQ) 2, R 23Represent SQ or NQ ' 2; Perhaps R 22Representative=NH, R 23Represent OQ or SQ; Perhaps R 22Representative=O, R 23Represent leavings group, for example, the 1-imidazolyl that can be optionally substituted, wherein, Q and Q ' represent C 1-4Alkyl or benzyl.
By R wherein 6' represent hydrogen, R 6The formula I compound of representing the formula II of acyl group to represent can heat under 50-200 ℃ temperature in organic liquid such as dimethylbenzene by for example, and formula X compound and formula XII a compound or its tautomerism precursor reactant are prepared,
Figure 91105264X_IMG30
R in the formula 24And R 25Can be identical or different, represent C separately 1-6Alkyl or benzyl.
By R wherein 6The formula I compound of representing the formula II compound of acyl group to represent can heat under 50-250 ℃ temperature in organic liquid such as dimethylbenzene by for example, and formula X compound and formula XII b compound or its tautomerism precursor reactant are prepared,
Figure 91105264X_IMG31
R in the formula 24And R 25Can be identical or different, represent C separately 1-6Alkyl or benzyl.
By R wherein 6Represent CONR 12R 13The formula I compound that the formula II of group or esterifying carboxyl group is represented can be by for example, under 0-250 ℃, at random under organic liquid (preferably reactant solvents) also at random react with make in the presence of the catalyzer formula II ' compound respectively with formula NHR 12R 13Amine or formula R for example 15The alcohol of OH reacts and prepares,
Figure 91105264X_IMG32
R in the formula 10' represent R 10, Ra represents COA, and wherein A represents leavings group, for example, hydroxyl, halogen, C 1-6Alkoxyl group, aryloxy, aryl methoxy, C 1-6Acyloxy or C 1-6Alkyl oxy carbonyl oxygen.
By R wherein 6The formula I compound that the formula II compound of the group that representative is replaced by acyloxy is represented can be by preparing the formula II compound acylation that is replaced by hydroxyl accordingly with carboxylic acid halides.
By R wherein 6The formula I compound that the formula II compound of the group that representative is replaced by hydroxyl is represented can by hydrolysis by accordingly by acyloxy for example the formula I compound that replaces of acetoxyl group prepare.
By R wherein 10Represent the formula I compound that the formula II compound of acyloxy represents can be by Ra wherein being represented R with acylating agent 6And R 10Formula II ' the compound acylation of ' representation hydroxy prepares.This acylation reaction can be by making for example R of formula II ' compound and carboxylic acid halides under-10 ℃～40 ℃ temperature in the presence of the alkali 17COCl or acid anhydrides (R 17CO) 2O reacts and carries out.This acylation reaction can by dewatering agent for example in the presence of the dicyclohexyl carbodiimide, be preferably in alkali and for example make formula II ' compound and carboxylic acid R in the presence of the pyridine 17COOH reacts and carries out.R wherein 10Formula II ' the compound of ' representation hydroxy can pass through wherein R 10' represent C 1-6Formula II ' the compound of alkoxyl group and Lewis acid for example aluminum chloride or boron tribromide react and prepare.
By R wherein 6And R 6' formula I the compound of all representing the formula II of hydrogen to represent can be prepared as follows: make wherein R 6' represent hydrogen and R 6The formula II compound decarboxylation of representation carboxy; Perhaps by for example with sulfuric acid reaction, make wherein R 6' represent hydrogen and R 6Represent for example C of group that hydrolyzable becomes carboxyl 2-6The formula II compound hydrolysis of carbalkoxy or carbamyl, decarboxylation then.
By R wherein 6Represent C 1-6Alkyl sulfinyl or C 1-6The formula I compound that the formula II of alkyl sulphonyl is represented can be with 3-chlorine peroxybenzoic acid for example to R wherein 6Represent C 1-6The formula II compound of alkylthio carries out oxidation and prepares.
By R wherein 6The formula I compound that the formula II compound of representation carboxy is represented can be for example by for example handling from R wherein with trifluoroacetic acid and methyl-phenoxide in the methylene dichloride at solvent 6Represent the formula II compound of 4-methoxyl group benzyloxy carbonyl.
By R wherein 10The representation carboxy alkyl carbonyl oxy for example formula I compound represented of the formula II compound of carboxylic acetoxyl group can be by for example handling from R wherein with trifluoroacetic acid and methyl-phenoxide in the methylene dichloride at solvent 10Represent for example formula II compound of 4-methoxyl group benzyloxy carbonyl acetoxyl group of 4-methoxyl group benzyloxy carbonylic alkyl carbonyl oxygen base.
The formula I compound of being represented by the formula II can prepare by formula X III compound or its tautomer and alkali such as piperidines are reacted,
Figure 91105264X_IMG33
R in the formula 26Represent hydrogen, or R 26Represent COR 28Group, wherein R 28The C that represent hydrogen, replaces arbitrarily 1-4Alkyl or benzyl, R 27Represent COCHR 6R 6'.
The formula I compound of being represented by the formula III can prepare by the formula I compound of for example being represented by the formula II with sodium borohydride reduction.
The formula I compound of representing by formula III or IV can by with from formula II ' compound formula II compound similar methods from corresponding formula I ' compound,
Figure 91105264X_IMG34
The formula I compound of being represented by the formula III can be by for example, for example contains in the dimethylbenzene of tosic acid in 50-250 ℃ of heating down in acetate or at the inert organic liquid that contains acid catalyst, and the hydrazine reaction of formula X IV compound and formula X V is prepared,
Figure 91105264X_IMG35
R in the formula 3Represent hydrogen, R 5Represent CHR 6R 6', R 29Represent COOR 30Or carbamyl, R 30Represent C 1-4Alkyl or benzyl,
Figure 91105264X_IMG36
The formula I compound of being represented by the formula IV can prepare by formula X IV compound and the formula X V compound of Z representative-CH=are wherein reacted.In described formula X IV compound, X represents S, R 3Represent methylidene, R 5Represent hydrogen, R 29And R 30As defined above.
Prepare described when the formula I compound of being represented by formula V-IX can be as above-mentioned preparation formula II-IV compound.
Formula X compound can prepare the hydrazine reaction of formula X VI compound and formula X V by for example heating down in 50-200 ℃ in organic liquid such as toluene,
Figure 91105264X_IMG37
R in the formula 31Represent hydrogen, C 1-4Alkyl or benzyl.Excessive formula X VI compound when preferably using than stoichiometric calculation.
Formula X compound can by make formula X VII compound and acid for example hydrochloric acid or with alkali for example sodium hydroxide solution react and prepare,
Figure 91105264X_IMG38
R wherein 10The formula X compound of representation hydroxy can be by making wherein R 10Represent C 1-6The formula X compound of alkoxyl group and Lewis acid for example aluminum chloride or boron tribromide react and prepare.
R wherein 22Representative (OQ) 2And R 23Represent the formula XI compound of OQ to prepare by for example following method: a) making wherein, X is the formula R of halogen 6' R 6CH-CX 3Compound is C with Q wherein 1-4The sodium alkoxide reaction of the formula NaOQ of alkyl or benzyl, perhaps b) for example make formula R in the presence of the hydrogenchloride at anhydrous acid 6' R 6The alcohol reaction of the compound of CH-CN and formula QOH obtains formula R 6' R 6CH-C(=NH) the sour salify of OQ compound hydrochloride for example makes the latter and other formula QOH alcohol reaction then.
R wherein 22Representative (SQ) 2And R 23Represent the formula XI compound of SQ can be by for example making for example formula R in the presence of the zinc chloride at Lewis acid 6' R 6The CHCOCl compound is represented C with Q wherein 1-4The formula QSH thiol reactant of alkyl or benzyl, and from formula R 6' R 6The CHCOCl compound.
Other formula XI compound can be by the known method preparation of present technique field professional.
Formula XII b compound or its tautomer can pass through, and for example, under-10 ℃～50 ℃ temperature, in inert solvent, use acyl chlorides R in the presence of pyridine 16-COCl carries out acylation reaction to formula X IX compound and prepares,
Figure 91105264X_IMG39
R wherein 26Represent COR 28And R 27Represent COCHR 6R 6' formula X III compound can pass through, for example, with formula (R 6' R 6CHCO) 2The acid anhydrides of O or formula R for example 6' R 6The carboxylic acid halides of CHCOCl is to R wherein 26Represent COR 28, and R 27Represent the formula X III compound acylation of hydrogen to prepare.
R wherein 26Represent COR 28And R 27Represent the formula X III compound of hydrogen can be by in the presence of the salt (for example sodium salt) of respective acids, for example using formula (R 28CO) 2The acid anhydrides of O prepares formula X compound acylation.
R wherein 26And R 27Identical and all represent COCHR 6R 6' formula X III compound can be by in the presence of the salt (for example sodium salt) of respective acids, for example using formula (R 6' R 6CHCO) 2The acid anhydrides of O prepares formula X compound acylation.
R wherein 27Represent COCHR 6R 6' and R 26Represent formula X III compound or its tautomer of hydrogen can be by for example making wherein R in the ethanol at suitable solvent 26Represent COR 28, R 27Represent COCHR 6R 6' formula X III compound and alkali such as piperidines react and prepare.
R wherein 29Represent COOR 30, R 5Represent CHR 6R 6' formula X IV compound can prepare by formula XX compound is heated with for example glass powder or glass wool,
Figure 91105264X_IMG40
R in the formula 30Represent C 1-4Alkyl or benzyl.
R wherein 3Represent methylidene, R 5Represent hydrogen formula X IV compound can by for example make in the presence of sodium alkoxide such as the sodium methylate at alkali formula X VIII compound and methylating reagent for example methyl halide such as methyl-iodide react and prepare,
R wherein 29Represent the formula X IV compound of carbamyl can be by method known to those skilled in the art from R wherein 29Represent the formula X IV compound of cyano group.
Formula X V compound can prepare with the known method of those skilled in the art.
R wherein 31Represent hydrogen formula X VI compound can by acyl chlorides for example phosphoryl chloride and Lewis acid for example formula X XI compound and propanedioic acid are reacted in the presence of the zinc chloride to prepare,
Figure 91105264X_IMG42
R in the formula 33Represent hydrogen.
R wherein 31Represent the formula X VI compound of hydrogen to prepare: to make wherein R by following method 33Represent COR 34(R wherein 34Represent C 1-5Alkyl) for example sodium hydride reaction of formula X XI compound and alkali, using wherein then, Q represents C 1-4The formula of alkyl or benzyl (QO) 2The dialkyl carbonate of CO for example methylcarbonate is handled.
R wherein 31Represent C 1-4The formula X VI compound of alkyl or benzyl can be by making wherein R 31Represent the formula X VI compound of hydrogen to prepare with alkylation or the benzyl reaction that for example alkylogen or benzyl halide carry out alkaline catalysts.
Formula X VII compound can prepare the hydrazine reaction of formula X VI compound and formula X V by for example heating down in 50-200 ℃ in suitable solvent such as toluene.When obtain be the mixture of formula X and X VII compound the time, can by these compounds organic liquid for example the solubleness in the methylene dichloride difference and with its separation.
Formula X VIII-X XI compound can be by the known method preparation of those skilled in the art.
By R wherein 10Represent R 17The formula I compound that the formula II of OCO is represented can pass through wherein R 10The acylation reaction of the formula II compound of representation hydroxy prepares.During this acylation reaction, can form the compound of formula X XII,
Figure 91105264X_IMG43
This compound can be hydrolyzed into required above-mentioned formula II compound when for example being exposed in the atmospheric water.
Believe some formula X, XI, XII a) and b), X III, X IV, X V, X VI, X VII, X VIII, X IX, XX, X XI and X XII midbody compound be new compound.All new compounds wherein are as another aspect of the present invention and claimed.
By following non-limiting examples explanation the present invention.In an embodiment, umber and percentage number average by weight, the composition of mixed solvent provides with volume.By ultimate analysis and one or more following spectroscopic techniquess compound being carried out structure determines: nuclear magnetic resonance spectrum, infrared spectra and mass spectrum.
The preparation of new formula X VI compound
Embodiment 1
Under nitrogen atmosphere, stir and the boiling reflux condition under, with 20 fens clock times with 5 '-fluoro-2 '-mixture of hydroxy acetophenone (10g) in dry toluene (130ml) be added drop-wise to sodium hydride (6.2g; 60% mineral oil dispersion) in the suspension in dry toluene (130ml).After boiling 10 minutes again, continue heating, drip the solution of diethyl carbonate (15.7ml) in dry toluene (130ml) with 25 fens clock times simultaneously.Stir this mixture, and reflux 4 hours.After the cooling, reaction mixture is poured in the ice-cooled 2M hydrochloric acid (700ml).Filter and collect formed solid, be dissolved in then in the 4M aqueous sodium hydroxide solution (325ml).This solution is washed with ether, use the 5M hcl acidifying then.Filter and collect the solid that produces, wash with water, drying obtains 6-fluoro-4 hydroxy coumarin, m.p.250-251 ℃.
The preparation of new formula X IV compound
Embodiment 2
A) under agitation, dimethyl oxalate (1.4g) is added in the solution of sodium (0.3g) in methyl alcohol (10ml) warm promotion dissolving.This solution is cooled to envrionment temperature, drips the 6-methoxyl group-solution of 4-thiochromanone (1.2g) in methyl alcohol (6ml) with 15 fens clock times.Mixture was stirred 3 hours at ambient temperature, placed then 4 days.Decompression removes down and desolvates, and residue distributes between water and toluene.With 2M sodium hydroxide solution alkalization water layer, separate, and use the 2M hcl acidifying.Filter and collect formed solid, use recrystallizing methanol, obtain 6-methoxyl group-4-oxo-3-thiochroman glyoxalic acid methylester, m.p.85-89 ℃.
B) under agitation, the mixture with 6-methoxyl group-4-oxo-3-thiochroman glyoxalic acid methylester (6.2g) and glass powder (2.8g) heated 30 minutes down at 180 ℃.Mixture is cooled to envrionment temperature, extracts, filter then with boiling acetone.Evaporated filtrate, residue are dissolved in the Virahol of heat, and filtered while hot is removed tar then.The filtrate cooling is filtered then, obtain 6-methoxyl group-4-oxo-3-thiochroman carboxylate methyl ester, m.p.61-65 ℃.
C) under agitation, the 6-methoxyl group-4-oxo-solution of 3-thiochroman carboxylate methyl ester (1.0g) in toluene (10ml) is added to the solution of sodium (0.4g) in anhydrous methanol (15ml).Mixture boiled was refluxed 10 minutes, be cooled to envrionment temperature then, add methyl-iodide (1ml).Under agitation mixture boiled was refluxed 3 hours, placed at ambient temperature then 18 hours.With glacial acetic acid neutralize this mixture, reduction vaporization then.Residue is added in the water, uses methylbenzene extraction.The combining methylbenzene extracting solution is used saturated sodium bicarbonate solution and water washing successively, drying, reduction vaporization.Residue separates by dodging the formula silica gel column chromatography, uses ethyl acetate/petroleum ether (b.p.60-80 ℃, 1: 4) as moving phase.The gained solid obtains 6-methoxyl group-3-methyl-4-oxo-3-thiochroman carboxylate methyl ester, m.p.66-73 ℃ with ethyl acetate/petroleum ether (b.p.60-80 ℃) recrystallization.
Embodiment 3
A) under agitation, the mixture with 4-methoxyl group thiophenol (20g), ethoxy methylene diethyl malonate (29.3ml) and sal enixum (0.4g) heated 2 hours down in 160-170 ℃.In this reaction mixture, add Tripyrophosphoric acid (152g), heated 1 hour down in 80-90 ℃.Reaction mixture is poured in the water, used ether extraction, merge ether extracted liquid, drying.Except that after desolvating, the gained solid with ethyl acetate/petroleum ether (b.p.60-80 ℃) recrystallization, is obtained 6-methoxyl group-4-oxo-4H-1,2-benzothiopyran-3-carboxylic acid, ethyl ester, m.p.102-104 ℃.
B) under nitrogen atmosphere, under-78 ℃ and agitation condition, cupric chloride (150mg) is added to 6-methoxyl group-4-oxo-4H-1, in the 2-benzothiopyran-mixture of 3-carboxylic acid, ethyl ester (4g) in tetrahydrofuran (THF) (40ml).Temperature maintenance below-65 ℃, is added the 3M solution of methylmagnesium-bromide in ether (5ml) lentamente, then reaction mixture is warmed to envrionment temperature.Reaction mixture is poured in ether/2M hydrochloric acid, used the ether extraction water layer, the combined ether extracting solution, drying obtains crude product.Dodge the formula chromatography by silica gel and carry out purifying, as moving phase, obtain 6-methoxyl group-2-methyl-4-oxo-3-thiochroman carboxylic acid, ethyl ester, be oily matter with 1% ethanol/methylene.
The preparation of new formula XII b compound
Embodiment 4
Stir and 0 ℃ condition under, divide clock time with 3-5, (12g) is added drop-wise to 2 with pyridine, 2-dimethyl-1,3-diox-4 is in the solution of 6-diketone (20g) in methylene dichloride (220ml).The solution that produced was stirred 10 minutes down at 0 ℃, then with temperature maintenance in 0-2 ℃, drip 3-methoxycarbonyl propionyl chloride (22.8g).After adding, mixture was stirred 60 minutes down at 0 ℃, allow to be warmed to envrionment temperature then, under this temperature, kept 18 hours.Mixture is used 1M hydrochloric acid and water washing successively, drying, evaporation obtains 4-(2,2-dimethyl-4,6-dioxo-1,3-diox-5-yl)-4-ketobutyric acid methyl esters, be thickness oily matter.
Embodiment 5-15
By and similar methods described in the embodiment 4, as following table I institute is generalized, by making 2,2-dimethyl-1,3-diox-4,6-diketone (X IX) and R 16COCl(is R wherein 16As institute's definition in the table) react preparation formula XII b compound.
Note:
(1) product is a thickness oily matter.
(2) with after hydrochloric acid and the water washing, the solid collected by filtration product.
(3) be reflected under the nitrogen atmosphere and carry out.
(4) with methylene dichloride as moving phase by sudden strain of a muscle formula chromatography purification crude product.
(5) crude product is by industrial methylated spirit development the carrying out purifying with heat, and solid product is collected in the evaporation back.
(6) with after hydrochloric acid and the water washing, remove and desolvate, obtain the furvous solid.
The compound for preparing in the various embodiments described above is as follows:
52,2-dimethyl-5-phenylacetyl-1,3-diox-4,6-diketone
62,2-dimethyl-5-phenoxy group ethanoyl-1,3-diox-4,6-diketone
7 5-cyclohexyl-carbonyls-2,2-dimethyl-1,3-diox-4,6-diketone
8 5-cyclopropyl carbonyls-2,2-dimethyl-1,3-diox-4,6-diketone
92,2-dimethyl-5-(3-(4-p-methoxy-phenyl) propionyl)-1,3-diox-4,6-diketone
10 5-(4-chlorophenoxy ethanoyl)-2,2-dimethyl-1,3-diox-4,6-diketone
11 2,2-dimethyl-5-(3-(3-aminomethyl phenyl) propionyl)-1,3-diox-4,6-diketone
12 5-(2-cyclopentyl-1-hydroxy ethylene)-2,2-dimethyl-1,3-diox-4,6-diketone
13 5-(1-hydroxyl-2-(2-methylphenoxy) ethylidene)-2,2-dimethyl-1,3-diox-4,6-diketone
14 2,2-dimethyl-5-(3-methylthio group propionyl)-1,3-diox-4,6-diketone
15 5-methoxyl group ethanoyl-2,2-dimethyl-1,3-diox-4,6-diketone
The preparation of new formula XI compound
Embodiment 16
Stir and 0-5 ℃ condition under, the mixture usefulness hydrogenchloride of cyanoacetic acid propyl ester (30.5g), anhydrous propyl alcohol (18.5g) and dehydrated alcohol (134ml) is saturated.Make mixture be warmed to envrionment temperature, under this temperature, kept 66 hours.Behind the reduction vaporization, the residual oily matter of gained is stirred under 45-50 ℃ in anhydrous propyl alcohol (180ml) and heated 24 hours.After being cooled to envrionment temperature, add anhydrous diethyl ether (200ml), filtering mixt.Reduction vaporization filtrate obtains oily matter, underpressure distillation, (the third oxygen carbonyl) acetate three propyl ester that obtain, b.p.165-175 ℃ (5mmHg).
Embodiment 17
A) stir and 0-5 ℃ condition under, the mixture usefulness hydrogenchloride of cyanoacetic acid isopropyl ester (15.0g) and anhydrous methanol (4.2g) is saturated.Add anhydrous diethyl ether (70ml) in reaction mixture, the solid collected by filtration product with the ether washing, obtains the different third oxygen carbonyl iminodiacetic acid methyl ester hydrochloride.
B) mixture with different third oxygen carbonyl iminodiacetic acid methyl ester hydrochloride (17g) and anhydrous methanol (52.7ml) stirred 30 minutes.Add anhydrous diethyl ether (290ml), mixture was descended reflux 18 hours in stirring.Reaction mixture is cooled to 0 ℃, filters, filtrate is washed with 10% sodium carbonate solution (300ml) and saturated sodium carbonate solution (50ml), drying, and reduction vaporization obtains former (the different third oxygen carbonyl) 3-acetic acid methyl ester, is oily matter.
Embodiment 18
A) under 0-5 ℃, the solution in anhydrous diethyl ether (644ml) is saturated with hydrogenchloride with methylthio group acetonitrile (100g) and methyl alcohol (47ml).During 16 hours, mixture is warmed to envrionment temperature.Filter and collect the solid product that generates, washing, drying obtains methylthio group iminodiacetic acid methyl ester hydrochloride, is viscous solid.
B) mixture with this methylthio group iminodiacetic acid methyl ester hydrochloride and methyl alcohol (551ml) stirred 3 hours down at 35-45 ℃, placed at ambient temperature then 72 hours.Filtering mixt, evaporated filtrate obtains containing the oily matter of small amount of solid, removes by filter this small amount of solid by velveteen, obtains former (methylthio group) 3-acetic acid methyl ester, is oily matter, b.p.96-104 ℃ (5mmHg).
The preparation of new formula X compound
Embodiment 19
A) under agitation, the mixture heating up backflow with 4-hydroxy-5-methyl oxygen basic note legumin (6.5g), 4-chlorophenyl hydrazine (7.3g) and dry toluene (66ml) removes the water that forms in the dereaction simultaneously.After the cooling, filter the solid of collecting gained, obtain 4-(2-(4-chloro-phenyl-) diazanyl)-the 5-methoxy coumarin, m.p.206-209 ℃.
B) with 4-(2-(4-chloro-phenyl-) diazanyl)-mixture boiled of 5-methoxy coumarin (1.6g), 5M aqueous sodium hydroxide solution (1ml) and industrial methylated spirit (100ml) refluxed 4 hours.After the cooling, mixture is filtered.Filtrate is evaporated to dried, residue distributes between methylene dichloride and water.Tell dichloromethane layer, drying concentrates, and after the filtration, obtains the 1-(4-chloro-phenyl-)-3-(2-hydroxyl-6-p-methoxy-phenyl)-the 2-pyrazolin-5-one, m.p.185-188 ℃.
Embodiment 20
A) under agitation, the mixture heating up in dry toluene (82ml) refluxed 5.5 hours with 4-hydroxyl-6-methoxy coumarin (9.2g) and 4-chlorophenyl hydrazine (10.2g), removed the water that produces in the dereaction simultaneously.Add other 4-chlorophenyl hydrazine (5.0g), again mixture heating up was refluxed 2 hours.Mixture is cooled to envrionment temperature, filters and collect the solid that forms, obtain the 1-(4-chloro-phenyl-)-3-(2-hydroxy-5-methyl oxygen base phenyl)-the 2-pyrazolin-5-one, m.p.197-203 ℃.
B) with the 1-(4-chloro-phenyl-)-3-(2-hydroxy-5-methyl oxygen base phenyl)-2-pyrazolin-5-one (5.5g), aluminum chloride (9.35g) and anhydrous dimethyl benzene (66ml) stirs together and in 100 ℃ of down heating 1 hour.After the cooling, inclining dimethylbenzene, adds the mixture of 2M hydrochloric acid (90ml) and ice (200g) in residue.After the development, filter and collect the solid that forms, drying is used recrystallizing methanol then, obtains the 1-(4-chloro-phenyl-)-3-(2, the 5-dihydroxy phenyl)-the 2-pyrazolin-5-one, m.p.220-225 ℃ (decomposition).
Embodiment 21
A) under agitation, mixture backflow 25 hours altogether (intermittently storing totally 130 hours at ambient temperature therebetween) with 4-hydroxyl-6-methoxy coumarin (10.0g), 4-trifluoromethyl phenyl hydrazine (22.9g), dry toluene (375ml) and tosic acid (0.2g), in this process, after refluxing 7.5 hours, add other a tosic acid (0.2g), after refluxing 13 hours, add other 4-trifluoromethyl phenyl hydrazine (5g) and tosic acid (0.2g) then.After being cooled to envrionment temperature, filter reaction mixture, gained solid acetonitrile recrystallization, filtered while hot.Collect solid, boil with methylene dichloride, and filtered while hot, obtain 6-methoxyl group-4-(2-(4-trifluoromethyl) diazanyl) the tonka bean camphor crude product.
B) with 6-methoxyl group-4-(2-(4-trifluoromethyl) diazanyl) mixture of tonka bean camphor crude product (8.5g), 5M hydrochloric acid (8.5ml) and industrial methylated spirit (82ml) boiling reflux 29 hours under agitation.After the cooling, filter the solid of collecting gained, obtain 3-(2-hydroxy-5-methyl oxygen base phenyl)-the 1-(4-trifluoromethyl)-the 2-pyrazolin-5-one, m.p.212-216 ℃.
C) under agitation, with 3-(2-hydroxy-5-methyl oxygen base phenyl)-the 1-(4-trifluoromethyl)-(48%, mixture 200ml) refluxed 2 hours for 2-pyrazolin-5-one (2.0g) and Hydrogen bromide.With the reaction mixture filtered while hot, the solid of collecting carries out recrystallization with industrial methylated spirit, obtains the 1-(4-trifluoromethyl)-3-(2, the 5-dihydroxy phenyl) the 2-pyrazolone, m.p.253-257 ℃.
Embodiment 22
A) under agitation, the mixture with 4-hydroxyl-6-methoxy coumarin (17.1g), 4-bromophenyl-hydrazine (25.0g) and dry toluene (160ml) refluxed 3 hours.Add the described hydrazine of another part (25.0g), continue again to reflux 3 hours.Reaction mixture is cooled to envrionment temperature, and solid collected by filtration is with the methylene dichloride dissolving of boiling, filtered while hot then.Concentrated filtrate, cooling is filtered, and obtains the 1-(4-bromophenyl)-3-(2-hydroxy-5-methyl oxygen base phenyl)-the 2-pyrazolin-5-one, m.p.197-200 ℃.
B) under agitation, with the 1-(4-bromophenyl)-3-(2-hydroxy-5-methyl oxygen base phenyl)-mixture of 2-pyrazolin-5-one (5.4g), aluminum chloride (8.2g) and anhydrous dimethyl benzene (60ml) heated in vapor bath 5 hours, be cooled to envrionment temperature then, and under this temperature, kept 18 hours.Inclining dimethylbenzene, stays jelly, handles with dilute hydrochloric acid (117ml) and ice.Filter and collect the solidified jelly, water and sherwood oil (b.p.60-80 ℃) washing.As moving phase, dodge formula chromatography purification crude product with toluene/acetate (9: 1) by silica gel.Merge suitable wash-out part, washing, drying, evaporation obtains solids, with aqueous industrial methylated spirit recrystallization, obtains the 1-(4-bromophenyl)-3-(2, the 5-dihydroxy phenyl)-the 2-pyrazolin-5-one, m.p.237-239 ℃.
Embodiment 23
A) under agitation, with 4-hydroxyl-6-methoxy coumarin (15g), 3, the mixture of 4-dichloro phenyl hydrazine (23.8g) and dry toluene (200ml) refluxed 5 hours.Add a described hydrazine (12.4g) in addition, continue again to reflux 3 hours.Reaction mixture is cooled to envrionment temperature, solid collected by filtration, dry then with the methylene dichloride dissolving, obtain 1-(3, the 4-dichlorophenyl)-3-(2-hydroxy-5-methyl oxygen base phenyl)-the 2-pyrazolin-5-one, m.p.210-211 ℃.
B) under agitation, with 1-(3,4-dichlorophenyl)-3-(2-hydroxy-5-methyl oxygen base phenyl)-mixture of 2-pyrazolin-5-one (20g), aluminum chloride (34g) and dimethylbenzene (280 ml) heated in vapor bath 6 hours.Inclining dimethylbenzene, and remaining mixture is poured in the mixture of ice and 1M hydrochloric acid in stirring down.Mixture was stirred 1 hour, stores 18 hours at ambient temperature, filter, obtain 1-(3, the 4-dichlorophenyl)-3-(2, the 5-dihydroxy phenyl)-the 2-pyrazolin-5-one.
Embodiment 24
Under agitation, the mixture heating up in anhydrous dimethyl benzene (150 ml) refluxed 2.5 hours with 4 hydroxy coumarin (14.3g) and 4-chlorophenyl hydrazine (18.9g), removed the water that produces in the dereaction simultaneously.Mixture is cooled to envrionment temperature, filters then, collect solid product, obtain the 1-(4-chloro-phenyl-)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one, m.p.183-185 ℃.
Embodiment 25-34
According to similar methods described in the embodiment 24, as in the following table 2 institute generalized, (wherein X is an oxygen, R by making formula X VI compound 9And R 31Be hydrogen, R 10Such as the table in definition) (wherein Z is-CH=, R with formula X V compound 8' be hydrogen, R 7And R 8As institute's definition in the table) react preparation formula X compound.
Figure 91105264X_IMG45
Note:
(1) solid that filtration is collected heats with methylene dichloride, and filtered while hot after the cooling, settles out solid product.
(2) concentrated filtrate under the decompression is up to producing crystallization.
(3) dichloromethane extract is evaporated to dried.
(4) make the reaction soln cooling, the solid product that obtains after the evaporation is heated with methylene dichloride.
(5) use the acetonitrile recrystallization.
(6) solid product that filtration is collected boils with industrial methylated spirit/water (3: 1), cooling, solid collected by filtration product.
The compound for preparing in the various embodiments described above is as follows:
25 1-(3, the 4-dichlorophenyl)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one
26 1-(4-chloro-phenyl-s)-3-(5-fluoro-2-hydroxy phenyl)-the 2-pyrazolin-5-one
27 1-(4-bromophenyls)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one
28 1-(4-fluorophenyls)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one
29 1-(4-chloro-phenyl-s)-3-(2-hydroxy-5-methyl base phenyl)-the 2-pyrazolin-5-one
30 3-(2-hydroxy phenyls)-the 1-(4-trifluoromethyl)-the 2-pyrazolin-5-one
31 3-(2-hydroxy phenyls)-the 1-(4-p-methoxy-phenyl)-the 2-pyrazolin-5-one
32 3-(2-hydroxy phenyls)-the 1-(4-aminomethyl phenyl)-the 2-pyrazolin-5-one
33 1-(3-chloro-phenyl-s)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one
34 1-(4-chloro-phenyl-s)-and 3-(2, the 6-dihydroxy phenyl)-the 2-pyrazolin-5-one
Embodiment 35-43
According to similar methods described in the embodiment 24, as in the following table 3 institute generalized, (wherein X is an oxygen, R by making formula X VI compound 9And R 31Be hydrogen, R 10Such as the table in definition) (wherein Z is-N=, R with formula X V compound 7, R 8And R 8' as institute's definition in the table) react preparation formula X compound.
Figure 91105264X_IMG46
Note:
(1) reactant refluxes in following solvents:
A) ethyl acetate
B) toluene
C) toluene/ethyl acetate
D) toluene
After (2) 20 minutes, in the backflow mixture, add the toluene of ethyl acetate (50-100%(volume)).
(3) use ethyl alcohol recrystallization.
(4) with reaction mixture cooling and evaporation.With acetic acid ethyl dissolution gained solid, filtered while hot.Evaporated filtrate as moving phase, dodges formula chromatography purification gained oily matter by silica gel with 2% ethanol/methylene.Merge required wash-out part, after the evaporation, obtain solids, use re-crystallizing in ethyl acetate.
(5) crude product boils with ethanol and filters, and repeats once.
After (6) 3 hours, add a described hydrazine (2.0g) in addition.
(7) incline and the reaction mixture of heat, concentrate, filter.The solids of collecting is suspended in the ether (300ml), uses the 2.5M sodium hydroxide solution extraction.United extraction liquid with the ether washing, is used the concentrated hydrochloric acid acidifying then.The solid collected by filtration product washes after drying with water.
(8) after the backflow, toluene solution is evaporated to dried.Residue boils with methylene dichloride, filtered while hot, concentrated filtrate.Cooling and scratch filter the solid product of collecting gained.
The compound for preparing in the various embodiments described above is as follows:
35 3-(2-hydroxy phenyls)-1-(5-trifluoromethyl-2-pyridyl)-the 2-pyrazolin-5-one
36 1-(6-chloro-2-pyridyl)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one
37 1-(5-chloro-2-pyridyl)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one
38 3-(2-hydroxy phenyls)-1-(6-trifluoromethyl-2-pyridyl)-the 2-pyrazolin-5-one
39 1-(4-chloro-2-pyridyl)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one
40 1-(6-chloro-5-trifluoromethyl-2-pyridyl)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one
41 1-(5-bromo-2-pyridyl)-the 3-(2-hydroxy phenyl)-the 2-pyrazolin-5-one
42 1-(5-chloro-2-pyridyl)-and 3-(2, the 6-dihydroxy phenyl)-the 2-pyrazolin-5-one
43 3-(5-fluoro-2-hydroxy phenyls)-1-(5-trifluoromethyl-2-pyridyl)-the 2-pyrazolin-5-one
Embodiment 44
In nitrogen atmosphere with under stirring, mixture heating up in dry toluene (47ml) refluxed 4.5 hours with 4-hydroxyl thiocoumarin (4.5g) and 4-trifluoromethyl phenyl hydrazine (7.0g), therebetween, and after 2 hours, add other described hydrazine (1.5g), remove the water that produces in the dereaction simultaneously.Mixture is cooled to envrionment temperature, filters, filtrate stores 18 hours at ambient temperature.Evaporated filtrate is dissolved in solid residue in the methylene dichloride, the washing of gained solution with water, drying concentrates, and obtains the solid washed with dichloromethane, obtains 3-(2-sulfydryl phenyl)-the 1-(4-trifluoromethyl)-the 2-pyrazolin-5-one, m.p.161-164 ℃.
The preparation of new formula II ' compound
Embodiment 45
Under agitation, with the 1-(4-chloro-phenyl-)-the 3-(2-hydroxy phenyl)-mixture of 2-pyrazolin-5-one (2.9g) and former (the third oxygen carbonyl) acetate three propyl ester (8.7g) is in 145-150 ℃ of heating 40 minutes down.Mixture is cooled to below 100 ℃, dilutes with industrial methylated spirit.Filter and collect the solid that produces, obtain the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-propyl acetate also, m.p.138-140 ℃.
Embodiment 46
In the mode similar to embodiment 45, with the 1-(4-chloro-phenyl-)-3-(2, the 5-dihydroxy phenyl)-mixture of 2-pyrazolin-5-one (6.6g) and former (the different third oxygen carbonyl) 3-acetic acid methyl ester (21.9g) is in 140 ℃ of heating 2 hours down, cooling is then filtered, and washs solid product with ether, obtain the 2-(4-chloro-phenyl-)-8-hydroxyl-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-isopropyl acetate also, m.p.224-225 ℃.
Embodiment 47
Under agitation, with the 1-(4-chloro-phenyl-)-the 3-(2-hydroxy phenyl)-mixture of 2-pyrazolin-5-one (2.9g) and former (ethoxycarbonyl) triethyl acetate (7.0g) is 130-135 ℃ of heating 10 minutes down, and cooling is diluted with ether then.Filter and collect the solid that is produced, obtain the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also, m.p.159-161 ℃.
Embodiment 48-60
According to similar methods described in the embodiment 47, as generalized in the following table 4, (wherein Z is-CH=, R by making formula X compound 8' and R 9Represent hydrogen, X, R 7, R 8And R 10As institute's definition in the table) and former (ethoxycarbonyl) triethyl acetate (XI) react preparation formula II ' compound (R wherein 6' be hydrogen, Ra is COOC 2H 5).
Table 4 note:
(1) Heating temperature=140-150 ℃.
(2) with after the ether dilution and filtering, solid product is stirred with methylene dichloride, filter.Evaporated filtrate, the gained solid is developed with ether.
(3) store 18 hours after, add a described ortho ester (5g) in addition, again with mixture heating up 60 minutes.Mixture is developed the solid collected by filtration product with ether.
The compound for preparing in the various embodiments described above is as follows:
48 2-(4-chloro-phenyl-s)-and 8-hydroxyl-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also
49 2-(4-chloro-phenyl-s)-and 8-fluoro-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also
50 2-(4-chloro-phenyl-s)-and 8-methyl-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also
51 2-(3, the 4-dichlorophenyl)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also
52 2-(4-bromophenyls)-and 3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also
53 2-(4-fluorophenyls)-and 3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also
54 2-(4-chloro-phenyl-s)-and 9-hydroxyl-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also
55 3-oxo-2-(4-trifluoromethyl)-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also
56 2-(4-p-methoxy-phenyls)-and 3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also
57 2-(4-aminomethyl phenyls)-and 3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also
58 2-(3-chloro-phenyl-s)-and 3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also
59 2-(4-chloro-phenyl-s)-and 9-methoxyl group-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also
60 3-oxo-2-(4-trifluoromethyl)-2,3-dihydro (1) benzo thiapyran is (4,3-c) pyrazoles-4-ethyl acetate also
Embodiment 61-65
According to similar methods described in the embodiment 47, as in the following table 5 institute generalized, (wherein X is an oxygen, and Z is-CH=R by making formula X compound 8' and R 9Represent hydrogen, R 7, R 8And R 10As institute's definition in the table) and triethly orthoacetate (XI) react preparation formula II ' compound (wherein Ra and R 6' be hydrogen).
Figure 91105264X_IMG48
Note:
(1) Heating temperature=140-150 ℃.
Compound prepared in the various embodiments described above is as follows:
61 2-(4-chloro-phenyl-s)-9-methoxyl group-4-methyl (1) chromene (4,3-c) pyrazoles-3(2H)-ketone also
62 2-(4-chloro-phenyl-s)-8-hydroxy-4-methyl (1) chromene (4,3-c) pyrazoles-3(2H)-ketone also
63 2-(3,4-dichlorophenyl)-8-hydroxy-4-methyl (1) chromene (4,3-c) pyrazoles-3(2H)-ketone also
64 2-(4-bromophenyls)-8-hydroxy-4-methyl (1) chromene (4,3-c) pyrazoles-3(2H)-ketone also
65 8-hydroxy-4-methyl-2-(4-trifluoromethyl)-(1) chromene (4,3-c) pyrazoles-3(2H)-ketone also
Embodiment 66
With the 2-(4-chloro-phenyl-)-also (4,3-c) pyrazoles-3(2H)-ketone (0.5g) and the mixture of aluminum chloride (0.78g) in dimethylbenzene (4.8ml) place 100-110 ℃ of oil bath of preheating to keep 35 minutes to 9-methoxyl group-4-methyl (1) chromene.After the cooling, in reaction mixture, add 2M hydrochloric acid (10ml) and ice.Filter to collect the yellow solid of gained, obtain the 2-(4-chloro-phenyl-)-9-hydroxy-4-methyl (1) chromene (4,3-c) pyrazoles-3(2H)-ketone also, m.p.213-215 ℃.
Embodiment 67
With 3, the solution of 4-dichloro phenyl hydrazine (3.2g) in dimethylbenzene (75ml) is added in 6-methoxyl group-3-methyl-4-oxo-3-thiochroman carboxylate methyl ester (2.0g) and the mixture of tosic acid (0.4g) in dimethylbenzene (50ml).With this mixture boiling reflux 22 hours under nitrogen atmosphere, remove the water that forms in the dereaction simultaneously.Cooling and reduction vaporization mixture.Use methylene dichloride and methylene dichloride/sherwood oil (b.p.40-60 ℃, 1: 1) as moving phase successively, dodge formula chromatography, separating residual thing by twice silica gel.The Virahol crystallization of gained oily matter obtains 2-(3, the 4-dichlorophenyl)-8-methoxyl group-3a-methyl-3a, 4-dihydro (1) benzo thiapyran is (4,3-c) pyrazoles-3(2H)-ketone also, m.p.73-76 ℃.
Embodiment 68-71
According to similar methods described in the embodiment 67, as generalized in the following table 6, by making formula X IV compound (the preparation embodiment of initial compounds is provided) and formula X V compound (R wherein 8' represent hydrogen, R 7And R 8As institute's definition in the table) react, (wherein X is a sulphur to preparation formula I ' compound, and Z is-CH=R 9Be hydrogen, R 10' be the 8-methoxyl group).Under each situation, all use the 0.4g tosic acid in the reaction.
Figure 91105264X_IMG49
Note:
(1) use following a) or b) once dodge the formula chromatography purification as moving phase:
A) methylene dichloride
B) methylene chloride (99.5: 0.5)
(2) use the Virahol recrystallization.
(3) use the 0.2g tosic acid
(4) reaction mixture is filtered filtrate
A) concentrate after, obtain solids, use methanol crystallization; Or
B) after the evaporation, obtain solids, use methanol crystallization, dodge the formula chromatography then.
The prepared compound of the various embodiments described above is as follows:
68 8-methoxyl group-3a-methyl-2-(4-trifluoromethyl)-and 3a, 4-dihydro (1) benzo thiapyran is (4,3-c) pyrazoles-3(2H)-ketone also
69 2-(4-chloro-phenyl-s)-and 8-methoxyl group-3a-methyl-3a, 4-dihydro (1) benzo thiapyran is (4,3-c) pyrazoles-3(2H)-ketone also
70 2-(4-fluorophenyls)-and 8-methoxyl group-3a-methyl-3a, 4-dihydro (1) benzo thiapyran is (4,3-c) pyrazoles-3(2H)-ketone also
71 8-methoxyl group-4-methyl-2-(4-trifluoromethyl)-(1) benzo thiapyran (4,3-c) pyrazoles-3(2H)-ketone also
Embodiment 72
Under nitrogen atmosphere, stirring and-70 ℃ of conditions, with boron tribromide (21.4ml, the 1M dichloromethane solution) be added drop-wise to 8-methoxyl group-3a-methyl-2-(4-trifluoromethyl)-3a, 4-dihydro (1) benzo thiapyran is also in (4,3-c) pyrazoles-the 3(2H)-mixture of ketone (4.2g) in anhydrous methylene chloride (80ml).Mixture was stirred 1 hour at ambient temperature.Reaction mixture is poured in the methyl alcohol (800ml), then reduction vaporization.Gained oily matter is dissolved in the ethyl acetate, washes with water, then with the washing of 10% sodium bicarbonate aqueous solution, dry ethyl acetate layer, evaporation.Solids obtains 8-hydroxyl-3a-methyl-2-(4-trifluoromethyl with ethyl acetate/petroleum ether (b.p.40-60 ℃) recrystallization)-3a, 4-dihydro (1) benzo thiapyran is (4,3-c) pyrazoles-3(2H)-ketone also, m.p.211-213 ℃.
Embodiment 73-76
According to similar methods described in the embodiment 72, as institute in the following table 7 is generalized, from formula I ' compound (R wherein 10' be the 8-methoxyl group, provided the preparation embodiment of initial compounds) (wherein X is a sulphur to preparation formula I ' compound, and Z is-CH=R 9Be hydrogen, R 10' be the 8-hydroxyl).In embodiment 76a, in being cooled to-70 ℃ reaction mixture, added other a boron tribromide, as shown in Table:
Figure 91105264X_IMG50
Note:
After (1) 18 hour, add other a BBr 3(5.5ml).With the methyl alcohol processing with behind ethyl acetate and the sodium bicarbonate recrystallization, as moving phase, dodge formula chromatographic separation gained residue with methylene dichloride by silica gel, obtain solid, with ether/sherwood oil (b.p.40-60 ℃) recrystallization.
After (2) 2 hours, add other a BBr 3(5.2ml).
(3) leach the solid that produces when pouring into reaction mixture on the methyl alcohol, drying obtains product.
The prepared compound of the various embodiments described above is as follows:
73 2-(3,4-dichlorophenyl)-and 8-hydroxyl-3a-methyl-3a, 4-dihydro (1) benzo thiapyran is (4,3-c) pyrazoles-3(2H)-ketone also
74 2-(4-chloro-phenyl-s)-and 8-hydroxyl-3a-methyl-3a, 4-dihydro (1) benzo thiapyran is (4,3-c) pyrazoles-3(2H)-ketone also
75 2-(4-fluorophenyls)-and 8-hydroxyl-3a-methyl-3a, 4-dihydro (1) benzo thiapyran is (4,3-c) pyrazoles-3(2H)-ketone also
76 8-hydroxy-4-methyl-2-(4-trifluoromethyl)-(1) benzo thiapyran (4,3-c) pyrazoles-3(2H)-ketone also
The preparation of new formula I compound
Embodiment 77-90
According to similar methods described in the embodiment 47, as in the following table 8 institute generalized, (wherein X is an oxygen, and Z is-N=R by making formula X compound 9Be hydrogen, R 7, R 8, R 8' and R 10As institute's definition in the table) and triethly orthoacetate (XI) react preparation.
Figure 91105264X_IMG51
Note:
(1) Heating temperature=140-150 ℃.
(2) use the ethanol/dichloromethane recrystallization.
(3) with the solution of 4% methyl alcohol in methylene dichloride as moving phase, dodge formula chromatography purification crude product by silica gel.United extraction liquid is used the development of methylene dichloride/sherwood oil (b.p.40-60 ℃) and acetone successively, and drying under reduced pressure obtains product then.
After (4) 5 minutes, add other a ortho-acetate (7.2ml).To develop with industrial methylated spirit by the solid that this reaction mixture produces.
Embodiment 87
According to similar methods described in the embodiment 47, under agitation, with 1-(5-chloro-2-pyridyl)-the 3-(2-hydroxy phenyl)-mixture of 2-pyrazolin-5-one (1.4g) and former (methylthio group) 3-acetic acid methyl ester (2.5ml) is 140-145 ℃ of heating 10 minutes down, cooling then, develop with industrial methylated spirit, obtain 2-(5-chloro-2-pyridyl)-4-methylthiomethyl (1) chromene (4,3-c) pyrazoles-3(2H)-ketone also, m.p.217-219 ℃.
Embodiment 88
According to similar methods described in the embodiment 47, with 1-(5-chloro-2-pyridyl)-the 3-(2-hydroxy phenyl)-mixture of 2-pyrazolin-5-one (3.0g) and former (ethoxycarbonyl) triethyl acetate (7.3g) stirred 45 minutes down at 140-145 ℃, therebetween, after 15 and 30 minutes, each adds a described ortho ester (3.7g) in addition.Reaction mixture is developed with ether.The gained solid is dissolved in the methylene dichloride, passes through Florisil with the methylene dichloride wash-out
Figure 91105264X_IMG52
Post.Evaporation of eluate, residue is developed with ether, obtains 2-(5-chloro-2-pyridyl)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate also, m.p.152-154 ℃.
Embodiment 89
0 ℃ and stir under, Acetyl Chloride 98Min. (0.5ml) is added drop-wise to 2-(5-chloro-2-pyridyl)-9-hydroxy-4-methyl (1) chromene is also in the mixture of (4,3-c) pyrazoles-3(2H)-ketone (2.0g), anhydrous tetrahydro furan (30ml) and triethylamine (1.0ml).Make mixture be warmed to envrionment temperature, stirred then 2.5 hours.Solid collected by filtration washes with water, and is dry then with the hot ethanol development, obtains 2-(5-chloro-2-pyridyl)-4-methyl-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-9-yl acetate also, m.p.252-255 ℃.
Embodiment 90
Under agitation, with 2-(5-chloro-2-pyridyl)-3-oxo-2,3-dihydro (1) chromene also the mixture of (4,3-c) pyrazoles-4-ethyl acetate (1.4g) and cyclobutanemethanol (3.5ml) 150 ℃ of heating 1 hour down.Make reaction mixture be cooled to envrionment temperature, with ether development, solid collected by filtration product, with ether washing, obtain 2-(5-chloro-2-pyridyl)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-acetate cyclobutylmethyl ester, m.p.157-160 ℃.
Embodiment 91
With the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) the chromene also mixture of (4,3-c) pyrazoles-4-propyl acetate (1.9g) and 2-piperidino-(1-position only) ethanol (6.4ml) stirred 1 hour down at 150 ℃.Reaction mixture is cooled to room temperature, pours in the water (30ml).With this mixture of dichloromethane extraction, merge organic extracting solution, water thorough washing, drying, evaporation.Residual oily matter is dissolved in the dehydrated alcohol, handles with ethanol solution of hydrogen chloride.The solids that scrapes after the cooling is collected by filtering, and drying obtains the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-acetate 2-piperidino-(1-position only) carbethoxy hydrochloride also, m.p.193-197 ℃ (decomposition).
Embodiment 92-100
According to similar methods described in the embodiment 91, generalized like that as institute in the following table 9, react preparation by making formula II ' compound (having provided the preparation embodiment of this initial ester) and suitable alcohol.
Note:
(1) with triethylamine product is changed into its free alkali, use methylene chloride (9: 1) then, dodge the formula chromatography by silica gel and carry out purifying as moving phase.
(2),, wash with water after 15 minutes in heating under 150 ℃ with methylene dichloride (100ml) diluted reaction mixture.Filter and collect isolating solid product.
(3) product is softening at 55 ℃.
Embodiment 101
With the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) the chromene also mixture of (4,3-c) pyrazoles-4-ethyl acetate (3.0g) and 4-methoxyl group benzylalcohol (9.6ml) stirred 50 minutes down at 150 ℃.Reaction mixture is cooled to envrionment temperature,, filters and collect product, obtain the 2-(4-chloro-phenyl-with the ether dilution)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-acetate 4-methoxy benzyl ester also, m.p.152-155 ℃.
Embodiment 102-134
According to similar methods described in the embodiment 101, as institute in the following table 10 is generalized, by making the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-ethyl acetate (II ') and suitable alcohol reaction, preparation.
Figure 91105264X_IMG54
Figure 91105264X_IMG56
Note:
(1) cooled reaction mixture:
A) produce a kind of solid, filter and collect;
B) produce a kind of solid, with toluene and ether development;
C) be dissolved in the methylene dichloride, wash with water, drying, evaporation;
D) be dissolved in the methylene dichloride, wash with water, drying, evaporation is then with ether development gained jelly;
E) pour in the water solid collected by filtration into.
(2) product following solvents recrystallization:
A) acetonitrile;
B) ethyl acetate.
(3) reacting by heating mixture under following temperature:
a）120℃;
b）150-160℃;
c）180℃;
d）214℃。
(4) use the following solvents system as moving phase, dodge the formula chromatography by silica gel, the purifying crude product:
A) toluene/acetate (9: 1);
B) toluene;
C) ethyl acetate/acetate (9: 1).
Each wash-out part of evaporation gained after the ether development, obtains product.
(5) cooled reaction mixture is dissolved in the methylene dichloride, washes with water.After dry and concentrated, the methylene dichloride of using the acetone (1～10%) that contains ever-increasing amount passes through Florisil as moving phase
Figure 91105264X_IMG57
The column chromatography purification mixture.Develop gains with ether, obtain product.
(6) reaction mixture is cooled to about 90 ℃, dilutes with following solvents then:
A) industrial methylated spirit;
B) dehydrated alcohol;
Filter and collect product.
Embodiment 135-141
According to similar methods described in the embodiment 101, generalized like that as institute in the following table 11, react preparation by making formula II ' compound (having provided the preparation embodiment of initial ester) and suitable alcohol.
Note:
(1) circulation comprises backflow in 26 hours and storages in 140 hours at ambient temperature.Back adding a described alcohol (2g) in addition refluxed at 13 hours.
Embodiment 142 and 143
With the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-ethyl acetate (2.0g), 1, the mixture heating up of 2-ethylene glycol ethyl ethers acid esters (2.0ml, about 1: 1 mixture of list and diacetate esters), N-methylmorpholine (0.6ml) and anhydrous dimethyl benzene (20ml) refluxed 6 hours.The reduction vaporization mixture as moving phase, dodges formula chromatographic separation residue by silica gel with toluene/acetate (9: 1).Obtain the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-acetate 2-acetoxyl group ethyl ester (embodiment 142), m.p.136-139 ℃ and 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-acetate 2-hydroxy methacrylate (embodiment 143), m.p.161-162 ℃.
Embodiment 144
To contain 4
Figure 91105264X_IMG59
The 2-(4-chloro-phenyl-of molecular sieve)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethyl acetate (2.0g), 4-(2-hydroxyethyl also) mixture of thiomorpholine (1g), anhydrous dimethyl benzene (20ml) and N-methylmorpholine (0.6ml) stir and 150 ℃ condition under heated 3 hours.Add other 4-(2-hydroxyethyl again) thiomorpholine (1.0g), continue heating 1 hour.Reaction mixture is cooled to envrionment temperature, dilutes with ethyl acetate.From molecular sieve, incline after, wash gained solution with water, drying, reduction vaporization.Residual jelly is dissolved in the ethanol, handles, be cooled to 0 ℃ then with ethanol solution of hydrogen chloride.The solid that filter to collect forms, drying obtains the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-acetate 2-thiomorpholine for the ethyl ester hydrochloride, m.p.223-226 ℃.
Embodiment 145
With the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) the chromene also mixture of (4,3-c) pyrazoles-4-ethyl acetate (2.00g), 2-methylthio group ethanol (0.5ml), N-methylmorpholine (0.6ml) and anhydrous dimethyl benzene (40ml) stirred 5 hours down at 170 ℃.The reduction vaporization reaction mixture, residue obtains the 2-(4-chloro-phenyl-with acetonitrile recrystallization twice)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-acetate 2-methylthio group ethyl ester also, m.p.113-114 ℃.
Embodiment 146
With the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-ethyl acetate (2.0g), 4,4, the mixture stirring of 4-three fluoro butanols (1.3g), N-methylmorpholine (0.6ml) and anhydrous dimethyl benzene (40ml) and boiling reflux 5 hours.Add other dimethylbenzene (10ml) and other 4,4 again, 4-three fluoro butanols (1.5g).Again mixture boiled was refluxed 2 hours, then reduction vaporization.Solid residue obtains the 2-(4-chloro-phenyl-with acetonitrile recrystallization twice)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-acetate 4,4 also, 4-trifluoro butyl ester, m.p.114-115 ℃.
Embodiment 147
With the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-ethyl acetate (2.0g), 2-cyano group ethanol (0.4ml), N-methylmorpholine (0.6ml) and the mixture of molecular sieve (20) in anhydrous dimethyl benzene (40ml) stirred 5 hours down at 170 ℃.Add other 2-cyano group ethanol (0.4ml) again, mixture was stirred 18 hours down at 170 ℃.The reduction vaporization reaction mixture, with methylene dichloride as moving phase at Florisil
Figure 91105264X_IMG60
The residual oily matter of purifying on the short column.With toluene/acetate (9: 1) as moving phase, dodge the formula chromatography by silicagel column, separating obtained thing will be developed with sherwood oil (b.p.60-80 ℃) except that the material that obtains after desolvating, obtain the 2-(4-chloro-phenyl-after the filtration)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-acetate 2-cyano group ethyl ester, m.p.120-122 ℃.
Embodiment 148
According to embodiment 145 similar methods, with the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-ethyl acetate (2.0g), 3-hydroxy-propionic acid ethyl ester (1.2ml), the mixture of N-methylmorpholine (0.6ml) and anhydrous dimethyl benzene (40ml) heated 6 hours down at 170 ℃, with toluene/acetate (9: 1) as moving phase, behind silica gel sudden strain of a muscle formula chromatography, obtain the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-acetate 2-ethoxycarbonyl ethyl ester, m.p.126-129 ℃.
Embodiment 149
According to embodiment 145 similar methods, with the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-ethyl acetate (1.1g), 2-phenyl-1-propyl alcohol (0.4ml) and N-methylmorpholine (0.3g) mixture in anhydrous dimethyl benzene (3ml) stirs and boiling reflux 15 hours, adds other 2-phenyl-1-propyl alcohol (0.2ml) and N-methylmorpholine (0.2ml) after 14 hours again.Reaction mixture, the solid collected by filtration thing is used the acetonitrile recrystallization, obtains the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-acetate 3-methylbenzene ethyl ester also, m.p.86-90 ℃.
Embodiment 150
With the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) the chromene also mixture heating up of (4,3-c) pyrazoles-4-ethyl acetate (2.0g), cyclohexyl ethyl alcohol (0.7ml), N-methylmorpholine (0.6ml) and dimethylbenzene (40ml) refluxed 6 hours.Add other a cyclohexyl ethyl alcohol (0.7ml), again mixture heating up was refluxed 3 hours.The reduction vaporization mixture, residue obtains the 2-(4-chloro-phenyl-with acetonitrile recrystallization twice)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-acetate 2-cyclohexyl ethyl ester also, m.p.149-151 ℃.
Embodiment 151
With the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) solution of pyrazoles-4-ethyl acetate (1.0g), 1-methyl-2-morpholino ethyl ester (0.8ml) and dry toluene (10ml) stirs under the condition of continuous still battery and heated 9 hours, adds fresh toluene simultaneously and keeps original volume.Add other 1-methyl-2-morpholino ethanol (0.8ml), continued heating/still-process 7 hours.Add other 1-methyl-2-morpholino ethanol (0.8ml), again with mixture heating up 5 hours.Reaction mixture is cooled to 0 ℃, filters the solid product of collecting gained, wash with ether, drying obtains the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-acetate 1-methyl-2-morpholino ethyl ester, m.p.176-179 ℃.
Embodiment 152
According to embodiment 151 similar methods, with the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) mixture reaction of pyrazoles-4-ethyl acetate (1.0g), (1-methyl-2-piperidyl) methyl alcohol (0.7ml) and toluene (15ml), after dodging the formula chromatography then, obtain the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-acetate 1-methyl-2-piperidines methyl esters, m.p.159-163 ℃.
Embodiment 153
Stir and 0-5 ℃ condition under, with sodium borohydride (0.6g) batch treatment 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene is (4, the 3-c) pyrazoles-suspension of 4-acetate 2-morpholino carbethoxy hydrochloride (1.5g) in dehydrated alcohol (50ml) also.Reaction mixture was stirred 4 hours under this temperature, after 1 hour, 3 hours and 3.5 hours, add respectively other three parts of sodium borohydrides (0.28g, 0.28g, 0.14g).Reaction mixture is poured in the water, be cooled to 0-5 ℃, neutralize with glacial acetic acid.Use the dichloromethane extraction water layer.With the extracting solution washing, drying, evaporation obtains the 2-(4-chloro-phenyl-)-3-oxo-1,2,3,4-tetrahydrochysene (1)-chromene is (4,3-c) pyrazoles-4-acetate 2-morpholino ethyl ester also, m.p.125-128 ℃.
Embodiment 154
Under 0 ℃, to the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene also adds Acetyl Chloride 98Min. (2.3ml) and triethylamine (1.1ml) in the solution (embodiment 124) of (4,3-c) pyrazoles-4-acetate 3-hydroxy propyl ester in methylene dichloride (75ml).Reaction mixture was at room temperature stirred 18 hours, washing then, drying is filtered, and evaporated filtrate.As moving phase, make residual mixture pass through Florisil with methylene dichloride
Figure 91105264X_IMG61
Post.Merge required wash-out part, evaporation.As moving phase, dodge formula chromatography, purifying crude product with ethyl acetate by silica gel.The product re-crystallizing in ethyl acetate obtains the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-acetate 3-acetoxyl group propyl ester also, m.p.129-131 ℃.
Embodiment 155
Under agitation, with the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) the chromene also mixture heating up of (4,3-c) pyrazoles-4-ethyl acetate (1.9g) (embodiment 47), methylphenylamine (0.5g) and dimethylbenzene (15ml) refluxed 22 hours.Add other methylphenylamine (0.3g), again mixture heating up was refluxed 5 hours.Cooling mixture, scratch.Filter and collect the solid that forms, drying obtains the 2-(4-chloro-phenyl-)-N-methyl-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-Acetanilide also, m.p.200-202 ℃.
Embodiment 156-170
According to similar methods described in the embodiment 155, generalized like that as institute in the following table 12, react preparation by making formula II ' compound (having provided the preparation embodiment of initial ester) and suitable amine.
Figure 91105264X_IMG62
Figure 91105264X_IMG63
Note:
(1) solids is used the acetonitrile recrystallization.
(2) reduction vaporization reaction mixture, residue methylene dichloride/industrial methylated spirit (33: 1) recrystallization.
(3) filter the solid of collecting gained, be dissolved in then in the methylene dichloride, filter, in filtrate, add industrial methylated spirit.This solution of concentrating under reduced pressure, cooling, solid collected by filtration.
(4) solid acetone recrystallization.
(5) evaporation reaction mixture, residue acetonitrile recrystallization.
(6) softening in the time of 158 ℃.
Embodiment 170
A) with the 2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) the chromene also mixture of (4,3-c) pyrazoles-4-propyl acetate (1.9g) (embodiment 45) and 1-piperazine ethanol (5.9ml) stirs under 150 ℃ and heated 1.5 hours.Mixture is cooled to envrionment temperature, and dilute with water is used dichloromethane extraction.Merge organic extracting solution, wash with water, drying, evaporation.Residue is dissolved in the ethanol, handles with ethanol solution of hydrogen chloride.Form solid behind cooling and the scratch, filter and collect, obtain the 2-(4-chloro-phenyl-)-N, N-(3-(2-hydroxyethyl)-3-azepine pentamethylene)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-acetamide hydrochloride also, 200-205 ℃ (decomposition).
B) under agitation, with the 2-(4-chloro-phenyl-)-N, N-(3-(2-hydroxyethyl)-3-azepine pentamethylene)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-solution of 4-acetamide hydrochloride (0.7g) in methylene dichloride (28ml) is cooled to 0 ℃, after triethylamine (0.42ml) processing, handle with Acetyl Chloride 98Min. (0.14ml).Mixture was stirred in ice bath 2 hours.Add other Acetyl Chloride 98Min. (0.07ml) again, again mixture was stirred 30 minutes down at 0 ℃, place down at 0 ℃ then and spend the night.Mixture is washed with water, dry then, reduction vaporization.The gained solid is developed with ether, filters and collects the solid that forms, drying; obtain 2-{ 4-(2-(4-chloro-phenyl-)-3-oxo-2; 3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethanoyl also) piperazine-1-yl } ethylhexoate, m.p.162-166 ℃.
Embodiment 171
Stir and 0 ℃ of condition under, use triethylamine (0.5ml) and propionyl chloride (0.3ml) to handle the 2-(4-chloro-phenyl-successively)-N, N-(3-(2-hydroxyethyl)-3-azepine pentamethylene)-3-oxo-2,3-dihydro (1) chromene is the mixture of (4,3-c) pyrazoles-4-acetamide hydrochloride (0.8g) (embodiment 170a) and methylene dichloride (45ml) also.Reaction mixture was stirred 3.5 hours under this temperature.Wash mixture with water, dry then, reduction vaporization.The gained solid is developed with ether, filters and collects the solid that forms, drying; obtain 2-{ 4-(2-(4-chloro-phenyl-)-3-oxo-2; 3-dihydro (1) chromene is (4,3-c) pyrazoles-4-ethanoyl also) piperazine-1-yl } the propionic acid ethyl ester, m.p.173-175 ℃.
Embodiment 172
Under agitation, with 3-oxo-2-(4-trifluoromethyl)-2,3-dihydro (1) the benzo thiapyran also mixture heating up of (4,3-c) pyrazoles-4-ethyl acetate (0.9g) (embodiment 60), morpholine (0.4ml) and anhydrous dimethyl benzene (3.5ml) refluxed 2.3 hours.Make reaction mixture be cooled to envrionment temperature, solid collected by filtration after dimethylbenzene and ether washing, is dissolved in the methylene dichloride.With this solution with water washing, drying, evaporation is with ether development and scratch.The solid collected by filtration product obtains N, N-(3-oxa-pentamethylene)-3-oxo-2-(4-trifluoromethyl)-2,3-dihydro (1) benzo thiapyran is (4,3-c) pyrazoles-4-ethanamide also, m.p.210-212 ℃.
Embodiment 173
Under agitation, with 3-oxo-2-(4-trifluoromethyl)-2,3-dihydro (1) the benzo thiapyran also mixture heating up of (4,3-c) pyrazoles-4-ethyl acetate (0.6g) (embodiment 60), N-ethylaniline (0.4ml) and anhydrous dimethyl benzene (2.4ml) refluxed 4 hours.Add other a N-ethylaniline (0.1ml), again with reaction mixture refluxed 2 hours.Reaction mixture is stored 72 hours at ambient temperature, add other a N-ethylaniline (0.2ml), refluxed again 3 hours.The solid collected by filtration product with dimethylbenzene and ether washing, obtains N-ethyl-3-oxo-N-phenyl-2-(4-trifluoromethyl)-2,3-dihydro (1) benzo thiapyran is (4,3-c) pyrazoles-4-ethanamide also, m.p.179-181 ℃.
Embodiment 174
In nitrogen atmosphere with under stirring, with the 1-(4-chloro-phenyl-)-the 3-(2-hydroxy phenyl)-2-pyrazolin-5-one (17.0g) and 4-(2,2-dimethyl-4,6-dioxo-1,3-oxane-5-yl)-mixture heating up of 4-ketobutyric acid methyl esters (30.0g) (embodiment 4) in dimethylbenzene (200ml) refluxed 6 hours.Mixture is cooled to envrionment temperature, evaporating solvent, gained solid Virahol recrystallization obtains 5-(2-(4-chloro-phenyl-)-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-4-yl also)-the 4-oxopentanoie acid methyl esters, m.p.142-143 ℃.
Embodiment 175-186
According to similar methods described in the embodiment 174, as in the following table 13 institute generalized, (wherein X is an oxygen, and Z is-CH=R by making formula X compound 8' and R 9Be hydrogen, R 7, R 8And R 10As institute's definition in the table) and formula XII b compound (having provided the preparation embodiment of initial compounds XII b) react preparation.
Figure 91105264X_IMG64
Note:
(1) except that after desolvating, gained oily matter is placed Virahol.Gained solution activated carbon treatment, filtered while hot, concentrated filtrate.Filter and collect the solid that produces,, use the Virahol recrystallization with the ether washing.
(2) use the industrial methylated spirit recrystallization.
(3) use recrystallizing methanol.
(4) reaction mixture leaches solid product.
(5) develop solids with ether, filter, washing, drying obtains product.
(6) behind evaporation reaction mixture and the scratch, obtain product, with the industrial methylated spirit development of heat, washing after the drying, obtains product.
(7) reaction mixture is cooled to room temperature after, filter, obtain solid product.
(8) make reaction mixture be cooled to envrionment temperature, under this temperature, kept 18 hours.Incline solution after, the cooling, scratch obtains solid product.
(9) in 18 hours, be cooled to envrionment temperature.The solid collected by filtration product is used re-crystallizing in ethyl acetate, filtered while hot.
Embodiment 187
Under agitation, with the 2-(4-chloro-phenyl-)-9-hydroxy-4-methyl (1) chromene also (4,3-c) mixture of pyrazoles-3(2H)-ketone (2.0g) (embodiment 66), triethylamine (1.4g) and methylene dichloride (20ml) cools off in ice bath, adds propanedioic acid mono-methyl list acyl chlorides (1.5ml) simultaneously.Add other methylene dichloride (20ml), in 18 hours, make mixture be warmed to envrionment temperature.Filtering mixt, residue are used methylene dichloride and water washing successively.Behind the acetonitrile recrystallization, obtain (2-(4-chloro-phenyl-)-4-methyl-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-9-yl also) (methyl) malonic ester, m.p.204-206 ℃.
Embodiment 188-206
According to similar methods described in the embodiment 187, generalized like that as institute in the following table 14, by making the 2-(4-chloro-phenyl-)-8-hydroxy-4-methyl (1) chromene (4,3-c) pyrazoles-3(2H)-ketone (embodiment 62) and suitable acyl chlorides (R also 17COCl) reaction, preparation.
Figure 91105264X_IMG65
Figure 91105264X_IMG66
Note:
(1) reduction vaporization filtrate.Residue is dissolved in the methylene dichloride, washing, drying is added to Florisil then
Figure 91105264X_IMG67
On the post, with obtaining product behind the methylene dichloride wash-out.
(2) with reaction mixture washing, drying, evaporation.
(3) with the residue washing, with the ether development, filter, obtain solid product.
(4) comprise pyridine (0.4ml) and starting raw material in the reaction mixture.After the filtration, the solid of collecting is developed with triethylamine/water (1: 6), filtered,, obtain product with Virahol and ether washing.
(5) solvent evaporated obtains product, heats in the ethyl acetate of boiling then.
(6) will filter solids water/triethylamine (6: 1) development of collecting the back, filter then, obtain product.
Embodiment 207-220
According to similar methods described in the embodiment 187, generalized like that as institute in the following table 15, by making formula II ' compound (having provided the preparation embodiment of initial ester) and suitable acyl chlorides (R 17COCl) reaction, preparation.
Figure 91105264X_IMG68
Note:
(1) reaction mixture is evaporated to dried, solids is developed with ethyl acetate, filters then.The solids of collecting industrial methylated spirit recrystallization.
(2) reaction mixture is washed with water, be evaporated to dried then.
(3) products therefrom is developed with ether.
After (4) 12 hours, add other a acyl chlorides (0.2ml) and triethylamine (0.3ml), at ambient temperature reaction mixture was stirred 3 hours again.With the reaction mixture washing, drying concentrates, and obtains solid.
(5) use methylene dichloride as moving phase, dodge formula chromatography, purifying solids by silica gel.The product re-crystallizing in ethyl acetate.
(6) solids washs with triethylamine aqueous solution, filters water, Virahol and ether washing.
(7) solid product re-crystallizing in ethyl acetate.
(8) filter reaction mixture, product diox recrystallization.
(9) reaction mixture is added in the ether, filters, filtrate is evaporated to dried, use the industrial methylated spirit recrystallization.
(10) reaction mixture is washed with dilute hydrochloric acid, wash with water then, drying, evaporation.Gained solid Virahol recrystallization.
(11) use the acetonitrile recrystallization.
After (12) 20 hours, add other acyl chlorides (0.6ml) and triethylamine (0.6ml).Steam solvent, obtain oily matter, it is dissolved in the methylene dichloride, with dilute hydrochloric acid and water washing, drying, evaporation obtains jelly, after the ether development, obtains product.
(13) compound is softening in the time of 129 ℃.
Embodiment 221
With the 2-(4-chloro-phenyl-)-8-hydroxy-4-methyl (1) chromene also (4,3-c) pyrazoles-the 3(2H)-solution of ketone (1.95g) (embodiment 62) in anhydrous pyridine (58ml) stirs in ice bath, and handles with monomethyl succinate list acyl chlorides (1.6ml).In 18 hours, make reaction mixture be warmed to envrionment temperature, then restir 24 hours at ambient temperature.Reaction mixture is added in the water, uses ethyl acetate extraction.Merge organic extracting solution, wash with water, drying, reduction vaporization.Residue is dissolved in the methylene dichloride, is added to the Florisil that does dress
Figure 91105264X_IMG70
On the post, this post methylene dichloride/acetone (99: 1) wash-out.Evaporate required wash-out part, residue is developed with ether, obtains (2-(4-chloro-phenyl-)-4-methyl-3-oxo-2, and 3-dihydro (1) chromene is (4,3-c) pyrazoles-8-yl also) (methyl) succinate, m.p.152-153 ℃.
Embodiment 222-225
According to similar methods described in the embodiment 221, as institute at table 16 is generalized, by making the 2-(4-chloro-phenyl-)-8-hydroxy-4-methyl (1) chromene also (4,3-c) pyrazoles-3(2H)-ketone (II ') (embodiment 62) and suitable acyl chlorides (R 17COCl) reaction, preparation.In embodiment 223,224 and 225, added other a acyl chlorides, mixture has been stirred other for some time, as shown.
Figure 91105264X_IMG71
Note:
(1) this post methylene dichloride wash-out.
(2) some material is insoluble in the methylene dichloride in the crude product, removes by filter this material.This post methylene dichloride wash-out is used methylene dichloride/acetone (99: 1) wash-out then.
(3) filter to collect the material that is insoluble in ethyl acetate/water mixture, drying need not chromatography and directly obtains product.
Embodiment 226
Under agitation, handle the 2-(4-chloro-phenyl-with Benzoyl chloride (0.8ml))-9-hydroxy-4-methyl (1) chromene also (4,3-c) mixture of pyrazoles-3(2H)-ketone (2g) (embodiment 66) and pyridine (20ml), and stirred at ambient temperature 48 hours.Reaction mixture is poured in the water, filtered.Gained solid toluene recrystallization obtains the 2-(4-chloro-phenyl-)-4-methyl-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-9-yl benzoic acid ester also, m.p.218-222 ℃.
Embodiment 227
With the 2-(4-chloro-phenyl-)-8-hydroxy-4-methyl (1) chromene also (4,3-c) pyrazoles-3(2H)-ketone (embodiment 62) (1.5g) and the solution of nicotinoyl chlorine hydrochloride (1.6g) in the mixture of pyridine (45ml) and triethylamine (2.55ml) under envrionment temperature, stirred 18 hours.Reaction mixture was placed 48 hours at ambient temperature, is added to then in the water, filter, obtain the 2-(4-chloro-phenyl-)-4-methyl-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-8-base nicotinate also, m.p.230-235 ℃.
Embodiment 228
With the 2-(4-chloro-phenyl-)-8-hydroxy-4-methyl (1) chromene also (4,3-c) pyrazoles-3(2H)-ketone (embodiment 62) (1.8g) and the mixture of propanedioic acid list 4-methoxy benzyl ester (2.0g) in anhydrous pyridine (18ml) in cooling bath, stir.Add 1 with 5 fens clock times, 3-dicyclohexyl carbodiimide (1.6g) in batches.Mixture was stirred 18 hours at ambient temperature, pour in the water then.Use the ethyl acetate extraction mixture, merge organic extracting solution, wash with water, drying, evaporation.Residue is developed with ether, and solid collected by filtration stirs with methylene dichloride then.After removing by filter some insolubless, dichloromethane solution is added to Florisil
Figure 91105264X_IMG72
On the post.Use the methylene dichloride wash-out, obtain solids, develop with ether, after the filtration, obtain (2-(4-chloro-phenyl-)-4-methyl-3-oxo-2,3-dihydro (1) chromene also (4,3-c) (4-methoxy-benzyl) malonic ester pyrazoles-8-yl), m.p.162-163 ℃.
Embodiment 229
In ice bath, with (2-(4-chloro-phenyl-)-4-methyl-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-8-yl) (4-methoxy-benzyl) malonic ester (embodiment 228) (0.7g) stirs with methylene dichloride (3ml), and handles with methyl-phenoxide (0.14ml) and trifluoroacetic acid (1.54ml).This solution was stirred 2.5 hours down at 0 ℃, wash with water then, have solid to separate out subsequently.Solid collected by filtration is used washed with dichloromethane, and drying obtains propanedioic acid list (2-(4-chloro-phenyl-)-4-methyl-3-oxo-2, and 3-dihydro (1) chromene is (4,3-c) pyrazoles-8-base ester also, m.p.166 ℃.
Embodiment 230
According to embodiment 227 similar methods, with the 2-(4-chloro-phenyl-)-8-hydroxy-4-methyl (1) chromene also (4,3-c) pyrazoles-3(2H)-ketone (embodiment 62) (1.5g), N, the mixture of N-N-methylsarcosine (0.78g) and anhydrous pyridine (15ml) stirs at ambient temperature.Add 1,3-dicyclohexyl carbodiimide (1.35g), reaction mixture was stirred two days at ambient temperature, with methylene dichloride/acetone (99: 1) as the moving phase chromatography after, obtain (2-(4-chloro-phenyl-)-4-methyl-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-8-yl also) the dimethylamino acetic ester, m.p.174-176 ℃.
Embodiment 231
According to embodiment 227 similar methods, under stirring and envrionment temperature, with 1,3-dicyclohexyl carbodiimide (1.35g) is handled the 2-(4-chloro-phenyl-)-8-hydroxy-4-methyl (1) chromene also (4,3-c) pyrazoles-3(2H)-ketone (embodiment 62) (1.5g), the mixture of methylthio group acetate (0.6ml) and anhydrous pyridine (15ml).Mixture was stirred two days at ambient temperature, behind the chromatography, obtain (2-(4-chloro-phenyl-)-4-methyl-3-oxo-2,3-dihydro (1) chromene is (4,3-c) pyrazoles-8-yl also) the methylmercaptan ethyl acid esters, m.p.163-166 ℃.
Embodiment 232
Under 0 ℃, to the 2-(4-chloro-phenyl-)-8-hydroxyl-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-mixture of 4-ethyl acetate (2.0g) (embodiment 48) in anhydrous methylene chloride (60ml) stirs, add triethylamine (1.6ml) simultaneously, then add alpha-Acetoxyacetyl chloride (1.2ml).In 30 minutes, make mixture be warmed to envrionment temperature, wash with water then, dry and evaporation.Solid residue is developed with ether, filter, obtain 3,8-two (acetyl oxygen acetoxy)-2-(4-chloro-phenyl-)-2,4-dihydro (1) chromene also (4,3-c) pyrazoles-4-subunit ethyl acetate, after in air, placing, be hydrolyzed into the 8-acetyl oxygen acetoxy-2-(4-chloro-phenyl-that contains 1 mole of acetoxy acid)-3-oxo-2,3-dihydro (1) chromene also (4,3-c) pyrazoles-4-ethyl acetate semihydrate, m.p.157-160 ℃.
Embodiment 233
Under agitation, with monoethyl malonate list acyl chlorides (0.56ml) to 2-(3, the 4-dichlorophenyl)-8-hydroxyl-3a-methyl-3a, 4-dihydro (1) the benzo thiapyran also mixture of (4,3-c) pyrazoles-3(2H)-ketone (1.50g) (embodiment 73), triethylamine (0.61ml) and methylene dichloride (30ml) drips processing.Mixture was stirred 2 hours at ambient temperature, then reduction vaporization.Residue distributes between ether (50ml) and water (50ml).Tell organic layer, use the ether extraction water layer.The combined ether extracting solution, drying, evaporation obtains solids, after re-crystallizing in ethyl acetate, obtain (2-(3,4-dichlorophenyl)-3a-methyl-3-oxo-2,3,3a, 4-tetrahydrochysene (1) benzo thiapyran is (4,3-c) pyrazoles-8-yl also) (ethyl) malonic ester, m.p.139-141 ℃.
Embodiment 234-251
According to similar methods described in the embodiment 233, generalized like that as institute in the following table 17, by making formula I ' compound (having provided the preparation embodiment of initial compounds) and acyl chlorides R 17The COCl reaction, preparation.
Figure 91105264X_IMG73
Figure 91105264X_IMG74
Note:
(1) use the following solvents recrystallization:
A) ether
B) ethanol
C) ethyl acetate/petroleum ether (b.p.60-80 ℃)
D) methyl alcohol
E) ethyl acetate
F) Virahol
(2) evaporation ether extracting solution adds entry then in residue.Use ethyl acetate extraction, then, obtain product with re-crystallizing in ethyl acetate twice.
After (3) 1 hours, add the triethylamine and the acyl chlorides of another aliquot.
In reaction mixture, add N, dinethylformamide (2ml) when (4) beginning.Add other a triethylamine (0.3ml) and acetyl oxygen Acetyl Chloride 98Min. (0.3ml) after 16 hours.
(5) dodge formula chromatography, purifying crude product as moving phase by silica gel with methylene dichloride.
Following compounds has chiral carbon atom, can exist with R-and S-enantiomeric forms:
Embodiment 111,133,149,151,152,153
Embodiment 252
In the preparation of capsule, 10 parts of (weight) active compounds and 240 parts of (weight) lactose are pulverized and thorough mixing.This mixture is filled in the hard gelatin capsule, and each capsule contains the 10mg active compound.
Embodiment 253
In the preparation of capsule, 50 parts of (weight) active compounds, 300 parts of (weight) lactose and 3 parts of (weight) Magnesium Stearates are pulverized, and thorough mixing.This mixture is filled in the hard gelatin capsule, and every contains 50 mg active ingredients.
Embodiment 254
Prepare tablet by following composition:
Umber (weight)
Active compound 10
Lactose 190
W-Gum 22
Polyvinylpyrolidone (PVP) 10
Magnesium Stearate 3
Active compound, lactose and a part of starch are pulverized and thorough mixing, and the ethanolic soln of using Polyvinylpyrolidone (PVP) is with the gained granulating mixture.This dry granules is mixed with Magnesium Stearate and remaining starch.Then with tabletting machine with this mixture compressing tablet, contained a) 10mg respectively, b) 100mg, c) tablet of 500mg active compound.
Embodiment 255
Method by embodiment 254 prepares tablet.With the method for routine, adopting concentration is that 20% Cellacefate and the solution of 3% diethyl phthalate in ethanol/dichloromethane (1: 1) are given the tablet enteric coating.
Embodiment 256
In the preparation of suppository, 100 parts of (weight) active compounds are mixed 1300 parts (weight) as in the semi-synthetic glyceryl ester of suppository base, and this mixture is made every suppository that contains the 100mg active ingredient.
Embodiment 257
In the preparation of ointment, by homogenization with in the active compound doped matrix, till drug distribution evenly.This ointment is packed in the amber wide-necked bottle of 10g of the screw-cap that has belt material,
Active compound 0.1g
Soft Chinese wax adds to 10g
The compounds of this invention is an immunomodulator, is respectively immunosuppressor, and they can present therapeutic activity when 200mg/kg or lower dosage.Preferred compound can present activity among the present invention when 50mg/kg or lower dosage.Confirmed the therapeutic activity of preferred compound of the present invention by skin anaphylactic test (CH test), in this test, given BALB/c mouse by non-stomach and intestine approach compound.Implement this test with following method.
Getting body weight is the female BALB/c mouse of 16-24g, is one group with eight.The belly of every mouse is lost hair or feathers, and be coated with acetone (1: 1, volume ratio) solution) with 20 μ l sensitiser solution (5%W/V 4-oxyethyl group methylene radical-2-phenyl-2-oxazoline-5-ketone (azolactone) at the position of depilation.After the sensitization, immediately by the suspension (sterilized water that contains 1.5%V/V Isosorbide Dinitrate (commodity are called tween-80) of test-compound (100 μ l) solution) of one of dosage that hereinafter provides peritoneal injection test-compound.In afterwards 7 days, injected the same suspension of 100 μ l in the same way every 24 hours.The dosage that is adopted is selected following numerical value for use: 50,30,10,3,1,0.3,0.1,0.03 or 0.01mg/kg.
Each test adopts two treated animals be at least eight BALB/c mouse to organize in contrast simultaneously, handles to be similar to previously described mode, and difference is not contain test-compound in the injection liquid of every day.
After the sensitization the 7th day, propyl alcohol/sweet oil (3: 1 V/V) solution of 10 μ l 1%W/V azolactones is applied on every ear (being referred to as to be tried ear) that is tried mouse and contrast mouse.(under a few cases, adopt bigger test dose: the acetone/olive oil solution of 1.5%W/V azolactone).After 24 hours, the thread profile gauge micrometer of using with the technician is measured same animal and is tried ear and the non-thickness that is tried ear.Thickness difference between two ears of every animal is this moving thing measuring the azolactone reaction.Do one relatively with accepting the reaction of test-compound mouse and accepting between the reaction of mouse of control treatment, can show the effectiveness of test-compound as immunomodulator.If under a certain concrete dosage, have two groups at least (perhaps in three groups of CH tests, most of test in more than three groups CH test), its ear oedema alleviates 20% or more (according to Dunnett check, being statistics significantly (p＜0.05)), then think under this dosage compound be effectively (referring to: for example, Int, Arch.Allergy, 38, p 246-259(1970)).
Unless otherwise indicated outside (referring to table back note), hereinafter all formula I compounds of listing of Table A have at least 2 groups to be active when 50mg/kg in the test of 3 groups of 50mg/kg.Provided the minimum effective dose of each compound in the Table A.The embodiment numbering that list on the compound next door indicates the preparation method who has provided this compound in this embodiment.
Table A
Embodiment compound title minimum effective dose (mg/kg)
77 4-methyl-2-(5-fluoroform 3
Base-2-pyridyl) ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
3(2H)-ketone
78 2-(5-chloro-2-pyridyl-3
4-methyl ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-3(2H)
-ketone
79 2-(6-chloro-2-pyridyl-50
4-methyl ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-3(2H)
-ketone
80 4-methyl-2-(6-fluoroform 50
Base-2-pyridyl) ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
3(2H)-ketone
81 2-(4-chloro-2-pyridyl)≤3
-4-methyl ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-3(2H)
-ketone
82 2-(6-chloro-5-trifluoromethyls 3
-2-pyridyl)-the 4-methyl
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-3(2H)-ketone
83 2-(5-bromo-2-pyridyl) 50
-4-methyl ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-3(2H)
-ketone
84 2-(5-chloro-2-pyridyl) 50
-9-hydroxyl)-4-methyl ［ 1 ］
Chromene is ［ 4,3-c ］ pyrrole also
Azoles-3(2H)-ketone
85 8-fluoro-4-methyl-2-(5-≤50
Trifluoromethyl-2-pyridyl) ［ 1 ］
Chromene is ［ 4,3-c ］ pyrrole also
Azoles-3(2H)-ketone
86 2-(5-chloro-2-pyridyl) 50
-8-fluoro-4-methyl ［ 1 ］ benzene
And pyrans ［ 4,3-c ］ pyrazoles also
-3(2H)-ketone
87 2-(5-chloro-2-pyridyl) 50
-4-methylthiomethyl ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
3(2H)-ketone
88 2-(5-chloro-2-pyridyl)≤3(a)
-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also 4,
3-c ］ pyrazoles-4-ethyl acetate
89 (2-(5-chloro-2-pyridyl)≤3(a)
-4-methyl-3-oxo-2,
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-9-yl)
Acetic ester
90 2-(5-chloro-2-pyridyl) 50
-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-4-acetic ester
91 2-(4-chloro-phenyl-s)-3-oxygen 50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-piperidino-(1-position only) ethyl ester
Hydrochloride 0.4 hydrate
92 2-(4-chloro-phenyl-s)-3-oxygen 50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 3-(4-methyl isophthalic acid-
Piperazinyl) propyl diester 2.5 hydrochloric acid
The monocalcium salt compound
93 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-morpholino ethyl ester salt
The hydrochlorate semihydrate
94 2-(3, the 4-dichlorophenyl)-≤50
3-oxo-2,3-dihydro ［ 1 ］
Chromene is ［ 4,3-c ］ pyrrole also
Azoles-4-acetate 2-morpholino ethyl
Ester
95 2-(4-chloro-phenyl-s)-8-hydroxyl 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-4-acetate 2-morpholino second
The base ester
96 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 3-morpholino propyl diester salt
The hydrochlorate monohydrate
97 2-(4-bromophenyls)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-morpholino ethyl ester salt
The hydrochlorate semihydrate
98 2-(4-fluorophenyls)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-morpholino ethyl ester salt
Hydrochlorate
99 2-(4-chloro-phenyl-s)-8-fluorine≤50
-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-4-acetate 2-morpholino second
Base ester hydrochloride 0.4 hydrate
100 2-(4-chloro-phenyl-s)-9-first 50
Oxygen base-3-oxo-2,3-two
Hydrogen ［ 1 ］ chromene is ［ 4,3-c ］ also
Pyrazoles-4-acetate 2-morpholino second
The base ester hydrochloride
101 2-(4-chloro-phenyl-s)-3-oxygen≤1
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 4-methoxy-benzyl ester
102 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
The 4-jasmal
103 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate styroyl ester
104 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetic acid cyclopentyl base ester
105 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-methoxy ethyl ester
106 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-(2-thienyl)
Ethyl ester
107 2-(4-chloro-phenyl-s)-3-oxygen 3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate cyclobutylmethyl ester
108 2-(4-chloro-phenyl-s)-3-oxygen 50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-(2-pyridyl)
Ethyl ester
109 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate cyclobutyl ester
110 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-(2-methoxyl group second
The oxygen base) ethyl ester
111 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate tetrahydro furfuryl ester
112 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate tetrahydrochysene-2H-pyrans-
4-base ester
113 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-(4-methyl-5-
Thiazolyl) ethyl ester
114 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 3-methoxy-benzyl ester
115 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 4-methyl-benzyl ester
116 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 4-anisole ethyl ester
117 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 4-chlorobenzene ethyl ester
118 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-chlorine benzyl ester
119 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 3-oxo butyl ester
120 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-chlorobenzene ethyl ester
121 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 3-methylbenzene ethyl ester
122 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-ethyl cyclohexyl base ester
123 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 3-chlorine benzyl ester
124 2-(4-chloro-phenyl-s)-3-oxygen 50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 3-hydroxy-propyl ester
125 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-phenoxy group ethyl ester
126 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 4-dimethylamino styroyl
Ester
127 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-kharophen ethyl ester
128 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 3-methyl-benzyl ester
129 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-methyl-benzyl ester
130 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 4-chlorine benzyl ester
131 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-methoxy-benzyl ester
132 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 3-(3-pyridyl)
Propyl diester
133 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate Alpha-Methyl styroyl ester
134 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate cyclopropyl methyl ester
135 3-oxo-2-(4-fluoroform≤50
The base phenyl)-2,3-dihydro ［ 1 ］
Chromene is ［ 4,3-c ］ pyrrole also
Azoles-4-acetate cyclobutylmethyl ester
136 2-(4-chloro-phenyl-s)-8-first≤50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-4-acetate cyclobutylmethyl ester
137 2-(4-p-methoxy-phenyls)-3-≤50
Oxo-2,3-dihydro ［ 1 ］ benzene
And pyrans ［ 4,3-c ］ pyrazoles also
-4-acetate cyclobutylmethyl ester
138 2-(4-aminomethyl phenyls)-3-≤50
Oxo-2,3-dihydro ［ 1 ］ benzene
And pyrans ［ 4,3-c ］ pyrazoles also
-4-acetate cyclobutylmethyl ester
139 2-(3-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate cyclobutylmethyl ester
140 2-(4-chloro-phenyl-s)-9-hydroxyl≤50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-4-acetate cyclobutylmethyl ester
142 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-acetoxyl group ethyl ester
143 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-hydroxyethyl ester
144 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-thiomorpholine is for ethyl
Ester hydrochloride
145 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-methylmercaptoethyl ester
146 2-(4-chloro-phenyl-s)-3-oxygen 50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 4,4,4-trifluoro fourth
The base ester
147 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-cyano ethyl ester
148 2-(4-chloro-phenyl-s)-3-oxygen 50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-ethoxycarbonyl-ethyl ester
149 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate Beta-methyl styroyl ester
150 2-(4-chloro-phenyl-s)-3-oxygen≤3
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-cyclohexyl ethyl ester
151 2-(4-chloro-phenyl-s)-3-oxygen 50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 1-methyl-2-morpholine
For ethyl ester
152 2-(4-chloro-phenyl-s)-3-oxygen 50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 1-methyl-2-piperidines
The ylmethyl ester
153 2-(4-chloro-phenyl-s)-3-oxygen 50
Generation-1,2,3, the 4-tetrahydrochysene
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-4-acetate 2-morpholino second
The base ester
154 2-(4-chloro-phenyl-s)-3-oxygen≤50
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 3-acetoxyl group propyl diester
155 2-(4-chloro-phenyl-s)-N-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-4-Acetanilide
156 N-benzyl-2-(4-chloro-phenyl-) 50
-N-methyl-3-oxo-2,
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-4-second
Acid amides
157 2-(4-chloro-phenyl-s)-N-first 50
Base-N-(2-morpholino ethyl)
-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-4-ethanamide
158 2-(4-chloro-phenyl-s)-N-first 50
Base-3-oxo-N-(3-pyrrole
The pyridine ylmethyl)-2,3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-4-ethanamide
159 2-(4-chloro-phenyl-s)-N-second 3
Base-3-oxo-N-phenyl-2,
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-4-second
Acid amides
160 N-benzyl-2-(4-bromophenyl) 50
-N-methyl-3-oxo-2,
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-4-second
Acid amides
161 N-benzyl-2-(3,4-2 50
Chloro-phenyl-)-N-methyl-3-oxygen
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
The 4-ethanamide
162 N-benzyl-2-(4-chloro-phenyl-) 50
-8-fluoro-N-methyl-3-oxygen
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
The 4-ethanamide
163 2-(4-chloro-phenyl-s)-N-first 50
Base-3-oxo-N-styroyl-
2,3-dihydro ［ 1 ］ chromene
And ［ 4,3-c ］ pyrazoles-4-
Ethanamide
164 2-(4-chloro-phenyl-s)-N-50
(2-cyano ethyl)-N-methyl
-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-4-ethanamide
165 2-(4-chloro-phenyl-s)-and N, N-50
(3-oxa-pentamethylene)-3-
Oxo-2,3-dihydro ［ 1 ］ benzene
And pyrans ［ 4,3-c ］ pyrazoles also
-4-ethanamide
166 4 '-chloro-2-(4-chloro-phenyl-) 50
-N-methyl-3-oxo-2,
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-4-second
Anilide
167 N-benzyl-2-(4-fluorophenyl) 50
-N-methyl-3-oxo-2,
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-4-second
Acid amides
168 2-(4-chloro-phenyl-s)-N-50
(1,3-two oxa-s penta ring-2-
Ylmethyl)-N-methyl-3-oxygen
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
The 4-ethanamide
169 4-the 2-(4-chloro-phenyl-)-50
N-methyl-3-oxo-2,3-
Dihydro ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-4-kharophen ］
Methyl benzoate
170 2-{ 4-［ 2-(4-chlorobenzene 50
Base)-and 3-oxo-2,3-two
Hydrogen ［ 1 ］ chromene is ［ 4,3-c ］ also
Pyrazoles-4-ethanoyl ］ piperazine-1-
Base } ethylhexoate
171 2-{ 4-［ 2-(4-chlorobenzene 50
Base)-and 3-oxo-2,3-two
Hydrogen ［ 1 ］ chromene is ［ 4,3-c ］ also
Pyrazoles-4-ethanoyl ］ piperazine-1-
The propionic acid ethyl ester
172 N, N-(3-oxa-pentamethylene)≤50
-3-oxo-2-(4-(three
The methyl fluoride phenyl)-2,3-dihydro
［ 1 ］ benzo thiapyran also ［ 4,3-c ］
Pyrazoles-4-ethanamide
173 N-ethyl-3-oxo-N-benzene≤50
Base-2-(4-trifluoromethyl)
-2,3-dihydro ［ 1 ］ benzo thiophene
Also ［ 4,3-c ］ pyrazoles-4-mutters
Ethanamide
174 5-the 2-(4-chloro-phenyl-)-50
3-oxo-2,3-dihydro ［ 1 ］
Chromene is ［ 4,3-c ］ pyrrole also
Azoles-4-yl ］-4-oxopentanoie acid
Methyl esters
175 2-(4-chloro-phenyl-s)-4-50
(2-oxo-3-phenyl propyl)
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-3(2H)-ketone
176 2-(4-chloro-phenyl-s)-4-3
(2-oxo-3-phenoxy propyl)
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-3(2H)-ketone
177 2-(4-chloro-phenyl-s)-4-50
(2-cyclohexyl-2-oxoethyl)
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-3(2H)-ketone
178 2-(4-chloro-phenyl-s)-4-50
(2-cyclopropyl-2-oxoethyl)
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-3(2H)-ketone
179 2-(4-chloro-phenyl-s)-4-≤50
The 4-(4-p-methoxy-phenyl)-
2-oxo butyl ］ ［ 1 ］ benzo pyrrole
Mutter also ［ 4,3-c ］ pyrazoles-
3(2H)-ketone
180 4-the 3-(4-chlorophenoxy)≤3
-2-oxopropyl ］-2-(4-
Chloro-phenyl-) ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-3(2H)
-ketone
181 2-(4-chloro-phenyl-s)-4-≤50
The 4-(3-aminomethyl phenyl)-2-
The oxo butyl ］ ［ 1 ］ chromene is also
［ 4,3-c ］ pyrazoles-3(2H)
-ketone
182 2-(4-chloro-phenyl-s)-4-≤50
(3-cyclopentyl-2-oxopropyl)
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-3(2H)-ketone
183 2-(4-chloro-phenyl-s)-4-≤50
The 3-(2-methylphenoxy)-
2-oxopropyl ［ 1 ］ chromene
And ［ 4,3-c ］ pyrazoles-
3(2H)-ketone
184 2-(4-chloro-phenyl-s)-4-≤50
(4-methylthio group-2-oxo butyl ］
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-3(2H)-ketone
185 2-(3, the 4-dichlorophenyl)-≤50
4-(2-oxo-3-phenoxy group
Propyl group) ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-3(2H)-
Ketone
186 2-(4-chloro-phenyl-s)-4-≤3(a)
(3-methoxyl group-2-oxopropyl)
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-3(2H)-ketone
187 (2-(4-chloro-phenyl-)-4-≤3
Methyl-3-oxo-2,3-two
Hydrogen ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-9-yl) (first
Base) malonic ester
188 (2-(4-chloro-phenyl-)-4-≤1
Methyl-3-oxo-2,3-two
Hydrogen ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-8-yl) (second
Base) malonic ester
189 2-(4-chloro-phenyl-s)-4-≤3(a)
Methyl-3-oxo-2,3-two
Hydrogen ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-8-ylmethoxy
Acetic ester
190 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-basic ring propane carboxylicesters
191 2-(4-chloro-phenyl-s)-4-first≤3
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base 1-adamantanecarboxylic acid
Ester
192 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base 3-phenylpropionic acid ester
193 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base phenylacetate
194 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base 2-anisole first
Acid esters
195 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base 2-furancarboxylic acid ester
196 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base 2-ester thiohenic acid
197 2-(4-chloro-phenyl-s)-4-first≤3
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-basic ring butane carboxylicesters
198 2-(4-chloro-phenyl-s)-4-first≤50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base 2-tolyl acid
Ester
199 2-(4-chloro-phenyl-s)-4-first≤50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base 4-chloro-benzoic acid ester
200 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base crotonate
201 2-(4-chloro-phenyl-s)-4-first≤50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base 4-anisole first
Acid esters
202 2-(4-chloro-phenyl-s)-4-first≤50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base 4-tolyl acid
Ester
203 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-basic ring pentane carboxylicesters
204 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-basic ring cyclohexane carboxylic-acid ester
205 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base 3-tolyl acid
Ester
206 2-(4-chloro-phenyl-s)-4-first≤50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base iso-nicotinate
207 2-(4-chloro-phenyl-s)-3-oxygen 50
Generation-8-phenyl acetoxyl group-2,
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-4-second
Acetoacetic ester
208 2-(4-chloro-phenyl-s)-8-first 50
Oxygen base acetoxy-3-oxo-2,
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-4-second
Acetoacetic ester 0.3 methoxyacetic acid solvent
Change thing
209 (2-(4-chloro-phenyl-)-4-50
Ethoxycarbonylmethyl group-3-oxo-2,
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-8-yl)
(methyl) succinate
210 4-methyl-3-oxo-2-≤50
(4-trifluoromethyl)-2,
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-8-base
Acetyl fluoroacetic acid ester
211 2-(4-bromophenyls)-4-first≤50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base acetyl fluoroacetic acid ester
212 2-(3, the 4-dichlorophenyl)-≤50
4-methyl-3-oxo-2,3-
Dihydro ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-8-base methoxy second
Acid esters
213 2-(3, the 4-dichlorophenyl)-≤50
4-methyl-3-oxo-2,3-
Dihydro ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-8-base 3-
(methylthio group) propionic ester
214 2-(3, the 4-dichlorophenyl)-50
4-methyl-3-oxo-2,3-
Dihydro ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-8-base acetyl oxygen
Yl acetate
215 (2-(3,4-dichlorophenyl)≤50
-4-methyl-3-oxo-2,
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-8-yl)
(methyl) succinate
216 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-9-base methoxyimino acetic acid ester
217 9-acetyl oxygen acetoxy-2-≤50
(4-chloro-phenyl-)-3-oxo-
2,3-dihydro ［ 1 ］ chromene
And ［ 4,3-c ］ pyrazoles-4-
Acetate cyclobutylmethyl ester
218 8-acetyl oxygen acetoxy-2-≤50
(4-chloro-phenyl-)-3-oxo-
2,3-dihydro ［ 1 ］ chromene
And ［ 4,3-c ］ pyrazoles-4-
0.5 hydration of acetate cyclobutylmethyl ester
Thing 0.35 acetyl fluoroacetic acid solvation
Thing
219 8-acetyl oxygen acetoxy-2-≤50
(4-chloro-phenyl-)-3-oxo-
2,3-dihydro ［ 1 ］ chromene
And ［ 4,3-c ］ pyrazoles-4-
Acetate isopropyl esters 0.2 hydrate
0.5 acetyl fluoroacetic acid solvate
220 (2-(4-chloro-phenyl-)-4-≤3
Methyl-3-oxo-2,3-two
Hydrogen ［ 1 ］ chromene is ［ 4,3-c ］ also
Pyrazoles-9-yl) (methyl) amber
Acid esters
221 (2-(4-chloro-phenyl-)-4-≤1
Methyl-3-oxo-2,3-two
Hydrogen ［ 1 ］ chromene is ［ 4,3-c ］ also
Pyrazoles-8-yl) (methyl) succsinic acid
Ester
222 2-(4-chloro-phenyl-s)-4-first≤1
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base acetyl fluoroacetic acid ester
223 2-(4-chloro-phenyl-s)-4-first 3
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base 3-(methylthio group)
Propionic ester
224 (2-(4-chloro-phenyl-)-4-50
Methyl-3-oxo-2,3-two
Hydrogen ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-8-yl) (second
Base) succinate
225 2-(4-chloro-phenyl-s)-4-first 3
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-yl benzoic acid ester
226 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-9-yl benzoic acid ester
227 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base nicotinate
228 (2-(4-chloro-phenyl-)-4-50
Methyl-3-oxo-2,3-two
Hydrogen ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-8-yl) (4-
Methoxy-benzyl) malonic ester
229 (2-(4-chloro-phenyl-)-4-50
Methyl-3-oxo-2,3-two
Hydrogen ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-8-yl) the third two
Acid monoester
230 2-(4-chloro-phenyl-s)-4-first≤3
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base dimethylamino acetic ester
231 2-(4-chloro-phenyl-s)-4-first 50
Base-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base (methylthio group) acetate
Ester
232 8-acetyl oxygen acetoxy-2-3
(4-chloro-phenyl-)-3-oxo-
2,3-dihydro ［ 1 ］ chromene
And ［ 4,3-c ］ pyrazoles-4-
Ethyl acetate semihydrate acetyl fluoroacetic acid
Solvate
233 (2-(3,4-dichlorophenyl)≤3
-3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-yl) (ethyl) malonic ester
234 (2-(3,4-dichlorophenyl)≤3
-3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base methoxyimino acetic acid ester
235 2-(3, the 4-dichlorophenyl)-≤3
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base acetyl fluoroacetic acid ester
236 2-(3, the 4-dichlorophenyl)-≤3
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base phenylacetate
237 2-(3, the 4-dichlorophenyl)-≤1
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-yl benzoic acid ester
238 (2-(3,4-dichlorophenyl)≤1
-3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-yl) (methyl) succinate
239 2-(3, the 4-dichlorophenyl)-≤50
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base crotonate
240 2-(3, the 4-dichlorophenyl)-≤50
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base propionic ester
241 2-(3, the 4-dichlorophenyl)-50
4-methyl-3-oxo-2,3-
Dihydro ［ 1 ］ benzo thiapyran also 4,
3-c ］ pyrazoles-8-base acetyl oxygen
Acetic ester
242 3a-methyl-3-oxo-2-≤50
(4-trifluoromethyl)-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base acetyl fluoroacetic acid ester
243 2-(4-chloro-phenyl-s)-3a-≤50
Methyl-3-oxo-2,3,
3a, 4-tetrahydrochysene ［ 1 ］ benzo thiophene
Also ［ 4,3-c ］ pyrazoles-8-mutters
Base methoxyimino acetic acid ester
244 2-(4-fluorophenyls)-3a-≤50
Methyl-3-oxo-2,3,
3a, 4-tetrahydrochysene ［ 1 ］ benzo thiophene
Also ［ 4,3-c ］ pyrazoles-8-mutters
Base acetyl fluoroacetic acid ester
245 (2-(4-fluorophenyl)-3a≤50
-methyl-3-oxo-2,3,
3a, 4-tetrahydrochysene ［ 1 ］ benzo thiophene
Also ［ 4,3-c ］ pyrazoles-8-mutters
Base) (ethyl) malonic ester
246 3a-methyl-3-oxo-2-≤3
(4-trifluoromethyl)-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base methoxyimino acetic acid ester
247 2-(4-fluorophenyls)-3a-50
Methyl-3-oxo-2,3,
3a, 4-tetrahydrochysene ［ 1 ］ benzo thiophene
Also ［ 4,3-c ］ pyrazoles-8-mutters
Base methoxyimino acetic acid ester
248 2-(4-chloro-phenyl-s)-3a-≤50
Methyl-3-oxo-2,3,
3a, 4-tetrahydrochysene ［ 1 ］ benzo thiophene
Also ［ 4,3-c ］ pyrazoles-8-mutters
Base acetyl fluoroacetic acid ester
249 (ethyl) (3a-methyl-3-≤50
Oxo-2-(4-trifluoromethylbenzene
Base)-2,3,3a, 4-four
Hydrogen ［ 1 ］ benzo thiapyran also 4,
3-c ］ pyrazoles-8-yl) the third two
Acid esters
250 4-methyl-3-oxo-2-≤50
(4-trifluoromethyl)-2,
3-dihydro ［ 1 ］ benzo thiapyran also
［ 4,3-c ］ pyrazoles-8-base
Acetyl fluoroacetic acid ester
251 (ethyls) (4-methyl-3-oxygen≤50
Generation-2-(4-trifluoromethyl)
-2,3-dihydro ［ 1 ］ benzo thiophene
Also ［ 4,3-c ］ pyrazoles-8-mutters
Base) malonic ester
Twice test of note all presents activity when 3mg/kg.
The compounds of this invention also presents activity in screening in multiple other bodies, showing can be with these compounds as immunomodulator, especially for suppressing immune response.Can adopt and orally or non-give The compounds of this invention through the gi tract approach.(concrete grammar is: collect serum when the Shu azolactone induces skin anaphylactic test (CH test) to finish Qian the Zai testing the test of test-compound to the influence of humoral immunization, measure the change of the amount that produces De Kang azolactone antibody in the serum, determine the influence of test-compound with this to humoral immunization) and be similar to Smith S.R., Terminelli C., Kipilman C.T., with Smith Y.(J.Immunopharmacology, 1981; 3(2), in the Graft versus Host test of 133-170) being adopted, find that some compounds are active.
For example, in aforementioned antibody test, find, with the dosage of 50mg/kg with non-behind the gi tract administration, hereinafter described the compound that makes of embodiment also is active.If when a certain compound is pressed the 50mg/kg dosed administration, the relative concentration that connects the clear anti-azolactone antibody of blood that immune absorption measurement method (ELISA) is measured, that calculate by following formula by enzyme reduces by 0.5 or more words, then thinks this compound activity.Described formula is:
(O.D(C 1)-O.D.(T 1))/(O.D.(C 1)-O.D.(C 2))
Wherein, O.D.(C 1) be by after 1/128 dilution, the optical density(OD) of control serum,
O.D.(C 2) be by after 1/256 dilution, the optical density(OD) of control serum,
O.D.(T 1) be by after 1/128 dilution, tried the optical density(OD) of serum.
Dilute control serum and tried serum with the phosphate buffered saline buffer that contains 0.05%V/V polysorbas20 (trade(brand)name) (pH 7.3).
The compound that is active reaction in afore-mentioned test is: embodiment 77-79,81-137,139-140,142-159,161,164,166-7,169-197,199-240,242-251.
Following compound or have activity when being lower than as defined herein 50mg/kg dosage, these compounds are with similar in appearance to method preparation as herein described:
Embodiment compound title fusing point (℃)
258 4-morpholino tolyl acid 2-115-188
(4-chloro-phenyl-)-4-methyl-(decomposition)
3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base ester
259 5-［ 3-oxo-2-(4-140-143
Trifluoromethyl)-2,3-two
Hydrogen ［ 1 ］ benzo thiapyran also 4,
3-c ］ pyrazoles-4-yl ］-4-
The oxopentanoic acid methyl esters
260 2-(3, the 4-dichlorophenyl)-191-193
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base 2-ester thiohenic acid
261 2-(3, the 4-dichlorophenyl)-149-150
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base nicotinate
262 2-(3, the 4-dichlorophenyl)-132-135
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base 3-methyl benzoic acid ester
263 2-(5-chloro-2-pyridyl) 258-265
-8-hydroxyl-3-oxo-2, (decomposition)
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-4-second
Acetoacetic ester
264 2-(4-chloro-phenyl-s)-3-oxygen 210-213
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-(2-methyl piperidine
Subbase) ethyl ester hydrochloride
265 2-4,5-two (trifluoromethyl) 235-238
-2-pyridyl ］-the 4-methyl
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-3(2H)-ketone
266 2-(5-chloro-2-pyridyl) 181-184
-N-ethyl-3-oxo-N-
Phenyl-2,3-dihydro ［ 1 ］ benzene
And pyrans ［ 4,3-c ］ pyrazoles also
-4-ethanamide
267 2-(5-chloro-2-pyridyl) 157-160
-3-oxo-2, the 3-dihydro
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-4-acetate cyclobutylmethyl ester
268 4-the 3-(3-chlorophenoxy) 193-195
-2-oxopropyl ］-2-(4-
Chloro-phenyl-) ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-3(2H)
-ketone
269 4-the 3-(2-chlorophenoxy) 215-217
-2-oxopropyl ］-2-(4-
Chloro-phenyl-) ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-3(2H)
-ketone
270 4-(4-methylpiperazine-1-base 153-156
Methyl) phenylformic acid 2-(4-chlorobenzene
Base)-4-methyl-3-oxo-
2,3-dihydro ［ 1 ］ chromene
And ［ 4,3-c ］ pyrazoles-8-
Base ester hydrochloride hydrate
271 2-(3, the 4-dichlorophenyl)-188-190
3-oxo-2,3-dihydro ［ 1 ］
Benzo thiapyran is ［ 4,3-c ］ pyrrole also
Azoles-4-acetate 4-methoxy-benzyl
Ester
272 2-(4-chloro-phenyl-s)-3-oxygen 131
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
4-acetate 2-acetyl oxygen acetoxy
Ethyl ester
273 4-diethylin tolyl acid 2-147-151
(4-chloro-phenyl-)-4-methyl-
3-oxo-2,3-dihydro ［ 1 ］
Chromene is ［ 4,3-c ］ pyrrole also
Azoles-8-base
274 2-(4-chloro-phenyl-s)-4-first 305-310
Base-3-oxo-2,3-dihydro (decomposition)
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-8-base glycinate (0.9)
Hydrochloride
275 4-(2-oxo-3-phenyl third 173-175
Base)-the 2-(4-trifluoromethylbenzene
The base) ［ 1 ］ benzo thiapyran also 4,
3-c ］ pyrazoles-3(2H)-
Ketone
276 3-oxo-2-(4-fluoroform 137-138
The base phenyl)-2,3-dihydro ［ 1 ］
Benzo thiapyran is ［ 4,3-c ］ pyrrole also
Azoles-4-acetate 4-methoxy-benzyl
Ester
277 2-(5-chloro-2-pyridyl) 254-256
-9-methoxyl group-4-methyl ［ 1 ］
Chromene is ［ 4,3-c ］ pyrrole also
Azoles-3(2H)-ketone
278 2-(4-chloro-phenyl-s)-4-221-223
(4-methylsulfonyl-2-oxo fourth
The base ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-3(2H)-
Ketone
279 t-butoxycarbonyl amino acetate 2-(4-192-193
Chloro-phenyl-)-4-methyl-3-oxygen
Generation-2,3-dihydro ［ 1 ］ benzo
Pyrans also ［ 4,3-c ］ pyrazoles-
8-base ester
280 4-the 3-(4-methoxyphenyl) 184-187
-2-oxopropyl ］-2-(4-
Trifluoromethyl) ［ 1 ］ benzo thiophene
Mutter also ［ 4,3-c ］ pyrazoles-
3(2H)-ketone
281 2-(4-chloro-phenyl-s)-4-178-180
The 3-(4-p-methoxy-phenyl)-
The 2-oxopropyl ］ ［ 1 ］ benzo pyrrole
Mutter also ［ 4,3-c ］ pyrazoles-
3(2H)-ketone
282 2-(3, the 4-dichlorophenyl)-141-142
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base 4-methoxybenzoic acid ester
283 2-(3, the 4-dichlorophenyl)-189-190
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base 2-furancarboxylic acid ester
284 2-(3, the 4-dichlorophenyl)-170-173
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base 4-chloro-benzoic acid ester
285 2-(3, the 4-dichlorophenyl)-97-99
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-8-base 3-(methylthio group) propionic acid
Ester
286 3-oxo-2-(4-fluoroform 144-146
The base phenyl)-2,3-dihydro ［ 1 ］
Benzo thiapyran is ［ 4,3-c ］ pyrrole also
Azoles-4-acetate 2-(2-thiophene
Base) ethyl ester
288 4-(2-oxo-3-phenoxy group 205-208
Propyl group)-the 2-(4-trifluoromethyl
Phenyl) ［ 1 ］ benzo thiapyran also 4,
3-c ］ pyrazoles-3(2H)-
Ketone
289 3-oxo-2-(4-fluoroform 134-137
The base phenyl)-2,3-dihydro ［ 1 ］
Benzo thiapyran is ［ 4,3-c ］ pyrrole also
Azoles-4-acetate 2-methoxy ethyl
Ester
290 3-oxo-2-(4-fluoroform 154-156
The base phenyl)-2,3-dihydro ［ 1 ］
Benzo thiapyran is ［ 4,3-c ］ pyrrole also
Azoles-4-acetate 2-morpholino ethyl
Ester
291 4-(3-methoxyl group-2-oxo 148-150
Propyl group)-the 2-(4-trifluoromethyl
Phenyl) ［ 1 ］ benzo thiapyran also 4,
3-c ］ pyrazoles-3(2H)-
Ketone
292 4-［ 2-oxo-3-(2-169-179
Thienyl) propyl group ］-2-(4-
Trifluoromethyl) ［ 1 ］ benzo thiophene
Mutter also ［ 4,3-c ］ pyrazoles-
3(2H)-ketone
293 3-oxo-2-(4-fluoroform 172-175
The base phenyl)-2,3-dihydro ［ 1 ］
Benzo thiapyran is ［ 4,3-c ］ pyrrole also
Azoles-4-acetate tetrahydrochysene-2H-pyrrole
Mutter-4-base ester
294 2-(3, the 4-dichlorophenyl)-123-126
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-6-base propionic ester
295 2-(3, the 4-dichlorophenyl)-113
3a-methyl-3-oxo-2,
3,3a, 4-tetrahydrochysene ［ 1 ］ benzene
And thiapyran ［ 4,3-c ］ pyrazoles also
-6-base acetyl fluoroacetic acid ester
296 2-(4-chloro-phenyl-s)-4-135-138
［ 2-oxo-3-(2-thiophene
Base) propyl group ］ ［ 1 ］ chromene is also
［ 4,3-c ］ pyrazoles-3(2H)
-ketone
297 2-(4-chloro-phenyl-s)-N-encircles 160-162
Propyl group-N-cyclopropyl methyl-3-
Oxo-2,3-dihydro ［ 1 ］ benzene
And pyrans ［ 4,3-c ］ pyrazoles also
-4-acetic ester
298 2-(4-chloro-phenyl-s)-4-166-168
The 4-(2-chloro-phenyl-)-2-
The oxo butyl ］ ［ 1 ］ chromene is also
［ 4,3-c ］ pyrazoles-3(2H)
-ketone
299 2-(4-chloro-phenyl-s)-6-first 164-166
Oxygen base-3-oxo-2,3-two
Hydrogen ［ 1 ］ chromene also 4,
3-c ］ pyrazoles-4-acetate ring fourth
The ylmethyl ester
300 N-benzyl-2-(4-chloro-phenyl-) 197-199
-N-cyclopentyl-3-oxo-2,
3-dihydro ［ 1 ］ chromene also
［ 4,3-c ］ pyrazoles-4-second
Acid amides
301 2-(5-chloro-2-pyridyl) 218-223
-6,8-two fluoro-4-methyl
［ 1 ］ chromene also ［ 4,3-c ］
Pyrazoles-3(2H)-ketone
302 (ethyls) (4-methyl-3-oxygen 146-147
Generation-2-(4-trifluoromethyl)
-2,3-dihydro ［ 1 ］ benzo thiophene
Also ［ 4,3-c ］ pyrazoles-8-mutters
Base) malonic ester

Claims (3)

1, the method for preparation or its pharmacologically acceptable salt,
Figure 91105264X_IMG2
X represents oxygen or sulphur in the formula;
R 1And R 2Represent a key together; R 3And R 4Represent a key together;
When X represents oxygen, Z representative-CH=or-N=;
When X represents sulphur, Z representative-CH=;
R 5Representative
Figure 91105264X_IMG3
-R 6';
R 6Represent hydrogen, halogen, S (O) nY 1, carboxyl, carbamyl, acyl group, esterification carboxyl or CONR 12R 13
R 6' represent hydrogen or methyl;
Perhaps, R 6And R 6' represent cyclopropyl with the carbon atom that they connected;
R 7Represent hydrogen, halogen, trifluoromethyl, C 1-6Alkyl, methoxyl group or S (O) mY 1
R 8Represent hydrogen, halogen or trifluoromethyl;
R 8' represent hydrogen, halogen or trifluoromethyl;
R 9And R 10Can be identical or different, represent halogen; Perhaps R 9Represent hydrogen, and R 10Represent hydrogen, halogen, trifluoromethyl, nitro, C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl or acyloxy;
R 12Represent methylidene, ethyl or C 3-8Cycloalkyl, R 13Representative can be by cyano group, phenyl, 3～8 Yuans non-aromatic heterocycles, 5 or 6 element heterocycle aryl or C 3-8The C that cycloalkyl replaces arbitrarily 1-6Alkyl, perhaps R 13Representative can be by C 2-6The phenyl that carbalkoxy or halogen replace arbitrarily; Perhaps
R 12And R 13Representing with the nitrogen-atoms that they connected can be by C 2-6Acyloxy (C 1-6) 3-8 person's non-aromatic heterocycle of replacing of alkyl;
Y 1Represent C 1-6Alkyl;
N is 0,1 or 2; And m is 0 or 1,
Condition is:
I) represent oxygen as X, during Z representative-CH=, and
A) work as R 6Represent C 1-6During the dialkyl amino formyl radical, R then 10The acyloxy of representative except that acetoxyl group; Perhaps,
B) work as R 6Represent hydrogen, halogen, S (O) nY 1, carbamyl, carboxyl, C 2-6Carbalkoxy, C 2-6During alkanoyl, perhaps work as R 6And R 6' when forming cyclopropyl with the carbon atom that they connected, R then 10Representative removes C 2-6Acyloxy beyond the alkanoyloxy; Perhaps,
C) work as R 1And R 2Form a key, R 3And R 4Form a key, R 6', R 8, R 8', R 9And R 10Each represents hydrogen, R 7When representing chlorine, R then 6Do not represent 4-methoxyl group benzyloxy carbonyl; Perhaps,
II) represents sulphur, R as X 6Represent hydrogen, carboxyl, S (O) nY 1, C 2-6Carbalkoxy, carbamyl or C 1-6During the dialkyl amino formyl radical, R then 10The acyloxy of representative except that acetoxyl group,
Described method
A) comprise R wherein 1Represent hydrogen, R 2And R 3Represent a key, R 4Represent hydrogen and X, Z, R 5, R 7, R 8, R 8', R 9And R 10Formula I compound carries out oxidation as defined above;
B) comprise and make formula X compound or its tautomer and the reaction of formula XI compound,
Figure 91105264X_IMG4
R in the formula 22Representative (OQ) 2, and R 23Represent OQ or NQ ' 2Perhaps R 22Representative (SQ) 2, and R 23Represent SQ or NQ ' 2Perhaps R 22Representative=NH and R 23Represent OQ or SQ; Perhaps R 22Representative=O and R 23Represent leavings group; Q and Q ' represent C 1-4Alkyl or benzyl;
C) R wherein 6When being selected from acyl group, comprise making formula X compound and formula XII a compound or its tautomer or formula XII b compound or its tautomerism precursor reactant,
In the formula, R 16The group that representative can be optionally substituted, this group is selected from C 1-6Alkyl, C 2-6Alkenyl, C 3-10Cycloalkyl, 3-8 person's non-aromatic heterocycle, isocyclic aryl or 5 or 6 element heterocycle aryl, R 24And R 25Can be identical or different, represent C 1-6Alkyl or benzyl;
D) R wherein 6Be selected from CONR 12R 13Or during esterifying carboxyl group, comprise make formula II ' compound respectively with formula NHR 12R 13Amine or formula R 15The alcohol reaction of OH,
Figure 91105264X_IMG6
R in the formula 10' represent R 10, R aRepresent COA, A represents leavings group; Formula R 15Among the OH, R 15The group that representative can be optionally substituted, this group is selected from C 1-6Alkyl, C 2-6Alkenyl, C 3-10Cycloalkyl, 3-8 person's non-aromatic heterocycle, isocyclic aryl or 5 or 6 element heterocycle aryl;
E) R wherein 10When being selected from acyloxy, comprise making formula II ' compound and acylation reaction,
Figure 91105264X_IMG7
R in the formula aRepresent R 6, R 10' representation hydroxy;
F) comprise and make formula X III compound or its tautomer and alkali reaction,
Figure 91105264X_IMG8
R in the formula 26Represent hydrogen, or R 26Represent COR 28Group, wherein R 28The C that represent hydrogen, can be optionally substituted 1-4Alkyl or benzyl, R 27Represent COCHR 6R 6'.
2, the method for preparation or its pharmacologically acceptable salt,
Figure 91105264X_IMG9
X represents oxygen or sulphur in the formula;
R 1Represent hydrogen; R 2And R 3Represent a key together; R 4Represent hydrogen;
When X represents oxygen, Z representative-CH=or-N=;
When X represents sulphur, Z representative-CH=;
R 5Representative
Figure 91105264X_IMG10
;
R 6Represent hydrogen, halogen, S(O) nY 1, carboxyl, carbamyl, acyl group, esterification carboxyl or CONR 12R 13;
R 6' represent hydrogen or methyl;
Perhaps, R 6And R 6' represent cyclopropyl with the carbon atom that they connected;
R 7Represent hydrogen, halogen, trifluoromethyl, C 1-6Alkyl, methoxyl group or S(O) mY 1;
R 8Represent hydrogen, halogen or trifluoromethyl;
R 8' represent hydrogen, halogen or trifluoromethyl;
R 9And R 10Can be identical or different, represent halogen; Perhaps R 9Represent hydrogen, and R 10Represent hydrogen, halogen, trifluoromethyl, nitro, C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl or acyloxy;
R 12Represent methylidene, ethyl or C 3-8Cycloalkyl, R 13Representative can be by cyano group, phenyl, 3～8 Yuans non-aromatic heterocycles, 5 or 6 element heterocycle aryl or C 3-8The C that cycloalkyl replaces arbitrarily 1-6Alkyl, perhaps R 13Representative can be by C 2-6The phenyl that carbalkoxy or halogen replace arbitrarily; Perhaps
R 12And R 13Representing with the nitrogen-atoms that they connected can be by C 2-6Acyloxy (C 1-6) 3-8 person's non-aromatic heterocycle of replacing of alkyl;
Y 1Represent C 1-6Alkyl;
N is 0,1 or 2; And m is 0 or 1,
Condition is:
I) represent oxygen as X, during Z representative-CH=, and
A) work as R 6Represent C 1-6During the dialkyl amino formyl radical, R then 10The acyloxy of representative except that acetoxyl group; Perhaps
B) work as R 6Represent hydrogen, halogen, S(O) nY 1, carbamyl, carboxyl, C 2-6Carbalkoxy, C 2-6During alkanoyl, perhaps work as R 6And R 6' when forming cyclopropyl with the carbon atom that they connected, R then 10Representative removes C 2-6Acyloxy beyond the alkanoyloxy; Perhaps,
II) represents sulphur, R as X 6Represent hydrogen, carboxyl, S(O) nY 1, C 2-6Carbalkoxy, carbamyl or C 1-6During the dialkyl amino formyl radical, R then 10The acyloxy of representative except that acetoxyl group,
Described method
A) comprise R wherein 1And R 2Represent a key, R 3And R 4Represent a key and R 5, R 7, R 8, R 8', R 9And R 10Formula I compound reduces as defined above; Or
B) comprise and make the reaction of formula X IV compound and formula X V compound,
Figure 91105264X_IMG11
R in the formula 3Represent hydrogen, R 5Represent CHR 6R 6', R 29Represent COOR 30Or carbamyl, and R 30Represent C 1-4Alkyl or benzyl,
Figure 91105264X_IMG12
3, the method for preparation or its pharmacologically acceptable salt,
Figure 91105264X_IMG13
X represents sulphur in the formula, R 1And R 2Represent a key, R 3Represent methylidene, R 4And R 5Represent hydrogen;
Z representative-CH=;
R 7Represent hydrogen, halogen, trifluoromethyl, C 1-6Alkyl, methoxyl group or S(O) mY 1;
R 8Represent hydrogen, halogen or trifluoromethyl;
R 8' represent hydrogen, halogen or trifluoromethyl;
R 9And R 10Can be identical or different, represent halogen; Perhaps R 9Represent hydrogen, and R 10Represent hydrogen, halogen, trifluoromethyl, nitro, C 1-6Alkyl, C 1-6Alkoxyl group, hydroxyl or acyloxy;
R 12Represent methylidene, ethyl or C 3-8Cycloalkyl, R 13Representative can be by cyano group, phenyl, 3～8 Yuans non-aromatic heterocycles, 5 or 6 element heterocycle aryl or C 3-8The C that cycloalkyl replaces arbitrarily 1-6Alkyl; Perhaps R 13Representative can be by C 2-6The phenyl that carbalkoxy or halogen replace arbitrarily; Perhaps
R 12And R 13Representing with the nitrogen-atoms that they connected can be by C 2-6Acyloxy (C 1-6) 3-8 person's non-aromatic heterocycle of replacing of alkyl;
Y 1Represent C 1-6Alkyl;
N is 0,1 or 2; And m is 0 or 1,
Condition is R 10The acyloxy of representative except that acetoxyl group,
Described method comprises makes formula X IV compound and the reaction of formula X V compound,
R in the formula 3Represent methylidene, X represents S, R 5Represent hydrogen, R 29Represent COOR 30Or carbamyl, and R 30Represent C 1-4Alkyl or benzyl,
Figure 91105264X_IMG15
Z representative-CH=in the formula.
CN 91105264 1991-08-02 1991-08-02 The method for preparing benzo pyrrole or thiapyran and pyrazoles Pending CN1069272A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100347173C (en) * 2002-11-22 2007-11-07 活跃生物技术股份公司 Pyrazoloquinolines with immunomodulating activity
WO2009012679A1 (en) * 2007-07-25 2009-01-29 Gengliang Yang 2,2,3a,4-TETRAHYDROTHIOCHROMENE[4,3-C]PYRAZOLE COMPOUNDS, PREPARATION METHOD AND USAGE THEREOF
CN102399229A (en) * 2010-09-07 2012-04-04 湖南大学 N-acylpyrazole derritol, preparation method thereof, and application thereof

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100347173C (en) * 2002-11-22 2007-11-07 活跃生物技术股份公司 Pyrazoloquinolines with immunomodulating activity
WO2009012679A1 (en) * 2007-07-25 2009-01-29 Gengliang Yang 2,2,3a,4-TETRAHYDROTHIOCHROMENE[4,3-C]PYRAZOLE COMPOUNDS, PREPARATION METHOD AND USAGE THEREOF
CN102399229A (en) * 2010-09-07 2012-04-04 湖南大学 N-acylpyrazole derritol, preparation method thereof, and application thereof
CN102399229B (en) * 2010-09-07 2013-09-04 湖南大学 N-acylpyrazole derritol, preparation method thereof, and application thereof

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