CN1037346C - Therapeutic agents - Google Patents

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Publication number
CN1037346C
CN1037346C CN90103295A CN90103295A CN1037346C CN 1037346 C CN1037346 C CN 1037346C CN 90103295 A CN90103295 A CN 90103295A CN 90103295 A CN90103295 A CN 90103295A CN 1037346 C CN1037346 C CN 1037346C
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phenyl
methyl
formula
morpholino
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CN1057648A (en
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巴拉苏布拉曼尼安·戈帕兰
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Boots Co PLC
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Boots Co PLC
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Abstract

The present invention relates to a compound of a formula I and a salt thereof, which can be used as a blood sugar reducing agent. In the formula I, n=0 or 1; R1 and R2 are respectively an aliphatic group or cycloalkyl, or NR1R2 is a heterocycle which can be substituted; R3 is alkyl, cycloalkyl or amido which can be substituted; R5 is an aliphatic group; R6 is H or an aliphatic group which can be substituted or cycloalkyl; or R3 and R5 together with bonded nitrogen atoms and carbon atoms form a heterocycle which can be substituted; or R5 and R6 together with bonded nitrogen atoms form a heterocycle which can be substituted; R7 is alkyl which can be substituted, alkoxy, alkylthio, alkyl sulfinyl, alkyl-sulfonyl, alkoxy carbonyl, trifluoromethyl or a cyan group.

Description

The preparation method of hypoglycemic amidine class and guanidine class
The present invention relates to prepare the method for the novel treatment that can be used as the particularly hypoglycemic medicament use of anti-diabetic medicament.
The invention provides compound and pharmacologically acceptable salt thereof with formula I; N=0 or 1 wherein;
R 1And R 2Can be identical or different, for: (a) contain the aliphatic group of 1 to 3 carbon atom, described aliphatic group can be replaced by methoxyl group; (b) contain the cycloalkyl of 3 to 7 carbon atoms; Or (c) R 1And R 2Forming one with the nitrogen-atoms that they connected can substituted formula II heterocycle;
Figure C9010329500112
R wherein 8Represent H or contain the alkyl of 1 to 3 carbon atom; B represents the alkylidene group of 2 to 4 carbon atoms, the middle nitrogen that can be inserted with oxygen, sulphur, sulfinyl or can be contained the alkyl replacement of 1 to 3 carbon atom of this alkylidene group, described alkylidene group can be replaced by one or more alkyl that contain 1 to 3 carbon atom, and perhaps the substituting group on two of this alkylidene group adjacent carbonss forms a phenyl ring; Perhaps B represents the alkenylene of 3 carbon atoms;
R 3For containing the straight or branched alkyl of 1 to 7 carbon atom, or contain the cycloalkyl of 3 to 7 carbon atoms, or the group of formula III;
Figure C9010329500121
R wherein 4And R 4' identical or different, for H or contain the alkyl of 1 to 4 carbon atom;
R 5Be the straight or branched aliphatic group of H or 1 to 4 carbon atom, described aliphatic group can be replaced by methoxyl group;
R 6For: (a) H; (b) the straight or branched aliphatic group of 1 to 6 carbon atom, this group can be replaced by following group, hydroxyl or its acylated derivatives, contain 1 to 3 carbon atom alkoxyl group, contain 1 to 3 carbon atom alkylthio, can be by alkylating amino, contain the carbocylic radical or the cyano group of 3 to 7 carbon atoms; Or its condition of cycloalkyl ring that (c) contains 3 to 7 carbon atoms is to work as NR 1R 2Be dialkyl amido and R 3R when being the group of formula III 4, R 4', R 5Or R 6In at least one be not hydrogen;
Or R 3Group and R 5The heterocycle that group forms formula IV with carbon atom that they connected and nitrogen-atoms; R wherein 6Limit as the front; R 9And R 10Identical or different, be the alkyl of H or 1 to 4 carbon atom that can be replaced by methoxyl group; D is the oxygen ethylidene, Sauerstoffatom wherein with have a R 9And R 10The carbon atom keyed jointing of group, perhaps D is the alkylidene group of 2 to 5 carbon atoms, this alkylidene group can be replaced by the alkyl of one or more 1 to 3 carbon atom;
Or R 6Group and R 5The heterocycle that group forms formula V with carbon atom that they connected and nitrogen-atoms;
Figure C9010329500131
R wherein 6As previously mentioned; R 11For H or contain the alkyl of 1 or 2 carbon atom; E is the alkylidene group of 2 to 4 carbon atoms, and this alkylidene group can be replaced by one or more alkyl that contain 1 to 3 carbon atom;
Perhaps R 5And R 6Form the heterocycle of formula VI with the nitrogen-atoms that they connected;
Figure C9010329500132
Wherein G is the alkylidene group of 4 or 5 carbon atoms, the middle nitrogen that can insert oxygen, sulphur or can be contained the alkyl replacement of 1 to 3 carbon atom of this alkylidene group, and the alkyl that described alkylidene group can one or morely contain 1 to 3 carbon atom replaces;
R 7Represent H or one or more dispensable substituting group, these substituting groups are selected from: halogen, contain 1 to 4 carbon atom and alkyl, the alkoxyl group that contains 1 to 3 carbon atom, the alkylthio that contains 1 to 3 carbon atom, the alkyl sulfinyl that contains 1 to 3 carbon atom that can be replaced by methylthio group, contain the alkane alkylsulfonyl of 1 to 3 carbon atom, contain carbalkoxy, trifluoromethyl or the cyano group of 2 or 3 carbon atoms altogether.
In the preferred formula I compound if n=0, then R 1And R 2Can be identical also can be different, be selected from the alkyl of 1 to 3 carbon atom that (a) replaced by methoxyl group; (b) allyl group; Or (o) cyclohexyl.In particularly preferred formula I compound if n=0, then R 1And R 2Be alkyl, allyl group or 2-methoxy ethyl; Perhaps R 1Be methyl, R 2Be 2-methoxy ethyl or cyclohexyl.In especially preferred formula I compound if n=0, then group NR 1R 2Be dimethylamino, diethylin, diallyl amino, (2-methoxy ethyl) methylamino-, cyclohexyl methylamino-or two (2-methoxy ethyl) amino.
In preferred formula I compound if n=0, group NR 1R 2Be the heterocycle shown in the formula II, then R 3Represent H or methyl, B represents a group that is selected from following groups :-(CH 2) a-,-CHMeCH a-, adjacent phenylene ,-(CH 2) 3-,-CH 2CHMeCH 2-,-(CH 3) 4-,-CH 2OCH 3-,-CHMeOCHMe-,-CH 2SCH 2-,-CH 2S (O) CH 2-,-CH 3NMeCH 2-or-CH=CHCH 2-.In especially preferred formula I compound if n=0, group NR 1R 2Be the group of formula II, then group NR 1R 2Be 1-pyrrolidyl, 2-methyl isophthalic acid-pyrrolidyl, piperidino-(1-position only), 4-methyl piperidine subbase, 1-hexahydroazepine base, morpholino, 2,6-thebaine generation, thia morpholino, thia morpholino-1-oxide compound, 2-iso-dihydro-indole-group, 4-methyl isophthalic acid-piperazinyl or 1-(1,2,5, the 6-tetrahydrochysene) pyridyl.In preferred formula I compound if n=1, then group NR 1R 2Be morpholino or thia morpholino.
In preferred formula I compound if R 3Be alkyl, then this R 3Group contains the alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl, the tertiary butyl or amyl group) of 1 to 5 carbon atom.In preferred formula I compound if R 3Group is a cycloalkyl, and then this cycloalkyl is a cyclohexyl.
In preferred formula I compound if R 3Be the group of formula III, then R 4And R 4' be H, methyl or ethyl (R for example 3Be amino, methylamino-, dimethylamino or ethylamino).
In preferred formula I compound if R 5Group does not constitute a heterocyclic part, then this R 5Group is H or the alkyl that contains 1 to 3 carbon atom (for example methyl or ethyl), and this alkyl can be by methoxyl group (R for example 5Be methoxy ethyl) or the allyl group replacement.
In preferred formula I compound, R 6For H or contain the straight or branched alkyl (for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl or amyl group) of 1 to 5 carbon atom, this alkyl can be replaced by following groups: hydroxyl (R for example 6Be 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxybutyl, 2-hydroxy-2-methyl propyl group or 2,3-dihydroxypropyl), the acylated derivatives of hydroxyl such as acetoxyl group or benzoyloxy (R for example 6Be 2-acetoxyl group ethyl or 2-benzoyloxy ethyl), methoxyl group (R for example 6Be the 2-methoxy ethyl), methylthio group (R for example 6Be 2-methylmercaptoethyl), dimethylamino (R for example 6Be the 2-dimethylaminoethyl), phenyl (R for example 6Be benzyl or 2-phenylethyl) or cyano group (R for example 6Be the 2-cyano ethyl); Perhaps R 6, be the straight or branched thiazolinyl that contains 3 to 6 carbon atoms (R for example 6Be allyl group or 2-methacrylic).
In preferred formula I compound if R 6Be cycloalkyl, then R 6Contain 5 or 6 carbon atoms (R for example 6Be cyclopentyl or cyclohexyl).
In particularly preferred formula I compound, if radicals R 3And R 5Do not constitute a heterocycle with nitrogen-atoms and carbon atom that they connected, then group-N=C (R 3) NR 5R 6For:
The ethanamidine base,
N-methyl ethanamidine base,
N, N-dimethyl ethanamidine base,
N, N-diethyl ethanamidine base,
N-(2-acetoxyl group second) ethanamidine base,
N-butyl ethanamidine base,
N-amyl group ethanamidine base,
N-methyl-prop amidino groups,
N, N-dimethyl propylene amidino groups,
N-ethyl third amidino groups,
The fourth amidino groups,
N-methyl fourth amidino groups,
N, N-dimethyl butyrate amidino groups,
N-ethyl fourth amidino groups,
The isobutyl amidino groups,
N-methyl isobutyl amidino groups,
N, N-dimethyl isobutyl amidino groups,
Penta amidino groups,
N-methylpent amidino groups,
N, N-dimethyl-penten amidino groups,
New penta amidino groups,
New penta amidino groups of N-methyl,
N, new penta amidino groups of N-dimethyl,
The own amidino groups of N-methyl,
N-methylcyclohexane carbonamidine,
Diamino methylene amino,
N-methyl guanidine radicals,
N, N-dimethyl guanidine radicals,
N, '-the dimethyl guanidine radicals,
N-ethyl guanidine radicals,
N-butyl guanidine radicals,
N-ethyl-N-methyl guanidine radicals,
N ,-diethyl guanidine radicals,
N, N '-diethyl guanidine radicals,
N, N ', N '-trimethylammonium guanidine radicals,
1,1,3,3-tetramethyl-guanidine radicals,
N-ethyl-N '-methyl guanidine radicals,
1-ethyl-1,3,3-trimethylammonium guanidine radicals,
1-butyl-1,3,3-trimethylammonium guanidine radicals,
N-methyl-N-propyl group guanidine radicals,
N-butyl-N-methyl guanidine radicals
N-sec-butyl-N '-methyl guanidine radicals,
The N-tertiary butyl-N '-methyl guanidine radicals,
N-isobutyl--N '-methyl guanidine radicals,
N-butyl-N-methyl guanidine radicals,
N-butyl-N '-ethyl guanidine radicals,
N-methyl-N '-amyl group guanidine radicals,
N-cyclopentyl-N '-methyl guanidine radicals,
N-(2-methoxy ethyl) guanidine radicals,
N-(2-methoxy ethyl)-N-methyl guanidine radicals,
N-(2-methoxy ethyl)-N '-methyl guanidine radicals,
N-ethyl-N-(2-methoxy ethyl) guanidine radicals,
N, two (2-methoxy ethyl) guanidine radicals of N-,
N-methyl-N-(2-methylmercaptoethyl) guanidine radicals,
N-allyl group-N-methyl guanidine radicals,
N-allyl group-N '-methyl guanidine radicals,
1-allyl group-1,3,3-trimethylammonium guanidine radicals,
N ,-diallyl guanidine radicals.
In one group of preferred formula I compound, if radicals R 3And R 5With carbon atom and the heterocycle of nitrogen-atoms constitutional formula IV, the then R that they connected 9And R 10Can be identical also can be different, for H or contain the alkyl (for example methyl, ethyl or sec.-propyl) of 1 to 3 carbon atom, this alkyl can be replaced (R for example by methoxyl group 9And/or R 10Be methoxy ethyl); D is selected from-(CH 2) 2-,-(CH 2) 3-,-(CH 2) 4-,-(CH 2) 5-,-CH 2CMe 2-or-O (CH 2) 2-; R 6Group is preferably H, methyl, ethyl, sec.-propyl, cyclohexyl, 2-cyano ethyl, 2-acetoxyl group ethyl or 2-methoxy ethyl.In particularly preferred formula I compound, formula IV representative:
The 2-pyrrolidylidene,
1-methyl-2-pyrrolidylidene,
3-methyl-2-pyrrolidylidene,
1-ethyl-2-pyrrolidylidene,
1-sec.-propyl-2-pyrrolidylidene,
1-cyclohexyl-2-pyrrolidylidene,
1-(2-methoxy ethyl)-2-pyrrolidylidene,
1,3-dimethyl-2-pyrrolidylidene,
5,5-dimethyl-2-pyrrolidylidene,
1,3,3-trimethylammonium-2-pyrrolidylidene,
1,5,5-trimethylammonium-2-pyrrolidylidene,
3-sec.-propyl-1-methyl-2-pyrrolidylidene,
1-ethyl-3,3-dimethyl-2-pyrrolidylidene,
3,3-diethyl-1-methyl-2-pyrrolidylidene,
2-piperidines subunit,
1,3-dimethyl-2-piperidines subunit,
1-ethyl-2-piperidines subunit,
1-sec.-propyl-2-piperidines subunit,
1-(2-cyano ethyl)-2-piperidines subunit,
1-(2-acetoxyl group ethyl)-2-piperidines subunit,
3-(2-methoxy ethyl)-1-methyl-2-piperidines subunit,
2-hexahydroazepine subunit,
1-methyl-2-hexahydroazepine subunit,
2-octahydro azocine subunit or
3-morpholine subunit.
Organize in the preferred formula I compound at another, if radicals R 3And R 5With the heterocycle that carbon atom that they connected and nitrogen-atoms form formula V, then E is-CH 2CH 2-,-CMe 2CH 2-,-CHMeCHMe-,-(CH 2) 2-,-CHMeCH 2-or-(CH 2) 4-, Rn is H, methyl or ethyl, R 6Be H, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, amyl group, allyl group, 2-methacrylic, 2-hydroxyethyl, 2-acetoxyl group ethyl, 2-benzoyloxy ethyl, 2-methoxy ethyl, cyclohexyl, benzyl, styroyl, 3-hydroxypropyl, 2-hydroxypropyl, 2-hydroxy-2-methyl propyl group, 2-hydroxybutyl, 2,3-dihydroxypropyl or 2-dimethylaminoethyl.In particularly preferred formula I compound, formula V representative:
2-imidazolidine subunit,
1-methyl-2-imidazolidine subunit,
4-methyl-2-imidazolidine subunit,
4,4-dimethyl-2-imidazolidine subunit,
4,5-dimethyl-2-imidazolidine subunit,
1-ethyl-2-imidazolidine subunit,
1-propyl group-2-imidazolidine subunit
1-sec.-propyl-2-imidazolidine subunit,
1-normal-butyl-2-imidazolidine subunit,
1-isobutyl--2-imidazolidine subunit,
1-amyl group-2-imidazolidine subunit,
1-allyl group-2-imidazolidine subunit,
1-(2-methacrylic)-2-imidazolidine subunit,
1-(2-hydroxyethyl)-2-imidazolidine subunit,
1-(2-hydroxyethyl)-3-methyl-2-imidazolidine subunit,
1-(2-acetoxyl group ethyl)-2-imidazolidine subunit,
1-(2-benzoyloxy ethyl)-2-imidazolidine subunit,
1-(2-benzoyloxy ethyl)-3-methyl-2-imidazolidine subunit,
4,5-dimethyl-1-(2-hydroxyethyl)-2-imidazolidine subunit,
1-(2-first hydrogen base ethyl)-2-imidazolidine subunit,
1-(2-methoxy ethyl)-3-methyl-2-imidazolidine subunit,
1-cyclohexyl-2-imidazolidine subunit,
1-benzyl-2-imidazolidine subunit,
1-(2-phenylethyl)-2-imidazolidine subunit,
1-(2-dimethylaminoethyl)-2-imidazolidine subunit,
1-(3-hydroxypropyl)-2-imidazolidine subunit,
1-(2 monohydroxy propyl group)-2-imidazolidine subunit,
1-(2-hydroxy-2-methyl propyl group)-2-imidazolidine subunit,
1-(2-hydroxybutyl)-2-imidazolidine subunit,
1-(2, the 3-dihydroxypropyl)-2-imidazolidine subunit,
1,3-dimethyl-2-imidazolidine subunit,
1,3-diethyl-2-imidazolidine subunit,
1-ethyl-3-methyl-2-imidazolidine subunit,
1-butyl-3-methyl-2-imidazolidine subunit,
1-sec.-propyl-4,4-dimethyl-2-imidazolidine subunit,
1-methyl-2-perhydro pyrimidine subunit or
1,3-Diazesuberane-2-subunit.
In preferred formula I compound, if R 5And R 6Form the heterocycle of formula VI with the nitrogen-atoms that they connected, then the group of G representative is selected from-(CH 2) 4-,-(CH 2) 5-,-(CH 2) 2O (CH 2) 2-,-(CH 2) 2S (CH 2) 2-,-(CH 2) 2NMe (CH 2) 2-,-(CH 2) 2CHMe (CH a) 2-or-CH 2CHM eOCHM eCH 2-.In particularly preferred compound, group NR 5R 6Be 1-pyrrolidyl, piperidino-(1-position only), 4-methyl piperidine subbase, morpholino, 2,6-thebaine generation, thia morpholino or-4-methyl isophthalic acid-piperazinyl.In particularly preferred formula I compound, if R 5And R 6Form the heterocycle of formula VI, then group-N=C (R with the nitrogen-atoms that they connected 2) NR 5R 6For:
N, N-(3-oxa-pentamethylene) guanidine radicals,
1,1-dimethyl-3,3-(3-oxa-pentamethylene) guanidine radicals,
N, N-(2,4-dimethyl-3-oxa-pentamethylene) guanidine radicals,
N, N-(3-thia pentamethylene) guanidine radicals,
N, N-(3-methyl pentamethylene) guanidine radicals,
N ,-(N-methyl-3-azepine pentamethylene) guanidine radicals,
N-methyl-N ', N '-tetramethylene guanidine,
N, N-pentamethylene guanidine radicals,
1,1-dimethyl-3,3-pentamethylene guanidine radicals.
In preferred formula I compound, R 7Represent H or one or more substituting groups (preferred 1 or 2 substituting groups), these substituting groups are selected from fluorine, chlorine, methyl, ethyl, isobutyl-, methylthiomethyl, methoxyl group, methoxycarbonyl, methylthio group, methanesulfinyl, methylsulfonyl, trifluoromethyl or cyano group.
Concrete formula I compound is following compounds and pharmacologically acceptable salt thereof
4-(2-(2-piperidines subunit amino) phenyl) morpholine
4-(2-(1-methyl-2-piperidines subunit amino) phenyl) morpholine
4-(2-(1-ethyl-2-piperidines subunit amino) phenyl) morpholine
4-(2-(1-sec.-propyl-2-piperidines subunit amino) phenyl) morpholine
4-(2-(2-hexahydroazepine subunit amino) phenyl) morpholine
4-(2-(1-methyl-2-hexahydroazepine subunit amino) phenyl) morpholine
4-(2-(2-octahydro azocine subunit amino) phenyl) morpholine
4-(2-(2-pyrrolidylidene amino) phenyl) morpholine
4-(2-(1-methyl-2-pyrrolidylidene amino) phenyl) morpholine
4-(2-(1,3-dimethyl-2-pyrrolidylidene amino) phenyl) morpholine
4-(2-(1,3,3-trimethylammonium-2-pyrrolidylidene amino) phenyl) morpholine
4-(2-(1-ethyl-2-pyrrolidylidene amino) phenyl) morpholine
4-(2-(1-(2-methoxy ethyl)-2-pyrrolidylidene amino) phenyl)
Quinoline
4-(2-(1-cyclohexyl-2-pyrrolidylidene amino) phenyl) morpholine
4-(2-(3,3-dimethyl-1-ethyl-2-pyrrolidylidene amino) phenyl)
Quinoline
4-(2-(3,3-diethyl-1-methyl-2-pyrrolidylidene amino) phenyl)
Quinoline
4-(2-(3-sec.-propyl-1-methyl-2-pyrrolidylidene amino) phenyl) morpholine
4-(2-(1,3-dimethyl-2-piperidines subunit amino) phenyl) morpholine
4-(3-methyl-2-(2-piperidines subunit amino) phenyl) morpholine
4-(3-methyl-2-(1-methyl-2-piperidines subunit amino) phenyl) morpholine
4-(4-methyl-2-(2-piperidines subunit amino) phenyl) morpholine
4-(4-methyl-2-(1-methyl-2-piperidines subunit amino) phenyl) morpholine
4-(5-methyl-2-(2-piperidines subunit amino) phenyl) morpholine
4-(6-methyl-2-(2-piperidines subunit amino) phenyl) morpholine
4-(4-ethyl-2-(2-piperidines subunit amino) phenyl) morpholine
4-(3-chloro-2-(2-piperidines subunit amino) phenyl) morpholine
4-(4-chloro-2-(2-piperidines subunit chloro) phenyl) morpholine
4-(4-chloro-2-(1-methyl-2-piperidines subunit amino) phenyl) morpholine
4-(5-chloro-2-(2-piperidines subunit amino) phenyl) morpholine
4-(6-chloro-2-(2-piperidines subunit amino) phenyl) morpholine
4-(4-fluoro-2-(2-piperidines subunit amino) phenyl) morpholine
4-(4-fluoro-2-(1-methyl-2-piperidines subunit amino) phenyl) morpholine
4-(4-methoxyl group-2-(2-piperidines subunit amino) phenyl) morpholine
4-(4-methoxycarbonyl-2-(2-piperidines subunit amino) phenyl) morpholine
4-(4-methylsulfonyl-2-(2-piperidines subunit amino) phenyl) morpholine
4-(2-(1-(2-acetoxyl group ethyl)-2-piperidines subunit amino) phenyl)
Quinoline
4-(2-(1-methyl-3-(2-methoxy ethyl)-2-piperidines subunit amino) benzene
Base) morpholine
4-(2-(3-methyl-2-pyrrolidylidene amino) phenyl) morpholine
N-methyl-N '-(2-morpholino phenyl) ethanamidine
N-(2-morpholino phenyl)-N '-propyl group ethanamidine
N-normal-butyl-N '-(2-morpholino phenyl) ethanamidine
N-n-pentyl-N '-(2-morpholino phenyl) ethanamidine
N-(2-acetoxyl group ethyl)-N '-(2-morpholino phenyl) ethanamidine
N, N-dimethyl-N '-(2-morpholino phenyl) ethanamidine
N, N-diethyl-N '-(2-morpholino phenyl) ethanamidine
N-methyl-N '-(2-morpholino phenyl) third amidine
N-ethyl-N '-(2-morpholino phenyl) third amidine
N, N-dimethyl-N '-(2-morpholino phenyl) third amidine
N-methyl-N '-(2-morpholino phenyl) fourth amidine
N-ethyl-N '-(2-morpholino phenyl) fourth amidine
N, N-dimethyl-N '-(2-morpholino phenyl) fourth amidine
N-methyl-N '-(2-morpholino phenyl)-2-methyl-prop amidine
N, N-dimethyl-N '-(2-morpholino phenyl)-2-methyl-prop amidine
N-methyl-N '-(2-morpholino phenyl) penta amidine
N, N-dimethyl-N '-(2-morpholino phenyl) penta amidine
N-methyl-N '-(2-morpholino phenyl) new penta amidine
N, N-dimethyl-N '-(2-morpholino phenyl) new penta amidine
N-methyl-N '-(2-morpholino phenyl) own amidine
N-methyl-N '-(2-(1-pyrrolidyl) phenyl) fourth amidine
N-methyl-N '-(2-(1-pyrrolidyl) phenyl) new penta amidine
N-methyl-N '-(2-morpholino phenyl) hexanaphthene carbonamidine
N-methyl-N '-(2-piperidino-(1-position only) phenyl) new penta amidine
1-(2-(2-piperidines subunit amino) phenyl) tetramethyleneimine
1-(2-(1-methyl-2-piperidines subunit amino) phenyl) tetramethyleneimine
1-(2-(1-ethyl-2-piperidines subunit amino) phenyl) tetramethyleneimine
1-(4-chloro-2-(1-methyl-2-piperidines subunit amino) phenyl) tetramethyleneimine
1-(3-methyl-(1-methyl-2-piperidines subunit amino) phenyl) tetramethyleneimine
1-(2-(1-methyl-2-pyrrolidylidene amino) phenyl) tetramethyleneimine
1-(2-(1,3-dimethyl-2-pyrrolidylidene amino) phenyl) tetramethyleneimine
1-(2-(1-methyl-2-hexahydroazepine subunit amino) phenyl) tetramethyleneimine
1-(4-methyl-2-(2-piperidines subunit amino) phenyl) tetramethyleneimine
1-(4-chloro-2-(2-piperidines subunit amino) phenyl) tetramethyleneimine
1-(3-methyl-2-(2-piperidines subunit amino) phenyl) tetramethyleneimine
1-(6-methyl-2-(2-piperidines subunit amino) phenyl) tetramethyleneimine
4-(2-(2-piperidines subunit amino) phenyl) thia morpholine
1-(2-(2-piperidines subunit amino) phenyl) piperidines
1-(2-(1-methyl-2-piperidines subunit amino) phenyl) piperidines
1-(2-(2-piperidines subunit amino) phenyl) hexahydroazepine
2,6-dimethyl-4-(2-(2-piperidines subunit amino) phenyl) morpholine
4-methyl isophthalic acid-(2-(2-piperidines subunit amino) phenyl) piperidines
1-(2-(2-piperidines subunit amino) phenyl)-1,2,5, the 6-tetrahydropyridine
2-methyl isophthalic acid-(2-(2-piperidines subunit amino) phenyl) tetramethyleneimine
2-(2-(2-piperidines subunit amino) phenyl) isoindoline
4-(2-(1-methyl-2-piperidines subunit amino) phenyl) thia morpholine
4-(4-methyl-2-(2-piperidines subunit amino) phenyl) thia morpholine
N-(2-methoxy ethyl)-N-(2-(2-piperidines subunit amino) phenyl) methylamine
N-(2-(2-piperidines subunit amino) phenyl) dimethylamine
N-(2-(2-piperidines subunit amino) phenyl) diallyl amine
N-cyclohexyl-N-(2-(2-piperidines subunit amino) phenyl) methylamine
N-(2-(2-piperidines subunit aminophenyl)-two (2-methoxy ethyl) amine
4-(2-(1,3,3-trimethylammonium-2-pyrrolidylidene amino) phenyl) thia
Quinoline
1-(2-(1,3,3-trimethylammonium-2-pyrrolidylidene) phenyl) piperidines
1-(2-(1,3,3-trimethylammonium-2-pyrrolidylidene) phenyl)-4-methyl piperazine
Piperazine
1-(2-(1,3,3-trimethylammonium-2-pyrrolidylidene) phenyl) tetramethyleneimine
4-(4-methyl-2-(1,3,3-trimethylammonium-2-pyrrolidylidene amino) phenyl)
Morpholine
1-(2-(1-methyl-2-pyrrolidylidene amino) phenyl) piperidines
1-(2-(1,3-dimethyl-2-pyrrolidylidene amino) phenyl) piperidines
4-(2-(5,5-dimethyl-2-pyrrolidylidene amino) phenyl) morpholine
4-(1,5,5-trimethylammonium-2-pyrrolidylidene amino) phenyl) morpholine
Two (the 2-of N-(2-(1,3,3-trimethylammonium-2-pyrrolidylidene amino) phenyl)
Methoxy ethyl) amine
N-(2-morpholino phenyl) ethanamidine
N-(5-methyl-2-morpholino phenyl) ethanamidine
N-(2-morpholino phenyl) third amidine
N-(2-morpholino phenyl) fourth amidine
N-(2-morpholino phenyl) NSC 18620
N-(5-methylthio group-2-morpholino phenyl) NSC 18620
N-(5-fluoro-2-morpholino phenyl) NSC 18620
N-(2-morpholino phenyl) penta amidine
New penta amidine of N-(2-morpholino phenyl)
4-(2-(1-(cyanoethyl)-2-piperidines subunit amino) phenyl) morpholine
4-(2-(3-morpholine subunit amino) phenyl) morpholine
4-(2-(2-piperidines subunit amino) benzyl) morpholine
4-(2-(1-methyl-2-pyrrolidylidene amino) benzyl) morpholine
4-(4-chloro-2-(2-piperidines subunit amino) benzyl) morpholine
4-(2-(1,3,3-trimethylammonium-2-pyrrolidylidene amino) benzyl) morpholine
N-methyl-N '-(2-morpholino aminomethyl phenyl) new penta amidine
4-(2-(1,3-dimethyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1,3-dimethyl-2-imidazolidine subunit amino)-4-fluorophenyl) morpholine
4-(2-(1,3-dimethyl-2-imidazolidine subunit amino)-3-aminomethyl phenyl)
Quinoline
4-(2-(1,3-dimethyl-2-imidazolidine subunit amino)-4-aminomethyl phenyl)
Quinoline
4-(2-(1,3-dimethyl-2-imidazolidine subunit amino)-5-aminomethyl phenyl)
Quinoline
4-(4-chloro-2-(1,3-dimethyl-2-imidazolidine subunit amino) phenyl)
Quinoline
4-(2-(1,3-dimethyl-2-imidazolidine subunit amino)-4-p-methoxy-phenyl)
Morpholine
4-(4,5-dimethoxy-2-(1,3-dimethyl-2-imidazolidine subunit amino)
Phenyl) morpholine
1-(2-(1,3-dimethyl-2-imidazolidine subunit amino) phenyl) tetramethyleneimine
1-(2-(1,3-dimethyl-2-imidazolidine subunit amino)-3-aminomethyl phenyl) pyrrole
Cough up alkane
1-(2-(1,3-dimethyl-2-imidazolidine subunit amino) phenyl) piperidines
4-(2-(1,3-dimethyl-2-imidazolidine subunit amino) phenyl) thia morpholine
2,6-dimethyl-4-(2-(1,3-dimethyl-2-imidazolidine subunit amino) benzene
Base) morpholine
N-(2-(1,3-dimethyl-2-imidazolidine subunit amino) phenyl) diethylamine
1-(2-(1,3-dimethyl-2-imidazolidine subunit amino) phenyl)-2-methyl pyrrole
Cough up alkane
4-(3-chloro-2-(1,3-dimethyl-2-imidazolidine subunit amino) phenyl) morpholine
1-(2-(1,3-dimethyl-2-imidazolidine subunit amino)-4-aminomethyl phenyl) pyrrole
Cough up alkane
N-(2-(1,3-dimethyl-2-imidazolidine subunit amino) phenyl)-two (2-
Methoxy ethyl) amine
4-(2-(1,3-diethyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1,3-dimethyl-2-imidazolidine subunit amino)-6-aminomethyl phenyl) pyrrole
Cough up alkane
4-(2-(1-ethyl-3-methyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-normal-butyl-3-methyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-(2-benzoyloxy ethyl)-3-methyl-2-imidazolidine subunit ammonia
Base) morpholine phenyl)
2-(2-morpholino phenyl)-1,1,3, the 3-tetramethyl guanidine
1-ethyl-2-(2-morpholino phenyl)-1,3,3-trimethylammonium guanidine
1-allyl group-2-(2-morpholino phenyl)-1,3,3-trimethylammonium guanidine
1-normal-butyl-2-(2-morpholino phenyl)-1,3,3-trimethylammonium guanidine
1-amyl group-2-(2-morpholino phenyl)-1,3,3-trimethylammonium guanidine
4-(2-(1-methyl-3-(2-methoxy ethyl)-2-imidazolidine subunit amino)
Phenyl) morpholine
4-(2-(1-methyl-3-(2-hydroxyethyl)-2-imidazolidine subunit amino) benzene
Base) morpholine
N, N-dimethyl-N '-(2-morpholino phenyl) morpholine-4-carbonamidine
N, N-dimethyl-N '-(2-morpholino phenyl) piperidines-1-carbonamidine
4-(2-(1,3-dimethyl-2-imidazolidine subunit amino) phenyl) thia morpholine-
The 1-oxide compound
4-(2-(2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-methyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-ethyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-n-propyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-sec.-propyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-normal-butyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-isobutyl--2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-amyl group-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-allyl group-2-imidazolidine subunit amino) phenyl)-4-(2-(1-
(2-hydroxyethyl)-2-imidazolidine subunit amino) morpholine phenyl)
4-(2-(1-(2-hydroxyethyl)-2-imidazolidine subunit amino)-3-methylbenzene
Base) morpholine
4-(2-(1-(2-methoxy ethyl)-2-imidazolidine subunit amino) phenyl)
Quinoline
4-(2-(1-cyclohexyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-benzyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-(2-phenylethyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-(2-dimethylaminoethyl)-2-imidazolidine subunit amino) phenyl)
Morpholine
4-(2-(1-(2, the 3-dihydroxypropyl)-2-imidazolidine subunit amino) phenyl)
Morpholine
4-(2-(1-(2-methacrylic)-2-imidazolidine subunit amino) phenyl)
Quinoline
Two (the 2-methoxyl group second of N-(2-(1-methyl 1-imidazolidine subunit amino) phenyl)
Base) amine
N-(2-(1-(2-hydroxyethyl)-2-imidazolidine subunit amino) phenyl) is two
(2-methoxy ethyl) amine
4-(2-(1-methyl-2-imidazolidine subunit amino) phenyl) thia morpholine
1-(2-(1-methyl-2-imidazolidine subunit amino) phenyl) tetramethyleneimine
4-(2-(1-normal-butyl-2-imidazolidine subunit amino) phenyl) thia morpholine
4-(2-(1-methyl-2-imidazolidine subunit amino)-3-aminomethyl phenyl) morpholine
4-(2-(1-methyl-2-imidazolidine subunit amino)-4-aminomethyl phenyl) morpholine
1-(2-(1-(2-hydroxyethyl)-2-imidazolidine subunit amino) phenyl) pyrroles
Alkane
1-(2-(1-(2-hydroxyethyl)-2-imidazolidine subunit amino) phenyl)-2-
Crassitude
4-(4-methyl-2-(1-normal-butyl-2-imidazolidine subunit) phenyl) morpholine
1-(2-(2-imidazolidine subunit amino) phenyl) piperidines
1-(2-(1-methyl-2-imidazolidine subunit amino) phenyl) piperidines
1-(2-(1-methyl-2-imidazolidine subunit amino)-3-aminomethyl phenyl) piperidines
4-(2-(1-(2-hydroxyethyl)-2-imidazolidine subunit amino) phenyl) thia
Morpholine
1-(2-(1-(2-hydroxyethyl)-2-imidazolidine subunit amino) phenyl) piperidines
4-(2-(1-(3-hydroxypropyl)-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-(2-hydroxypropyl)-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-(2-hydroxybutyl)-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(1-(2-hydroxy-2-methyl propyl group)-2-imidazolidine subunit amino) benzene
Base) morpholine
4-(2-(4-methyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(4,5-dimethyl-2-imidazolidine subunit amino) phenyl) morpholine
4-(2-(4,5-dimethyl-1-(2-hydroxyethyl)-2-imidazolidine subunit amino)
Phenyl) morpholine
4-(2-(1-sec.-propyl-4,4-dimethyl-2-imidazolidine subunit amino) phenyl)
Morpholine
4-(2-(1-methyl perhydro pyrimidine-2-subunit amino) phenyl) morpholine
2-(2-morpholino phenylimino)-1, the 3-Diazesuberane
1,1-dimethyl-2-(2-morpholino phenyl) guanidine
1,3-dimethyl-2-(2-morpholino phenyl) guanidine
1,3,3-trimethylammonium-2-(2-morpholino phenyl) guanidine
1-ethyl-2-(2-morpholino phenyl)-3-methylguanidine
1,3-diethyl-2-(2-morpholino phenyl) guanidine
4-(2-(1-(2-acetoxyl group ethyl)-2-imidazolidine subunit amino) phenyl)
Morpholine
4-(2-(1-(2-benzoyloxy ethyl)-2-imidazolidine subunit amino) phenyl)
Morpholine
1-normal-butyl-2-(2-morpholino phenyl)-3-methylguanidine
1-(2-methoxy ethyl)-2-(2-piperidino-(1-position only) phenyl) guanidine
1-(2-methylmercaptoethyl)-2-(2-morpholino phenyl) guanidine
1-(2-methoxy ethyl)-2-(2-morpholino phenyl) guanidine
1-n-propyl-2-(2-morpholino phenyl)-3-methylguanidine
1-(2-methoxy ethyl)-3-methyl-2-(2-morpholino phenyl) guanidine
1-cyclopentyl-2-(2-morpholino phenyl)-3-methylguanidine
N-methyl-N '-(2-morpholino phenyl) tetramethyleneimine-1-carbonamidine
1-normal-butyl-2-(2-morpholino phenyl)-3-ethyl guanidine
1,3-dimethyl-2-(5-chloro-2-morpholino phenyl) guanidine
1-allyl group-2-(2-(1-pyrrolidyl) phenyl)-3-methylguanidine
1,3-dimethyl-2-(5-methyl-2-morpholino phenyl) guanidine
4-(2-(1-(2-hydroxyethyl)-2-imidazolidine subunit amino)-4-aminomethyl phenyl)
Morpholine
1-methyl-2-(2-morpholino phenyl)-3-n-pentyl guanidine
1-normal-butyl-2-(5-methyl-2-morpholino phenyl)-3-methylguanidine
1-normal-butyl-2-(6-methyl-2-morpholino phenyl)-3-methylguanidine
1-normal-butyl-2-(5-fluoro-2-morpholino phenyl)-3-methylguanidine
1-normal-butyl-2-(5-methylthio group-2-morpholino phenyl)-3-methylguanidine
1-isobutyl--2-(2-morpholino phenyl)-3-methylguanidine
1-sec-butyl-2-(2-morpholino phenyl)-3-methylguanidine
The 1-tertiary butyl-2-(2-morpholino phenyl)-3-methylguanidine
1-allyl group-2-(2-morpholino phenyl)-3-methylguanidine
1-normal-butyl-2-(2-thia morpholino phenyl)-3-methylguanidine
1,1-dimethyl-2-(2-morpholino-5-trifluoromethyl) guanidine
1,1-dimethyl-2-(5-cyano group-2-morpholino phenyl) guanidine
1,3-di-2-(2-morpholino phenyl) guanidine
2-(2-morpholino phenyl) guanidine
1,1-dimethyl-2-(5-methyl-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(6-methyl-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(4-chloro-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(3-chloro-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(5-methoxyl group-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(5-methylthio group-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(4-methyl-2-morpholino phenyl) guanidine
1,1 dimethyl-2-(5-ethyl-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(5-methylthiomethyl-2-morpholino phenyl) guanidine
1,1-diethyl-2-(2-morpholino phenyl) guanidine
1-normal-butyl-1-methyl-2-(2-morpholino phenyl) guanidine
1, two (2-methoxy ethyl)-2-(the 2-morpholino phenyl) guanidines of 1-
N-(2-morpholino phenyl) morpholine-4-carbonamidine
N-(2-morpholino phenyl) tetramethyleneimine-1-carbonamidine
1,1-dimethyl-2-(2-piperidino-(1-position only) phenyl) guanidine
1,1-dimethyl-2-(2-(1-pyrrolidyl) phenyl) guanidine
1,1-dimethyl-2-(2-thia morpholino phenyl) guanidine
1,1-dimethyl-2-(2-dimethylamino phenyl) guanidine
1,1-dimethyl-2-(2-(N-(2-methoxy ethyl)-N-methylamino) benzene
Base) guanidine
1,1-dimethyl-2-(2-(4-methyl isophthalic acid-piperazinyl) phenyl) guanidine
N-(2-piperidino-(1-position only) phenyl) morpholine-4-carbonamidine
N-(2-piperidino-(1-position only) phenyl) piperidines-1-carbonamidine
1,1-dimethyl-2-(5-methoxycarbonyl-2-morpholino phenyl) guanidine
1-methyl-2-(2-morpholino phenyl) guanidine
1-ethyl-2-(2-morpholino phenyl) guanidine
1-butyl-2-(2-morpholino phenyl) guanidine
1-ethyl-1-methyl-2-(2-morpholino phenyl) guanidine
1-methyl isophthalic acid-(2-methylmercaptoethyl)-2-(2-morpholino phenyl) guanidine
1-(2-methoxy ethyl)-1-methyl-2-(2-morpholino phenyl) guanidine
1-allyl group-1-methyl-2-(2-morpholino phenyl) guanidine
1-ethyl-1-(2-methoxy ethyl)-2-(2-morpholino phenyl) guanidine
1,1-diallyl-2-(2-morpholino phenyl) guanidine
N-(2-morpholino phenyl)-4-methylpiperazine-1-carbonamidine
N-(2-morpholino phenyl)-2,6-thebaine-4-carbonamidine
N-(2-morpholino phenyl) thia morpholine-4-carbonamidine
N-(2-morpholino phenyl)-4-methyl piperidine-1-carbonamidine
N-(2-morpholino phenyl) thia morpholine-1-carbonamidine
1,1-dimethyl-2-(5-chloro-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(5-fluoro-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(3-methyl-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(4-methoxyl group-2-morpholino phenyl) guanidine
1 ,-dimethyl-2-(5-isobutyl--2-morpholino phenyl) guanidine
1,1-dimethyl-2-(5-methanesulfinyl-2-morpholino phenyl) guanidine
4-(2-(1,3-dimethyl-2-imidazolidine subunit amino) benzyl) morpholine
4-(4-chloro-2-(1,3-dimethyl-2-imidazolidine subunit amino) benzyl)
Quinoline
N, N-dimethyl-N '-(2-morpholino aminomethyl phenyl) guanidine
N-(2-morpholino aminomethyl phenyl) morpholine-4-carbonamidine
One group of preferred formula I compound comprises some formula I compounds like this, n=0 wherein ,-NR 1R 2Be morpholino, thia morpholino, piperidino-(1-position only) or 1-pyrrolidyl, R 3For-NH 2, R 5Be the aliphatic group (as methyl, ethyl or allyl group) that contains 1 to 4 carbon atom, R 6Be the aliphatic group (as methyl, ethyl, allyl group, methoxy ethyl or methylmercaptoethyl) of 1 to 4 carbon atom that can be replaced by methoxyl group or methylthio group, perhaps R 5And R 6Form the heterocycle (as morpholino or thia morpholino) of formula VI, R with the nitrogen-atoms that they connected 7Be H, fluorine, chlorine, methyl, ethyl, methylthiomethyl or methylthio group.
Particular compound in this group compound comprises following compounds and pharmacologically acceptable salt thereof:
1,1-dimethyl-2-(2-morpholino phenyl) guanidine
1,1-dimethyl-2-(5-fluoro-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(5-chloro-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(5-methyl-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(6-methyl-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(5-ethyl-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(5-methylthiomethyl-2-morpholino phenyl) guanidine
1,1-dimethyl-2-(5-methylthio group-2-morpholino phenyl) guanidine
1-ethyl-1-methyl-2-(2-morpholino phenyl) guanidine
1,1-diethyl-2-(2-morpholino phenyl) guanidine
1-(2-methoxy ethyl)-1-methyl-2-(2-morpholino phenyl) guanidine
1-methyl isophthalic acid-(2-methylmercaptoethyl)-2-(2-morpholino phenyl) guanidine
1,1-dimethyl-2-(2-thia morpholino phenyl) guanidine
1,1-dimethyl-2-(2-piperidino-(1-position only) phenyl) guanidine
1,1-dimethyl-2-(2-(1-pyrrolidyl) phenyl) guanidine
N-(2-morpholino phenyl) morpholine-4-carbonamidine
N-(2-morpholino phenyl) thia morpholine-4-carbonamidine
Another is organized preferred formula I compound and comprises some formula I compound, wherein n=0 like this;-NR 1R 2Be morpholino or thia morpholino; R 3Be the group of formula III, wherein R 4For containing the alkyl (as methyl) of 1 to 4 carbon atom, R 4' be H; R 5Be H; R 6Be the aliphatic group that contains 1 to 4 carbon atom (as methyl, butyl or the tertiary butyl) and can be replaced by methoxyl group (R for example 6Be methoxy ethyl); R 7Be H, fluorine, methyl, methylthio group or methylthiomethyl.
Particular compound in this group preferred compound comprises following compounds and pharmacologically acceptable salt thereof:
1-butyl-3-methyl-2-(2-morpholino phenyl) guanidine
1-methyl-3-the tertiary butyl-2-(2-morpholino phenyl) guanidine
1-methyl-3-the tertiary butyl-2-(4-fluoro-2-morpholino phenyl) guanidine
1-methyl-3-the tertiary butyl-2-(4-methyl-2-morpholino phenyl) guanidine
1-methyl-3-the tertiary butyl-2-(4-methylthio group-2-morpholino phenyl) guanidine
1-methyl-3-the tertiary butyl-2-(4-methylthiomethyl-2-morpholino phenyl) guanidine
1-(2-methoxy ethyl)-3-methyl-2-(2-morpholino phenyl) guanidine
1,3-dimethyl-2-(2-thia morpholino phenyl) guanidine
1-methyl-3-the tertiary butyl-2-(2-thia morpholino phenyl) guanidine
Comprise some formula I compounds so again in one group of preferred formula I compound, n=0 wherein ,-NR 1R 2Be morpholino, thia morpholino, morpholino methyl or thia morpholino methyl, R 3Be the alkyl (as the methyl and the tertiary butyl) of 1 to 4 carbon atom, R 5And R 6Be H, R 7Be H, fluorine, methyl, methylthio group or methylthiomethyl.
Particular compound in this group preferred compound comprises following compounds and pharmacologically acceptable salt thereof:
N-(2-morpholino phenyl) ethanamidine
N-(4-fluoro-2-morpholino phenyl) ethanamidine
N-(4-methyl-2-morpholino phenyl) ethanamidine
N-(4-methylthio group-2-morpholino phenyl) ethanamidine
N-(4-methylthiomethyl-2-morpholino phenyl) ethanamidine
N-(2-thia morpholino phenyl) ethanamidine
N-(2-morpholino aminomethyl phenyl) ethanamidine
New penta amidine of N-(2-morpholino phenyl)
New penta amidine of N-(2-morpholino aminomethyl phenyl)
Formula I compound can exist with the salt of pharmaceutically useful acid formation.The example of this class salt comprises hydrochloride, hydrobromate, hydriodate, vitriol, nitrate, maleate, acetate, Citrate trianion, fumarate, tartrate, succinate, benzoate, Pamoates and the salt that forms with acidic amino acid such as L-glutamic acid.Formula I compound and salt thereof can exist with the form of solvate (for example hydrate).
Some formula I compound has one or more unsymmetrical carbons, thereby exists with different optical activity forms.If contain a chiral centre in the formula I compound, these compounds then exist with two kinds of enantiomeric forms, the present invention includes these two kinds of enantiomeric forms and composition thereof.If contain in the formula I compound more than a chiral centre, these compounds then can exist with diastereomeric form.The present invention includes wherein each diastereomeric form 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.
In treatment was used, active compound can be taken orally, rectal administration, parenteral are cheated medicine or topical, preferably oral administration.Therefore, pharmaceutical composition of the present invention can take can be for oral administration, rectal administration, administered parenterally or topical oneself know any formulation of pharmaceutical composition.The pharmaceutically acceptable diluent or the carrier that are applicable to this based composition are that the present technique field is known.Can be mixed with tablet with the known mode of this area professional, thereby reach the lasting release of The compounds of this invention.If desired, can use currently known methods, for example utilize the rhodia phthalic ester, add enteric coating for these tablets.Equally, can prepare the capsule (as soft or glutoid wafer) that contains active compound and be added with or be not added with vehicle, can add enteric coating in a known manner if desired with ordinary method.Tablet and capsule can respectively contain 50 to 500 milligrams of active compounds easily.Other composition for oral administration comprises, for example contains the aqueous solution of active compound, closes active compound and have the aqeous suspension of nontoxic suspension agent (as Xylo-Mucine) and the oily suspensions that contains The compounds of this invention in suitable vegetables oil (as peanut oil) in aqueous medium
Using very in some preparation, granular (as grind the particle that obtains with fluid energy mill) The compounds of this invention of small grain size may be useful.
If desired, the active compound in the present composition can be united with other composition compatible, that pharmacologically active is arranged
The pharmaceutical composition that contains treatment significant quantity formula I compound can be used to treat human hyperglycemia.In this treatment, the amount of the formula I compound that gives every day is in 50 to 3000mg scope.Preferred route of administration is an oral administration.
The preparation method of present narrative I compound.These methods constitute another aspect of the present invention
Formula I compound can prepare with the following method: in the presence of a kind of condensing agent such as phosphoryl chloride, thionyl chloride, carbonyl chloride, phosphorus pentachloride or benzene sulfonyl chloride, make aminophenyl compound and the formula R of formula VII 2.CO.NR 5R 6Uride reaction.
Figure C9010329500391
In the formula I compound, if R 3And R 5Group forms the ring shown in the formula IV with carbon atom and the nitrogen-atoms that they connected, then available following method preparation:
A) the aminophenyl compound of formula VII and the lactone of formula VIII are reacted in the presence of condensing agent: Described condensing agent for example has phosphoryl chloride, thionyl chloride, cyanuryl chloride, carbonyl chloride, tetrachloro carbon/triphenyl phosphine, phosphorus pentachloride or benzene sulfonyl chloride.
B) the aminophenyl compound of formula VII and the compound of formula IX are reacted:
Figure C9010329500402
R wherein 12For chlorine ,-O-POCl 2,-O-SOCl ,-OCOCl or-OSO 2Ph, B -Be that a negatively charged ion such as halogen ion are (as Cl -) or POCl 4 -
C) the aminophenyl compound of formula VII and formula X compound are reacted:
Figure C9010329500411
R wherein 13Be alkyl, B -Be a negatively charged ion such as fluoroboric acid root or methyl-sulfuric acid root.
D) work as R 6During for H, the aminophenyl compound of formula VII and the ketoxime of formula XI are reacted in the presence of SULPHURYL CHLORIDE (as benzene sulfonyl chloride).
In the formula I compound if R 3And R 5Group forms the ring shown in the formula V with carbon atom and the nitrogen-atoms that they connected, then available following method preparation: in the presence of a kind of condensing agent such as phosphoryl chloride, thionyl chloride, carbonyl chloride, phosphorus pentachloride or benzene sulfonyl chloride, make the urea reaction of aminophenyl compound and the formula XII of formula VII:
In the formula I compound if R 3And R 5Group forms the ring shown in the formula V with carbon atom and the nitrogen-atoms that they connected, and then available following method preparation: the compound that makes formula XIII also can be the form of salt (as hydriodate) and the diamine reactant of formula XIV.
Figure C9010329500421
R wherein 14And R 15Be H,
R 11NHENHR 6 XIV
In the formula I compound if R 3Be the cycloalkyl of straight or branched alkyl or 3 to 7 carbon atoms of 1 to 7 carbon atom, group NR 5R 6Be NH 2, then available following method preparation: make the formula VII compound and the formula R that can be salt (example hydrochloric acid salt) form 2The cyano compound reaction of CN, this reaction can be carried out in the presence of aluminum chloride.
In the formula I compound if R 3Group is NH 2, then available following method system is put forth energy: make the formula VII compound and the formula R that can be salt (example hydrochloric acid salt) form 5R 6The cyanamide compound reaction of NCN.This reaction can be carried out in liquid reaction medium (as meta-cresol), also can be undertaken by reactant is heated together under the situation of liquid vehicle not having.
R in the formula I compound 3Group is NH 2, then available following method preparation: make formula XV compound and formula NHR 5R 6Amine reaction, this reaction can be carried out in liquid reaction medium (as ethanol).
In the formula I compound if R 2Be the group of formula III, and R in this group 4Be alkyl, R 4' be R or alkyl, then available following method preparation: make R 14Be R 4Group, R 15Be R 4The formula VIII compound of ' group and formula NHR 5R 6Amine reaction.This reaction can be carried out in alcoholic medium (as ethanol or propyl carbinol), also can carry out in the presence of alkali such as pyridine or triethylamine, also can carry out in the presence of potassium hydroxide and lead acetate.If NHR 5R 6Be ammonia, then this ammonia can be dissolved in the alcoholic medium, and this reaction can under high pressure be carried out in sealed reaction vessel.
In the formula I compound if R 3Be the group of formula III, and R in this group 4Be alkyl, R 4' be H or alkyl, then available following method preparation: the thiocarbamide and the formula HNR that make formula XVI 5R 6Amine reaction.
Figure C9010329500432
R wherein 14Be R 4Group, R 15Be R 4' group.This reaction can be carried out in the presence of alkali (as potassium hydroxide or salt of wormwood) and lead acetate.If HNR 5R 6Be ammonia, then this ammonia can be dissolved in the alcoholic medium (as ethanol), and this reaction can be carried out under high pressure in closed reaction vessel.
In the formula I compound if R 3Be R in the group of formula III and this group 4Be alkyl, R 4' be H, R 5Be H, then can be by carbodiimide and the formula H that makes formula XVII 2NR 6Amine react and prepare.
Figure C9010329500441
In the formula I compound if n=0, NR 1R 2Be morpholino, thia morpholino, 1-pyrrolidyl or piperidino-(1-position only), then available following method system is put forth energy: make the two substitution compounds reaction of compound and the formula XIX of formula XVIII.
Figure C9010329500442
K (CH 2) 2L (CH 2) 2K XIX wherein K is a leavings group such as halogen (as bromine or chlorine) or mesyloxy, L is-O-,-S-, directly key or-CH 2-.
In the formula I compound if R 3Be R in the group of formula III and this group 4Be propyl group, R 4' be H, R 5Be H, R 6Be propyl group, then available following method preparation: in the presence of potassium hydroxide and aluminum acetate, make formula H 2NR 6(R in the base 6Be propyl group) amine and formula XVI (R wherein 14And R 15Be methyl) thiocarbamide reaction.In this reaction, amino-NHR 6Thiocarbonyl group and dimethylamino have been replaced simultaneously.
In the formula I compound if R 3Be formula III group, R 4Be methyl, R 4' be H, R 5Be H, R 6Be methyl, then can be by making formula H 2NR 6(R wherein 6Be methyl) amine and formula XIII compound (group NR wherein 14R 15Be fourth amino) reaction prepare.In this reaction, amino-NHR 6Methylthio group and amino-NR have been replaced simultaneously 14R 15
In the formula I compound if NR 1R 2Be thia morpholino-1-oxide groups, then can pass through-NR 1R 2For the oxidation (for example using sodium metaperiodate) of the formula I compound of thia morpholino prepares.
In the formula I compound if R 6Replaced by acyloxy, then can pass through R 6The acidylate (as acetylize or benzoylation) of the corresponding formula I compound that is replaced by hydroxyl prepares.
R 7For the formula I compound of alkyl sulfinyl can pass through R 7For the oxidation (for example using sodium metaperiodate) of the formula I compound of alkylthio prepares.
But the also original preparation of nitro in the formula III compound through type XX compound:
Figure C9010329500451
For example use (a) hydrogen and Raney nickel catalyst; (b) hydrogen and palladium/carbon catalyst; (c) sodium sulphite; (d) stannous chloride dihydrate in hydrochloric acid, ethyl acetate or the ethanol; Or (e) iron of acid under existing arranged.
In the formula IX compound if R 12Be formula OPOCl 2, OSOCl, OCOCl and OSO 2The group of Ph then can prepare by formula VIII compound and phosphoryl chloride, thionyl chloride, carbonyl chloride or benzene sulfonyl chloride are reacted respectively.
Formula X compound can prepare in order to the below method: make formula VIII compound and react such as sulfuric acid dialkyl, three alcoxyl fluoroborates or boron trifluoride diethyl etherate compound/alkylating agents such as two diazoalkanes, alkalize with yellow soda ash or sodium hydroxide solution then.
Formula XIII compound can react by the thiocarbamide that makes methyl-iodide and formula XVI and prepare
Formula XV compound can prepare by potassium hydroxide and formula XIII compound are reacted in the presence of lead acetate.R in the formula XIII compound 14And R 15Be hydrogen, perhaps R 14Be benzoyl R 15Be H.
Formula XV compound can prepare with the following method: in the presence of alkali (as yellow soda ash) and copper catalyst (as the mixture of cuprous chloride or cupric chloride), make the thiocarbamide (R wherein of formula XVI 14And R 15Be H) react with Textone.
R in the thiocarbamide of formula XVI 14And R 15Be H, then can react and prepare by the lsothiocyanates of ammonia and formula XXI.
In the formula XVI compound if R 14Be alkyl, R 15Be H, then can be by aminophenyl and the formula R that makes formula VII 14The alkylisothiocyanate of NCS reacts and prepares.
The carbodiimide of formula XVII can be by making formula XVI thiocarbamide (R wherein 14Be R 4Group, R 15Be H) react and prepare with Textone.
Formula XVIII compound can prepare by the also original of through type XXII compound, for example utilizes hydrogen and Raney nickel to reduce.
Figure C9010329500471
In the formula XX compound if n=0, NR 1R 2Be morpholino, thia morpholino, 1-pyrrolidyl or piperidino-(1-position only), then can prepare by 2-N-methyl-p-nitroaniline and formula XIX compound are reacted.In the formula XX compound if n=0 ,-NR 1R 2Be morpholino, thia morpholino, 1-pyrrolidyl, piperidino-(1-position only), 1-hexahydroazepine base or 4-methyl isophthalic acid-piperazinyl, then can prepare with the following method: do not having solvent or having under the condition that exists such as benzene, ethanol or acetonitrile equal solvent, dividing to make morpholine, thia morpholine, tetramethyleneimine, piperidines, 1-hexahydroazepine and 4-methyl isophthalic acid-piperazine and halogenated nitrobenzene (as 2-fluoronitrobenzene or 2-chloronitrobenzene) reaction in addition.
Formula XXI compound can be put forth energy by making formula VII compound and sulfo-carbonyl chloride react to make in liquid reaction medium such as diox.
Formula XXII compound can be by making formula R 3.CO.NR 5R 6Acid amides or urea and 2-N-methyl-p-nitroaniline in the presence of condensing agent (as phosphoryl chloride or thionyl chloride), react and prepare.Formula XXII compound can be by making formula R 3.CNH.NR 5R 6Amidine or the reaction of guanidine and 2-halogenated nitrobenzene (as 2-fluoronitrobenzene or 2-chloronitrobenzene) prepare.
The hypoglycemic activity of the formula I compound that provides in following each example is confirmed by following test.Get the rat of heavy 150 to 200 grams, fasting 18 hours, subcutaneous injection glucose (800mg/4ml/kg), the compound that will test with the oral dosage administration (Xmg/kg in 4ml or 5ml 0.2% agar) then then.After 2 hours and 4 hours, by eye socket bloodletting blood sampling, and with specificity glucose oxidase method (Kadish A.H., Little R.L.and Sternberg J.C., Clin. Chem.14:116,1968) on the Beckman glucose analyser, estimate plasma glucose.Calculate the control animal that gives 0.2% agar homogenate with not giving testing compound then and compare, the per-cent that plasma glucose descends.In this test,, then be considered to have hypoglycemic activity when any one X value of height to 200 if compound after 2 hours and 4 hours or in one of these two times, all makes plasma glucose descend 15% or more.
Investigate in the above-mentioned test result who when any X value, obtains then, the hypoglycemic activity of each compound is classified by following yardstick.If the result more than the cover is arranged when specific X value, then adopts the mean value of decline per-cent to come the activity of compound is classified.
A all descends more than 25% when 2 hours and 4 hours.
B descended more than 25% in the time of 2 hours, but descended below 25% in the time of 4 hours.
C is decline 15-25% in the time of 2 hours, but descends more than 25% in the time of 4 hours.
The D 15-25% that when 2 hours and 4 hours, all descends.
E is decline 15-25% in the time of 2 hours, but descends below 15% in the time of 4 hours.
F descended below 15% in the time of 2 hours, but descended more than 15% in the time of 4 hours.
Following Table A provides the activity of the compound of narrating in each example that will provide in the back.
Table A example * active example * activity 1 25 A 2 25 B 3 25 B 4 25 B 5 25 A 6 25 E 7 25 B 8 36 B 9 200 E 10 25 B 11 25 A 12 25 A 13 50 D 14 200 A 15 100 E 16 25 D 17 50 B 18 25 E 19 40 A 20 25 A 21 25 C 22 25 B 23 50 A 24 25 B 25 25 D 26 25 B 27 25 A 28 25 A 29 25 E 30 25 D 31 50 D 32 25 D
A （ ） x x 33 25 B 34 25 B 35 25 D 36 200 F 37 200 E 38 200 D 39 200 A 40 200 A 41 200 A 42 36 D 43 25 B 44 200 A 45 200 D 46 36 B 47 37 B 48 200 A 49 38 E 50 36 A 51 200 D 52 36 B 53 36 B 54 37 B 55 36 A 56 35 A 57 25 A 58 25 B 59 35 A 60 37 E 61 36 D 62 25 C 63 100 A 64 25 B 65 25 A 66 36 D 67 200 A 68 25 C 69 43 D 70 36 A 71 36 A 72 25 B 73 25 A 74 25 A 75 50 F 76 25 D 77 25 E 78 25 F 79 200 A 80 25 D 81 200 D 82 50 E 83 25 A 84 25 E 85 25 D 86 25 F 87 200 D 88 200 F。
Active 89 200 C, 90 25 E91 of the active example x of Table A (continuing) example x 200 A 92 25 B93 25 C 94 200 C95 25 E 96 25 F97 50 D 98 50 A99 25 A 100 25 B101 25 B 102 200 A103 25 B 104 27 A105 37 E 106 37 E107 25 B 108 25 B109 25 B 110 36 B111 25 B 112 36 B113 25 D 114 25 E115 25 D 116 25 B117 25 B 118 25 A119 25 D 120 25 B121 25 E 122 25 A123 38 B 124 37 B125 36 B 126 200 A127 25 E 128 25 A129 25 B 130 100 B131 50 B 132 200 A133 25 B 134 25 A135 25 A 136 25 B137 25 B 138 25 B139 25 B 140 100 A141 25 E 142 25 A
Active 143 25 B, 144 25 B145 of the active example x of Table A (continuing) example x 25 C 146 200 A147 36 D 148 25 D149 36 D 150 68 F151 25 C 152 25 D153 25 B 154 39 D155 133 B 156 25 D157 25 A 158 25 A159 50 D 160 26 D161 34 A 162 35 B163 25 B 164 25 D165 200 B 166 25 D167 25 B 168 25 B169 25 A 170 25 A171 25 D 172 25 D173 25 D 174 25 B175 25 B 176 35 C177 25 B 178 200 A179 25 D 180 25 E181 43 D 182 25 D183 25 D 184 34 F185 200 D 186 25 A187 25 A 188 25 B189 25 A 190 25 A191 36 D 192 25 B193 25 A 194 200 C195 12.5 A 196 25 A
A （ ） x x 197 25 D 198 25 A 199 25 B 200 25 A 201 25 E 202 25 B 203 100 A 204 200 A 205 200 A 206 200 C 207 50 A 208 30 D 209 25 B 210 30 D 211 36 A 212 25 F 213 50 D 214 25 E 215 25 E 216 35 A 217 30 E 218 200 D 219 200 D 220 36 A 221 200 A 222 35 A 223 35 D 224 35 C 225 25 B 226 200 A 227 25 F 228 35 A 229 35 A 230 35 C 231 35 F 232 25 B 233 25 B 234 25 B 235 34 A 236 38 C 237 35 A 238 35 A 239 35 A 240 36 A 241 34 A 242 200 A 243 200 B 244 200 E 245 25 B 246 200 D 247 37 A 248 36 A 249 36 B 250 25 E 251 35 E 252 200 A 253 35 A 254 36 B。
A （ ） x x 255 36 A 256 34 B257 36 A 258 35 E259 34 D 260 35 B261 36 C 262 37 B263 38 B 264 36 B265 200 E 266 200 E267 200 E 268 35 B269 35 B 270 25 B271 25 B 272 25 B273 200 C 274 128 D275 25 E 276 36 B277 34 B 278 35 B279 25 B 280 35 B281 35 A 282 200 C283 200 E 284 200 E285 200 B 286 35 B287 36 B 288 38 E289 200 A 290 25 D291 25 B 292 85 C293 35 A 294 25 B295 25 B 296 25 D297 35 B 298 35 E299 34 E 300 200 A301 25 B 302 38 A303 39 B 304 40 B305 28 A 306 29 A307 30 B 308 NT309 100 D 310 200 D311 200 E 312 200 E。
NT=does not survey
The present invention will illustrate that cheating out these examples only is for example by following example.The final product of each example all carries out qualitative evaluation by ultimate analysis.
Example 1
The solution of δ-Wu Neizhi (24g) in dry-out benzene (100ml) put be cooled to 10 ℃ in the frozen water, and under nitrogen, handled 10-15 minute with the phosphoryl chloride that newly steams (22.2ml).The white solid of Xing Chenging is with becoming yellow transparent oily matter in 3 hours at first.Add the solution of 4-(2-aminophenyl) morpholine (36g) in dry-out benzene (150ml), this mixture was heated 32 hours with stirring down in 65 ℃.Inclining the benzene layer, and (2 * 40ml), adding ether (100ml) will under agitation be handled to alkaline pH with 10% aqueous sodium hydroxide solution with ice-cooled mixture with the benzene washed twice with this oily matter.(2 * 100ml) extractions merge ether extraction liquid and water and salt water washing water layer, and are dry then with ether.This solution is filtered and removes and desolvate, obtain a kind of thickness oily matter, it solidifies when adding the hexane development.Should rough solids with hot hexane crystallization, obtain 4-(2-(2-piperidines subunit amino) phenyl) morpholine (m.p.89-90 ℃).
Example 2
The solution of example 1 product (10.2g) in anhydrous methanol (30ml) is handled with fumaric acid (4.6g).Leach the solid that obtains and use methanol crystallization, obtain 4-(2-(2-piperidines subunit amino) phenyl) morpholine fumarate, be colourless crystallization solid (m.p.210 ℃ (decomposition)).
Example 3-37
To prepare compound listed in the Table I with above-mentioned example 1 similar mode, method is as follows: under 60-70 ℃, in the presence of phosphoryl chloride (Eml), make wherein NR 2R 2Amino-benzene subcompound (A gram in Bml benzene) and formula VIII compound (C gram in Dml benzene) reaction F hour for the formula VII of morpholino.
The note of Table I (1) is used the hexane recrystallized product.(2) on alumina column, product is carried out chromatography purification, usefulness methylene dichloride and hexane
Mixture was made eluent in 1: 1.(3) product is separated with its hydriodate, with 1: 1 mixture of methyl alcohol and ether
Carry out recrystallization.(4) at room temperature carry out linked reaction.(5) product ether recrystallization.(6) formula VIII compound is dissolved in the mixture of benzene (60ml) and acetonitrile (40ml).(7) on alumina column, product is carried out chromatography purification, uses following eluent successively:
1: 9 mixture, methylene dichloride and the hexane of hexane, methylene dichloride and hexane
1: 1 mixture, the methylene dichloride of 3: 7 mixtures, methylene dichloride and hexanes.(8) product is separated with its single fumarate, and mixes with methyl alcohol and ether 1: 1
The compound recrystallization.(9) product is separated with its single hydriodate, and mixes with methyl alcohol and ether 2: 3
The compound recrystallization.(10) linked reaction was carried out under room temperature 24 hours, carried out under 70 ℃ 8 hours.(11) product is separated with its fumarate, and carries out recrystallization with propan-2-ol.(12) product is separated with its sesqui fumarate, and with methyl alcohol and ether
1: 1 mixture carry out recrystallization.(13) formula VIII compound is dissolved in the acetonitrile (120ml).(14) on alumina column, product is carried out chromatography purification, usefulness methylene dichloride and methyl alcohol
Mixture was made eluent in 99: 1.With product with glycol dimethyl ether and hexane
1: 1 mixture recrystallization.
Table I
Figure C9010329500571
Example A B C D E F m R 7R 9R 10R 6mp （ ℃ ） 3 17.8 75 16.4 100 13.3 6 3 H H H Me 130 （ 1 ） 4 5.3 20 5.7 40 4.1 4 3 H H H Et 92-93 （ 1 ） 5 5.4 25 6.3 50 4.1 2 3 H H H i-Pr 104-105 （ 1 ） 6 5 25 4 25 3.3 40 4 H H H H 96-98 （ 1 ） （ 2 ） 7 5.4 30 7.5 50 5.5 6 4 H H H Me 79-80 （ 1 ） 8 10 25 12.7 50 9 6 5 H H H H 231-232 （ 3 ） 9 3.6 10 2 20 2.4 6 2 H H H H 143 （ 1 ） 10 10.7 60 7.2 120 7.2 8 2 H H H Me 89-90 （ 1 ） 11 3.6 10 2.8 20 2.4 6 2 H Me H Me 105-107 （ 1 ） （ 4 ）。
Table I (continuing) example A B C D E F m R 7R 9R 10R 6Mp (℃) note 12 3.6 10 3.2 30 2.4 14 2 H Me Me Me 72-75 (1) 13 4.5 10 3.5 25 352 H H H Et 94-96 (1) 14 3.6 25 4.3 50 2.7 52 H H H CH 2CH 2OMe 140-142 ( 7 ) ( 9 ) 15 7.1 80 10 40 5.5 8 2 H H H 110-112 ( 1 ) 16 3.5 10 3.4 30 2.4 5 2 H Me Me Et 72-74 ( 1 ) 17 3.6 30 3.8 15 2.4 2 H Et Et Me 190 ( 10 ) ( 11 ) 18 3.4 15 3.3 25 2.4 12 2 H i-Pr H Me 70 ( 1 ) 19 2.5 30 1.9 60 1.4 10 3 H Me H Me 184 ( 12 ) 20 6.8 30 8 50 7.3 5.5 3 3-Me H H H 167-168 ( 1 ) 21 3.1 25 2.7 25 2.2 4 3 3-Me H H Me 110-111 ( 1 ) 22 6.8 30 8 50 7.3 4.5 3 4-Me H H H 114 ( 1 ) 23 3.8 25 2.7 25 2.2 4 3 4-Me H H Me 108-109 ( 1 ) 24 6 30 6.3 50 5.8 10 3 5-Me H H H 119 ( 1 ) 25 2.5 10 3 20 2.7 10 3 6-Me H H H 98 ( 1 ) 26 4.1 20 4 30 3.7 5 3 4-Et H H H 204-205 ( 7 ) ( 8 )
Table I (continuing) example A B C D E F m R 7R 9R 10R 6mp （ ℃ ） 27 3 10 3 20 2.7 5 3 3-Cl H H H 166-167 （ 5 ） 28 5 40 5.25 30 3.4 8 3 4-Cl H H H 109-110 （ 1 ） 29 4.2 25 2.7 25 2.2 4 3 4-Cl H H Me 108-109 （ 1 ） 30 6.3 25 6 50 5.5 4.5 3 5-Cl H H H 140-141 （ 1 ） 31 6.3 20 6 40 5.8 4 3 6-Cl H H H 115-116 （ 1 ） 32 5 50 6 30 5.6 5 3 4-F H H H 82-83 （ 1 ） 33 3.7 25 2.7 25 2.2 4 3 4-F H H Me 110-111 （ 1 ） 34 3.1 20 3 30 2.7 5 3 4-OMe H H H 103-104 （ 1 ） 35 4.6 4 40 3.6 4 3 4-COOMe H H H 112-114 （ 1 ） （ 6 ） 36 5.1 8 60 2.2 3 3 4-SO。2Me H H H 151-152 (13) (14) 37 6.3 30 6.8 40 3.4 73 H H H CH 2CH 2OAc 66-67 (1)
Example 38
With with example 1 and 2 described similar modes, make 1-methyl-3-(2-methoxy ethyl)-2-piperidone (2.56g) and the reaction of 4-(2-aminophenyl) the morpholine quinoline (2.49g) in the benzene (30ml) in the benzene (30ml), react on 70 ℃ and in the presence of phosphoryl chloride (1.37ml), carried out 12 hours.Gains are 4-(2-(1-methyl-3-(2-methoxy ethyl)-2-piperidines subunit amino) phenyl) morpholine sesqui fumarate (m.p.174 ℃), with 1: 1 mixture recrystallization of methyl alcohol and ether.
Example 39
With with the described similar mode of example, make 1-benzyl-3-N-methyl-2-2-pyrrolidone N-(14.17g) and the reaction of 4-(2-aminophenyl) morpholine (8.9g) in the benzene (30ml) in the benzene (80ml), reacting on 70 ℃ carried out 24 hours in the presence of phosphoryl chloride (6.86ml), obtain 4-(2-(1-benzyl-3-methyl-2-pyrrolidylidene amino) phenyl) morpholine (m.p.96-97 ℃), use the hexane recrystallization.
Product behind the recrystallization of a last paragragh (2g) with tetrahydrobenzene (6ml), 10%Pd/C (1.5g) and methyl alcohol (100ml) reflux 4 hours, is obtained buttery 4-(2-(3-methyl-2-pyrrolidylidene amino) phenyl) morpholine.This oily matter (1g) is dissolved in the methyl alcohol (20ml), add the solution of fumaric acid (0.47g) in methyl alcohol, obtain m.p.185 ℃ of 4-(2-(3-methyl-2-pyrrolidylidene amino) phenyl) morpholine fumarate), with 1: 1 mixture recrystallization of methyl alcohol and ether.
Example 40-62
To prepare the listed compound of Table II with example 1 described similar mode, method is as follows: under 60-70 ℃ temperature, in the presence of phosphoryl chloride (Eml), make the aminophenyl compound (A gram in Bml benzene) and formula R of formula VII 3.CO.NR 5R 6Acid amides (in Dml benzene C gram) reaction F hour.
The note of Table II
Note (1) and (8) have the given meaning of Table I.
(15) product is separated with its single fumarate, and uses recrystallizing methanol.
(16) under 80 ℃, carry out linked reaction.
(17) under 75 ℃, carry out linked reaction.
(18) product that obtains with monohydrate.
(19) product is with twice in positive fourth pentane recrystallization.
(20) products therefrom is an oily matter, does not survey its boiling point.This oily matter is on alumina column
Carry out chromatography purification, use following eluent successively: hexane, methylene dichloride and
1: 1 mixture of hexane, methylene dichloride.
(seeing 52 pages, 53 page tables)
Example 63
The mixture of N-methyl pivalyl amine (11.5g) in benzene (120ml) and phosphoryl chloride (9.2ml) at room temperature stirred 3 days.Add the solution of 1-(2-aminophenyl) piperidines (14g) in benzene (80ml), and this mixture was heated 4 days down at 65-70 ℃, obtain N-methyl-N '-(2-piperidino-(1-position only) phenyl) new penta amidine (m.p.78 ℃), use the hexane recrystallization.Products therefrom is 0.25 hydrate.
Example 64-75
To prepare the listed compound of Table III with example 1 described similar mode, method is as follows: under 60-70 ℃ temperature, in the presence of phosphoryl chloride (Eml), make wherein NR 1R 2Aminophenyl compound (A gram in Bml benzene) and formula VIII compound (C gram in Dml benzene) reaction F hour for the formula VII of 1-pyrrolidyl.
Table II
Figure C9010329500621
Example A B C D E F NR 1R 2R 3R 5R 6R 7Mp (℃) note 40 7.1 30 7.3 50 9.1 6 morpholino Me H Me H 132-133 (1) 41 6.3 35 4 25 3.5 10 morpholino Me H Pr H 78-79 (1) 42 7.2 35 5.1 25 49 morpholino Me H n-Bu H 178-179 (15) 43 7.2 35 5.7 25 49 morpholino Me H n-C5H 11H 163-164 (15) 44 10.8 40 10 50 6.3 18 morpholino Me H (CH 2) 2OAc H 185-186, (15) 45 3.5 20 2.5 20 2.3 8 morpholino Me Me Me H 68-70, (1) 46 3.5 20 3 20 2.3 4.0 morpholino Me Et Et H 166-168, (8) 47 8.9 30 6.5 70 6.9 12 morpholino Et H Me H 70, (8) 48 5.3 30 4 20 3.7 5 morpholino Et H Et H 105-107, (1), (16)
Table II (continuing) example A B C D E F NR 1R 2R 3R 5R 6R 7mp （ ℃ ） 49 8.9 30 7.6 70 6.9 12 Et Me Me H 170 （ 8 ） （ 17 ） （ 18 ） 50 8.9 30 7.6 75 6.9 45 Pr H Me H 180 （ 8 ） 51 5.3 30 4.5 20 3.7 3 Pr H Et H 75-77 （ 16 ） （ 19 ） 52 8.9 30 8.6 75 6.9 45 Pr Me Me H 135-137 （ 8 ） 53 8.9 30 7.6 70 6.9 12 i-Pr H Me H 220 （ 8 ） （ 17 ） 54 8.9 30 8.6 70 6.9 12 i-Pr Me Me H 156-160 （ 8 ） （ 17 ） 55 7.2 30 5.1 35 4 16 Bu H Me H 168-169 （ 17 ） 56 8.9 30 10.7 80 6.9 12 Bu Me Me H 121-122 （ 8 ） 57 5.3 30 5.2 40 4.1 8 -CMe。3H Me H 128-129 (1) 58 5 20 5.5 20 4 14 morpholinoes-CMe 3Me Me H (20) 59 8.9 50 9.7 100 6.9 10 morpholino amyl group H Me H 134-135 (8) 60 8.1 50 7 80 6.4 8 1-pyrrolidyl Pr H Me H 135-137 (8) 61 3.7 20 3.9 30 3.1 8 1-pyrrolidyl-CMe 3H Me H 193-194 (8) 62 5 30 4.3 25 2.6 9 morpholino cyclohexyl H Me H 93-94 (1)
The note of Table III
Note (1), (4) and (8) have the given meaning of Table I.
(21) product is separated with its single fumarate, uses mix in 1: 2 of methyl alcohol and ether
The compound recrystallization.
(22) product is separated with its single fumarate, uses mix in 1: 3 of methyl alcohol and ether
The compound recrystallization.
(seeing 55 pages, 56 page tables)
Example 76-91
To prepare the listed compound of Table IV with example 1 described similar mode, method is as follows: under 60-70 ℃ temperature, in the presence of phosphoryl chloride (Eml), make the aminophenyl compound (A gram in Bml benzene) and 2-piperidone (C gram in Dml benzene) reaction F hour of formula VII.
The note of Table IV
Note (1), (8) (11)) and (21) have Table I and the given meaning of Table III.
(23) under 75-80 ℃, carry out linked reaction.
(24) product is separated with its single fumarate, and uses recrystallizing methanol.
(25) product 1: 2 mixture recrystallization of glycol dimethyl ether and hexane.
(26) product is used the hexane recrystallization earlier, uses the mixture of glycol dimethyl ether and hexane again
Recrystallization.
(27) product carries out chromatography purification on alumina column, usefulness methylene dichloride and methyl alcohol
Mixture was made eluent in 49: 1.Product is separated with its hydriodate,
1: 1 mixture recrystallization with ethanol and ether.
(28) under 90-100 ℃, carry out linked reaction.
Table III
Figure C9010329500651
Example A B C D E F m R 7R 9R 10R 6mp （ ℃ ） 64 3.2 20 3 20 2.8 6 3 H H H H 82-84 （ 1 ） 65 3 25 2.7 25 2.2 5 3 H H H Me 99-101 （ 1 ） 66 4.9 20 5.7 30 4.1 7 3 H H H Et 143-144 （ 21 ） 67 4 25 2.7 25 2.2 6 3 4-Cl H H Me 77-78 （ 1 ） 68 3.5 25 4 25 3.3 14 3 3-Me H H Me 92-93 （ 1 ） 69 4 25 3 25 2.7 8 2 H H H Me 157-158 （ 8 ） 70 4.8 25 4 30 3.3 8 2 H Me H Me 152-154 （ 22 ） 71 4.8 20 5.7 30 4.1 8 4 H H H Me 159-160 （ 21 ） 72 8.8 90 10 60 9.2 8 3 4-Me H H H 112-113 （ 1 ）。
Table III (continuing) example A B C D E F m R 7R 9R 10R 6Mp (℃) note 73 1.8 30 2 20 1.8 24 3 4-Cl H H H 138-139 (1) 74 8.8 60 10 60 9.2 53 3-Me H H H 113-115 (1) 75 4 30 4.5 30 4.2 14 3 6-Me H H H 83-85 (1) (4)
Table IV
Figure C9010329500671
Example A B C D E F NR 1R 2R 7R 6Mp (℃) note 76 3.5 10 2.4 20 2.4 5 thia morpholino H H 215-217 (8) 77 14 40 16 120 15.2 12 piperidino H H 70-72 (1) 78 3.4 25 2.7 25 2.2 8 piperidino H Me 87-89 (1) (23) 79 2.8 25 3 30 2.7 5 1-hexahydroazepine base H H 152-153 (18) 80 5 25 5 50 47 42,6-dimethyl H H 132-135 (1)
Morpholino 81 7.6 40 8 60 7.3 7 4-methyl piperidine subbase H H 145-146 (24) 82 5 25 6 50 5.5 7 1-(1,2,5,6-H H 62 (1)
Tetrahydrochysene) pyridyl
Table IV (continuing) example A B C D E F NR 1R 2R 7R 6Mp (℃) note 83 5.3 15 6 30 6 24 2-methyl isophthalic acid-H H 71 (1)
Pyrrolidyl 84 2.8 40 3 20 2.7 4 2-iso-dihydro-indole-group H H 124-125, (25) 85 3.7 25 2.6 25 2.2 6 thia morpholino H Me 124-125, (1) 86 4.2 60 4 40 3.6 5 thia morpholino 4-Me H 150-151, (26) 87 7.2 30 8 40 7.3 7 N, (Me) CH 2CH 2OMe H H 135-136 (27) 88 5.4 30 8 40 7.3 5 NMe 2H H 175-176 (8) 89 4.2 20 4.6 40 4.3 4 N (allyl group) 2H H 62-63 (1) 90 6.1 25 4.5 50 4.2 14 N (Me) cyclohexyl H H 183-185 (11) (28) 91 4.2 25 2.7 25 2.2 8 N (CH 2CH 2OMe) 2H Me 129-130 (21)
Example 92-101
To put forth energy the listed compound of Table V with example 1 described similar mode system, method is as follows: under 60-70 ℃ temperature, in the presence of phosphoryl chloride (Eml), make the aminophenyl compound (A gram in Bml benzene) and a kind of methyl substituted 2-Pyrrolidone (C gram in Dml benzene) reaction F hour of formula VII.
The note of Table V
Note (1) and (4) have the given meaning of Table I.
(29) product is separated with its two hydriodate, and with methyl alcohol and ether 1: 1
The mixture recrystallization.
(30) linked reaction was at room temperature carried out F hour.
(31) product branches away with its two hydriodate, and mixes with ethanol and ether 1: 3
The compound recrystallization.
(seeing 60 page tables)
Example 102
The mixture of 4-(2-aminophenyl) morpholine (5.34g), acetonitrile (4.52ml) and Aluminum chloride anhydrous (12g) in 160-170 ℃ of heating 4 hours, is obtained N-(2-morpholino phenyl) ethanamidine (m.p.140-141 ℃), use the hexane recrystallization.
Example 103
The mixture of 4-(2-amino-4-aminomethyl phenyl) morpholine (5.76g), acetonitrile (3.5g) and Aluminum chloride anhydrous (12g) in 160-170 ℃ of heating 5 hours, is obtained N-(5-methyl-2-morpholino phenyl) ethanamidine (m.p.121 ℃), use the hexane recrystallization.
Example 104
The mixture of 4-(2-aminophenyl) morpholine (5.34g), propionitrile (4.7g) and Aluminum chloride anhydrous (12g) in 160-170 ℃ of heating 6 hours, is obtained N-(2-
Table V Example A B C D E F NR 1R 2A G R 6R 7Mp (℃) note 92 2.5 20 2 20 1.5 4 thia morpholino CMe 2CH 2Me H 120-122 (1) 93 3.6 20 3.2 20 2.4 17 piperidino-(1-position only) CMe 2CH 2Me H 62-63 (1) 94 4.7 10 3.9 30 36 4-methyl isophthalic acid-CMe 2CH 2Me H 280 (29)
Piperazinyl 95 4.8 20 4.6 40 2.8 8 1-pyrrolidyl CMe 2CH 2Me H 85-86 (1) 96 8 80 7.2 70 5.2 20 morpholino CMe 2CH 2Me 4-Me 182-183 (11) 97 6 10 4.2 20 7.4 4 piperidino-(1-position only) CH 2CH 2Me H 65-66 (1) (4) (30) 98 3.5 20 2.8 20 2.4 5 piperidino-(1-position only) CHMe CH 2Me H 75-76 (1) (4) (30) 99 7.1 40 6.8 40 5.5 18 morpholino CH 2C Me 2H H 130-131 (1) 100 7.1 50 6.1 25 4.4 4 morpholino CH 2C Me 2Me H 63-64 (1) 101 4.4 10 3.1 20 2.4 20 N (CH 2CH 2OMe) 2CMe 2CH 2Me H 178 (31) quinolines are for phenyl) third amidine (m.p.114 ℃), use the hexane recrystallization.
Example 105
The mixture of 4-(2-aminophenyl) morpholine hydrochloride (7.5g) and n-Butyronitrile (20ml) is placed airtight stainless steel high pressure vessel, in 170 ℃ of heating 60 hours.Remove excessive n-Butyronitrile, resistates is soluble in water, alkalize to pH12 with 10% aqueous sodium hydroxide solution, and use dichloromethane extraction.Extraction liquid elder generation water is used the salt water washing again, and dry back is removed and desolvated.Resistates carries out chromatography purification on the neutral alumina post.Remove unreacted raw material with 1: 1 mixture wash-out of methylene dichloride and hexane, use 1: 99 mixture wash-out of methyl alcohol and methylene dichloride then, obtain a kind of solids, this solids is dissolved in the methyl alcohol (10ml), handle with fumaric acid (0.4g), obtain the single fumarate (m.p.168-170 ℃) of N-(2-morpholino phenyl) fourth amidine, with 1: 2 compound recrystallization of methyl alcohol and ether.
Example 106
Under 40-50 ℃, in 4-(2-aminophenyl) morpholine (5.34g) that powdered anhydrous aluminum chloride (12g) is divided several parts to be added to stir and the soup compound of n-Butyronitrile (6g).Then with this mixture in 160-170 ℃ of down heating 6 hours, make to add 40% aqueous sodium hydroxide solution after its cooling and be hydrolyzed.With this solution of extracted with diethyl ether, extraction liquid water and salt water washing, dry then.Remove the resistates that obtains after desolvating 1: 1 crystalline mixture of ethyl acetate and hexane, obtain N-(2-morpholino methyl) fourth amidine (m.p.131 ℃), be translated into single fumarate (m.p.173 ℃), use the propan-2-ol recrystallization.
Example 107
The mixture of 4-(2-aminophenyl) morpholine hydrochloride (10g) and isopropyl cyanide (60ml) is placed airtight stainless steel high pressure vessel,, obtain N-(2-morpholino phenyl) NSC 18620 (m.p.140-141 ℃), and use the hexane recrystallization in 165 ℃ of heating 26 hours.
Example 108
The mixture of 4-(2-aminophenyl) morpholine (5.34g), isopropyl cyanide (6g) and Aluminum chloride anhydrous (12g) was heated 6 hours down in 160-170 ℃, obtain N-(2-morpholino phenyl) NSC 18620 (m.p.138 ℃), with 1: 1 mixture recrystallization of ethyl acetate and hexane.
Example 109
The mixture of 5-methylthio group-2-morpholino aniline (1.8g), isopropyl cyanide (1.66g) and Aluminum chloride anhydrous (3.2g) was heated 2 hours down in 140 ℃, obtain N-(5-methylthio group-2-morpholino phenyl) NSC 18620 (m.p.155 ℃), use the alkane recrystallization.
Example 110
The mixture of 5-fluoro-2-morpholino aniline (1.96g), isopropyl cyanide (2g) and Aluminum chloride anhydrous was heated 4 hours in 150 ℃, obtain N-(5-fluoro-2-morpholino phenyl) NSC 18620 (m.p.142 ℃), and use the hexane recrystallization, be translated into its fumarate (m.p.172 ℃), and with 1: 1 mixture recrystallization of methyl alcohol and ether.
Example 111
The mixture of 4-(2-aminophenyl) morpholine hydrochloride (6.5g) and valeronitrile (35ml) was heated 25 hours cooling then down with nitrogen in 160-165 ℃.This mixture is handled with aqueous sodium hydroxide solution, and with the mixture after the dichloromethane extraction alkalization.Steaming desolventizes, and resistates distills, removes half unreacted valeronitrile under the pressure of 50mmHg.Filter to isolate the solids of telling through cooling, use the hexane recrystallization, obtain N-(2-morpholino phenyl) penta amidine (m.p.135-136C) with hexane (50ml) washing back.
Example 112
The mixture of 4-(2-aminophenyl) morpholine (3.56g), trimethylacetonitrile (5g) and Aluminum chloride anhydrous (8g) was heated 6 hours down in 160-170 ℃, obtain N-(2-morpholino phenyl) new penta amidine (m.p.126 ℃), behind the hexane recrystallization, be translated into its single fumarate (m.p.211 ℃) and use recrystallizing methanol.
Example 113-125
With with example 2 described similar modes; The compound that makes in the following example is converted into their fumarate, and with below the solvent recrystallization of cheating out: the initial example recrystallization solvent of the example of fumarate fusing point (℃) 113 20 methyl alcohol, 212,114 22 methyl alcohol 229-230115,32 methyl alcohol, 213,116 34 methyl alcohol 180 (decomposition), 117 64 methyl alcohol 197 (decomposition), 118 72 methyl alcohol, 188,119 73 methyl alcohol: ether (1: 2) 208-210120 99 methyl alcohol: ether (1: 2) 204-205121 100 methyl alcohol 117-118122 74 methyl alcohol: ether (1: 2) 179-180123 102 methyl alcohol: ether (1: 1) 189,124 107 methyl alcohol: ether (1: 1) 162-163125 111 isopropyl alcohol 156-158
Example 126
At room temperature, make the product (2.6g) of example 1 and excessive vinyl cyanide (5ml) reaction.Product is heavily tied with ethyl acetate, obtains 4-(2-(1-(2-cyano ethyl)-2-piperidines subunit amino) phenyl) morpholine (m.p.148 ℃).
Example 127
With the mixture of the 3-morpholone mai (4g) in the anhydrous acetonitrile (40ml), 4-(2-aminophenyl) morpholine (3.6g) in the anhydrous acetonitrile (20ml) and phosphoryl chloride (3.6ml) in 65-70 ℃ down heating obtained a kind of oily matter in 40 hours, carry out column chromatography purification on neutral alumina (72g), used eluent is: (a) hexane; (b) methylene dichloride: hexane (1: 1); (c) methylene dichloride.Gained oily matter obtains the light yellow solid thing with saturated methyl alcohol (25ml) solution-treated of hydrogenchloride, behind 1: 1 mixture recrystallization with methyl alcohol and ether, obtains 4-(2-(3-morpholine subunit amino) phenyl) morpholine hydrochloride (m.p.262-263 ℃).
Example 128
With the mixture of the piperidone (3.6g) in the benzene (30ml), 4-(2-aminobenzyl) morpholine (5.7g) in the benzene (20ml) and phosphoryl chloride (3.6ml) in 65-70 ℃ of heating 4g hour down, obtain 4-(2-(2-piperidines subunit amino) benzyl) morpholine (m.p.108-110 ℃), use the hexane recrystallization.
Example 129
With the mixture of the 2-piperidone (6g) in the benzene (50ml), 4-(2-amino-4-benzyl chloride base) morpholine (6.8g) in the benzene (50ml) and phosphoryl chloride (5.5ml) in 60-65 ℃ of heating 5 hours down, obtain 4-(4-chloro-2-(2-piperidines subunit amino) benzyl) morpholine (m.p.121-122 ℃), use the hexane recrystallization.
Example 130
With the mixture of the 1-Methyl-2-Pyrrolidone (4.8g) in the benzene (20ml), 4-(2-aminobenzyl) morpholine (7.6g) in the benzene (50ml) and phosphoryl chloride (4.8ml) in 65-70 ℃ of heating 18 hours, obtain a kind of oily matter, it is dissolved in the methyl alcohol (30ml).With obtaining 4-(2-(1-methyl-2-pyrrolidylidene amino) benzyl) morpholine two hydriodates (m.p.230-232 ℃) after 57% hydroiodic acid HI (10.1ml) processing, use ethyl alcohol recrystallization.
Example 131
With 1 in the benzene (20ml), 3,4-(2-aminobenzyl) morpholine (3.8g) in 3-trimethylammonium-2-Pyrrolidone (3g), the benzene (10ml) and the mixture of phosphoryl chloride (2.1ml) were placed under room temperature 28 hours, heated 14 hours down in 60-65 ℃ then, obtain a kind of oily matter (2.9g), it is dissolved in the methyl alcohol (15ml).With obtaining 4-(2-(1,3,3-trimethylammonium-2-pyrrolidylidene amino) benzyl) morpholine two hydriodates (m.p.256-258 ℃) after 57% hydroiodic acid HI (2.8ml) processing, with 1: 1 mixture recrystallization of ethanol and ether.
Example 132
With the mixture of the N-methyl pivalyl amine (6.2g) in the benzene (50ml), 4-(2-aminobenzyl) morpholine (9g) in the benzene (40ml) and phosphoryl chloride (5ml) in 80-85 ℃ of heating 12 hours down, obtain a kind of solids, it is dissolved in methyl alcohol (25ml) and uses fumaric acid (1.4g) to handle, obtain the single fumarate (m.p.167-168 ℃) of new penta amidine of N-methyl-N '-(2-morpholino aminomethyl phenyl), use the propan-2-ol recrystallization.
Example 133
With 1 in the benzene (45ml), the mixture of 4-(2-aminophenyl) morpholine (8.5g) in 3-dimethyl-2-imidazolone (7g), phosphoryl chloride (6ml) and the benzene (30ml) heated 30 hours down in 65-70 ℃.Product hexane recrystallization obtains 4-(2-(1,3-dimethyl-2-imidazolidine subunit amino) phenyl) morpholine (m.p.133-l34 ℃).
Example 134-154
To prepare the listed compound of Table VI with example 133 described similar modes, method is as follows: under 65-70 ℃ temperature, in the presence of phosphoryl chloride (Eml), make the aminophenyl compound (A gram in Bml benzene) and formula VIII compound (C gram in Dml benzene) reaction F hour of formula VII.
The note of Table VI
(32) product hexane recrystallization.
(33) linked reaction is carried out under 90-95 ℃.
(34) linked reaction is carried out under 70-75 ℃.
(35) linked reaction is carried out under 60-65 ℃.
(36) product is separated with its fumarate, uses mix in 2: 1 of Virahol and ether
The compound recrystallization.
(37) linked reaction is carried out under 75-80 ℃.
(38) product is separated with its single fumarate, and with methyl alcohol and ether 1: 2
The mixture recrystallization.
(39) product is separated with its single fumarate, and with methyl alcohol and ether 1: 3
The mixture recrystallization.
(40) linked reaction is carried out under 80-85 ℃.
(41) product carries out column chromatography purification on alumina column, makes eluent with methylene dichloride.
(42) linked reaction was carried out under 80-85 ℃ 48 hours, again under 90-95 ℃
Carried out 14 hours.Product carries out column chromatography purification on alumina column, use dichloro
99: 1 mixtures of methane and methyl alcohol are made eluent.
(43) product is separated with its sesqui fumarate, and with methyl alcohol and ether
1: 2 mixture recrystallization.
Table VI
Figure C9010329500771
Example A B C D E F NR 1R 2R 6R 11R 7Mp (℃) note 1 34 3.8 25 2.7 40 2.1 21 morpholino Me Me 4-F 115-117 (32) 135 9.8 25 12.6 10 7.3 50 morpholino Me Me 3-Me 85-86 (32) 136 2.9 30 2.6 30 2.1 23 morpholino Me Me 4-Me 105-106 (32) (33) 137 5 25 4.2 35 3.7 35 morpholino Me Me 5-Me 109-110 (32) (34) 138 8.5 40 9.1 60 7.3 18 morpholino Me Me 4-Cl 103-104 (32) 139 4 40 2.7 30 2.2 23 morpholino Me Me 4-OMe 79-80 (32) 140 3.5 30 2.5 30 2.3 6 morpholino Me Me 4,5-(OMe)2117-118, (32), (35) 141 3.2 20 2.7 30 2.2 28 1-pyrrolidyl Me Me H 162-163, (36) 142 5.2 30 5.1 30 4.1 70 1-pyrrolidyl Me Me 3-Me 75-76, (32) 143 8.8 60 8.5 50 6.8 10 piperidino-(1-position only) Me Me H 61, (32)
Table VI (continuing) example A B C D E F NR 1R 2R 6R 11R 7Mp (℃) note 1 44 5.8 50 5.1 60 4 26 thia morpholino Me Me H 96-98 (32) 145 8.2 80 6.8 40 5.4 14 2,6-dimethyl Me Me H 86-86 (32) (37)
Morpholino 146 6.3 30 6.8 40 5.4 28 NEt 2Me Me H 164-165 (38) (37) 147 3.6 60 3.4 40 2.7 90 2-methyl isophthalic acids-Me Me H 83-184 (39) (40)
Pyrrolidyl 148 5.3 25 4.3 25 3.4 80 morpholino Me Me 3-Cl 86-88 (32) (33) (41) 149 4.8 40 5.1 40 4.8 24 1-pyrrolidyl Me Me 4-Me 165-167 (38) (40) 150 8.9 50 6.8 50 5.4 12 N (CH 2CH 2OMe) 2Me Me H 105-106, (38), (37) 151 5.2 40 6.4 30 4.3 48 morpholino Et Et H 154-155, (42), (38) 152 7.6 30 6.8 30 5.5 14 morpholino Me Me 6-Me 106-108, (40), (32) 153 7.1 60 7.6 80 5.6 70 morpholino Et Me H 75-76, (40), (32) 154 4.4 20 5.9 50 4.4 60 morpholino Bu Me H 135-136, (40), (47), (43)
Example 155
With N-(2-hydroxyethyl)-1, the mixture of 2-quadrol (31.2g), urea (23.4g) and water (3ml) heated 3 hours down at 130 ℃, heated 8 hours down at 210 ℃ again, directly from reaction mixture, steam then, obtain buttery 1-(2-hydroxyethyl)-2-imidazolone (30g, b.p.150-160 ℃ (0.2mm)), obtain a kind of solid (m.p.50-51 ℃) after the curing.
With 1-(2-hydroxyethyl)-2-imidazolone (2.28g), benzoyl oxide (4.5g), triethylamine (2.4g), 4-Dimethylamino pyridine (0.1g) and 1, the mixture of 2-glycol dimethyl ether (20ml) stirred under room temperature 8 hours.Add saturated sodium bicarbonate solution (15ml), mixture extracts with methylene dichloride (100ml).Extraction liquid water and salt water washing, dry then and filtration.Removing desolvates obtains 1-(2-benzoyloxy ethyl)-2-imidazolone (m.p.130-132 ℃), uses re-crystallizing in ethyl acetate.
The mixture of 1-(2-benzoyloxy ethyl)-2-imidazolone (2.3g) and 4-toluenesulphonic acids methyl esters (2g) was heated 48 hours down in 90-95 ℃.Then reaction mixture is cooled to room temperature, handles, and (6 * 20ml) extract with ethyl acetate with saturated sodium bicarbonate solution (10ml).Extraction liquid water and salt water washing, dry then and filtration.Removing desolvates obtains oily resistates (2g), carries out column chromatography purification on silica gel (80g, 100-200 order), makes eluent with 1: 1 mixture of ethyl acetate and hexane, obtains buttery 1-(2-benzoyloxy ethyl)-3-methyl-2-imidazolone.
With with example 133 described similar modes, 4-(2-aminophenyl) morpholine (5.2g) in 1-(2-benzoyloxy ethyl)-3-methyl-2-imidazolone (8.8g) and the benzene (20ml) in the benzene (30ml) was reacted 35 hours in the presence of 80-85 ℃ and phosphoryl chloride (3.3ml), obtain a kind of oily matter.This oily matter is dissolved in methyl alcohol (10ml) and uses fumaric acid (1.8g) to handle.Steaming desolventizes, and resistates is soluble in water with ether washing back.This aqueous solution is alkalized to pH9-10 with sodium bicarbonate aqueous solution,, on alumina column, carry out chromatography purification, make eluent with methylene dichloride with obtaining a kind of oily matter after the extracted with diethyl ether.Purifying alkali (0.8g) in the methyl alcohol (10ml) is handled with fumaric acid (0.23g), obtain 4-(2-(1-(2-benzoyloxy ethyl)-3-methyl-2-imidazolidine subunit amino) phenyl) morpholine list fumarate (m.p.132-133 ℃), with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 156
Under 65-70 ℃, in the presence of phosphoryl chloride (8.3ml), make the tetramethyl-urea (10.4g in the dry-out benzene (80ml), 10.7ml) with dry-out benzene (100ml) in 4-(2-aminophenyl) morpholine (10.2g) reaction 30 hours, the oily matter of gained carries out column chromatography purification on neutral alumina post (100g), use the hexane wash-out, obtain a kind of oily matter.The solution of this alkali (2.5g) in methyl alcohol (10ml) is handled with 57% hydroiodic acid HI (1.3ml), obtained 2-(2-morpholino phenyl)-1,1,3,3-tetramethyl guanidine hydriodate is a kind of light yellow crystalline solid (m.p.215-216 ℃), with 2: 3 mixture recrystallizations of methyl alcohol and ether.
Example 157
Under 65-70 ℃, in the presence of phosphoryl chloride (4.71ml), make the 3-ethyl-1 in the benzene (70ml), 1,4-(2-aminophenyl) morpholine (6g) reaction in 3-trimethyl-urea (6.57g) and the benzene (30ml) 45 hours, obtain 1-ethyl-2-(2-morpholino phenyl)-1,3,3-trimethylammonium guanidine (bp.140 ℃ (0.2mmHg)).
Example 158
Under 70 ℃, in the presence of phosphoryl chloride (4.71ml), make the 3-allyl group-1 in the benzene (50ml), 1,4-(2-aminophenyl) morpholine (6g) reaction in 3-trimethyl-urea (7.17g) and the benzene (30ml) 45 hours, obtain 1-allyl group-2-(2-morpholino phenyl)-1,3,3-trimethylammonium guanidine (bp.148-150 ℃ (0.2mmHg)).
Example 159
Under 80-85 ℃, in the presence of phosphoryl chloride (4ml), make the 3-normal-butyl 1 in the benzene (60ml), 1,4-(2-aminophenyl) morpholine (7.2g) reaction in 3-trimethyl-urea (7g) and the benzene (30ml) 18 hours, obtain 1-normal-butyl-2-(2-morpholino phenyl)-1,3,3-trimethylammonium guanidine (bp.162-163 ℃ (0.7mmHg)).
Example 160
Under 70 ℃, in the presence of phosphoryl chloride (4.06ml), make the 3-amyl group-1 in the benzene (80ml), 1,4-(2-aminophenyl) morpholine (6.46g) reaction in 3-trimethyl-urea (7.5g) and the benzene (30ml) 45 hours, obtain 1-amyl group-2-(2-morpholino phenyl)-1,3,3-trimethylammonium guanidine (b.p.98 ℃ (1.5mmHg)).
Example 161
Under 10 ℃, make 1-(2-hydroxyethyl)-2-imidazolone (13g) and sodium hydride (50% paraffin oil suspension 12g) reaction 3 hours in the anhydrous dimethyl formamide (125ml), use methyl-iodide (35.5g) to handle then 1 hour.This mixture was stirred under room temperature 18 hours, obtain 1-methyl-3-(2-methoxy ethyl)-2-imidazolone (b.p.110-114 ℃ (0.4mmHg)).
Under 80-85 ℃, in the presence of phosphoryl chloride (7.2ml), 1-methyl-3-(2-methoxy ethyl)-2-imidazolone (11.4g) and 4-(2-aminophenyl) morpholine (8.9g) in the benzene (80ml) in the benzene (60ml) were reacted 30 hours, obtain an oily matter, its part (1.8g) is dissolved in the methyl alcohol (10ml) also with fumaric acid (0.9g) processing, obtain 4-(2-(1-methyl-3-(2-methoxy ethyl)-2-imidazolidine subunit amino) phenyl) morpholine list fumarate (m.p.127-129 ℃), use the propan-2-ol recrystallization.
Example 162
Under room temperature, in the presence of triethylamine (9g) and 4-Dimethylamino pyridine (0.1g), diacetyl oxide (9.2g) in 1-methyl-3-(2-hydroxyethyl)-2-imidazolone (13g) and the methylene dichloride (60ml) was reacted 18 hours, obtain buttery 1-methyl-3-(2-acetoxyl group ethyl)-2-imidazolone.
Under 80-85 ℃, in the presence of phosphoryl chloride (7ml), 1-methyl-3-(2-acetoxyl group ethyl)-2-imidazolone (13.4g) and 4-(2-aminophenyl) morpholine (10.6g) in the benzene (80ml) in the benzene (80ml) were reacted 30 hours, obtain 4-(2-(1-methyl-3-(2-acetoxyl group ethyl)-2-imidazolidine subunit amino) phenyl) morpholine.
Under 10 ℃, 4-(2-(1-methyl-3-(2-acetoxyl group ethyl)-2-imidazolidine subunit amino) phenyl) morpholine (2.7g) and the sodium hydroxide (0.4g) in the water (10ml) in the dimethyl formamide (10ml) were reacted 1 hour, obtain an oily matter, it is dissolved in the methyl alcohol (10ml), and handle with fumaric acid (0.4g), obtain 4-(2-(1-methyl-3-(2-hydroxyethyl)-2-imidazolidine subunit amino) phenyl) morpholine (m.p.129-131 ℃), with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 163
Under 80-85 ℃; in the presence of phosphoryl chloride (2.1ml); make 4-formyl-dimethylamino morpholine (3.8g) and 4-(2-aminophenyl) morpholine (3.5g) reaction 40 hours in the benzene (25ml); obtain N; N-dimethyl-N '-(2-morpholino phenyl) morpholine-4-carbonamidine (m.p.126-128 ℃) uses the hexane recrystallization.
Example 164
Under 80-85 ℃; in the presence of phosphoryl chloride; make 1-dimethylamino formyl piperidine (3.7g) and 4-(2-morpholino phenyl) morpholine (3.5g) reaction 35 hours in the benzene (25ml); obtain N; N-dimethyl-N '-(2-morpholino phenyl) piperidines-1-carbonamidine (m.p.88-90 ℃) is with sherwood oil recrystallization (b.p.40-60 ℃).
Example 165
Under 10 ℃, (2-(1 to make 4-in the methyl alcohol (20ml), 3-dimethyl-2-imidazolidine subunit amino) thia morpholine (1.5g phenyl), as preparation as described in the example 144) with water (4ml) in sodium metaperiodate (1.4g) reaction 4 hours, (2-(1 to obtain 4-, 3-dimethyl-2-imidazolidine subunit amino) thia morpholine-1-oxide compound monohydrate (m.p.103-105 ℃) phenyl), with 1,1: 1 mixture recrystallization of 2-glycol dimethyl ether and hexane.
Example 166
The solution of isothiocyanic acid 2-morpholino phenylester (2.3g) is handled with the saturated solution of ammonia in ethanol (20ml), reaction mixture was stirred under room temperature 3 hours.Leach the solids of gained,, obtain 1-(2-(4-morpholino) phenyl) thiocarbamide (m.p.194-195 ℃) with washing with alcohol and dry.
With the solution of 1-(2-morpholino phenyl) thiocarbamide (7.2g) in anhydrous methanol (30ml) with methyl-iodide (4.2g) reflux 2 hours.Add anhydrous diethyl ether (15ml) after the removal of solvent under reduced pressure, obtain 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (m.p.151-152 ℃) after mill is scraped.
With 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (5g) and 1, the mixture of 2-quadrol (2.4g) reflux 6 hours in dehydrated alcohol (50ml), obtain a kind of oily matter after the removal of solvent under reduced pressure, it is dissolved in the methylene dichloride (50ml), cooling, with the alkalization of 20% sodium hydroxide, organic layer is water and salt water washing successively, dry (Na 2SO 4), filter and remove and desolvate, obtain a kind of solid (4g), with obtaining 4-(2-(2-imidazolidine subunit amino) phenyl) morpholine (m.p.185-168 ℃) after the re-crystallizing in ethyl acetate.
Example 167
With 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (3g, as preparation as described in the example 166), the N-methyl isophthalic acid, the mixture heating up of 2-quadrol (2ml) and dehydrated alcohol (35ml) refluxed 8 hours, obtain a kind of solid, with obtaining 4-(2-(1-methyl-2-imidazolidine subunit amino) phenyl) morpholine (m.p.156 ℃) after the re-crystallizing in ethyl acetate.
Example 168-202
To prepare the listed compound of Table VII with example 167 described similar modes, method is as follows: incite somebody to action wherein R 14And R 15Formula XIII compound (G gram) and formula H for H 2N (CH 2) 2NHR 6The mixture heating up backflow of N-replacement-1 (H gram) in dehydrated alcohol (Iml) J hour.
The note of Table VII
Note (32), (38), (39) and (41) have the meaning that each table of front is cheated out.
(44) product re-crystallizing in ethyl acetate.
(45) product is separated with its single fumarate, and uses recrystallizing methanol.
(46) preparation of formula XIV compound provides as preparation method A in the back.
(47) product is separated with its fumarate, and with methyl alcohol and propan-2-ol
1: 2 mixture recrystallization.
(48) product is with 1,2-glycol dimethyl ether and sherwood oil (b.p.40-60 ℃)
1: 4 mixture recrystallization.
(49) preparation of formula XIV compound provides as preparation method B in the back.
(50) preparation of formula XIV compound provides as preparation method C in the back.
(51) preparation of formula XIV compound provides as preparation method D in the back.
(52) product 1: 2 mixture recrystallization of ethyl acetate and hexane.
(53) preparation of formula XIV compound provides as preparation method E in the back.
(54) preparation of formula XIV compound provides as preparation method F in the back.
(55) preparation of formula XIV compound provides as preparation method G in the back.
(56) product carries out chromatography purification on alumina column, uses following eluent successively.
1: 1 mixture of hexane, methylene dichloride and hexane, methylene dichloride.
(57) preparation of formula XIV compound provides as preparation method H in the back.
(58) product 1: 1 mixture recrystallization of ethyl acetate and hexane.
(seeing 76 pages, 77 pages, 78 page tables)
Preparation method A
6-methyl in Shi diox (25ml) and the water (100ml)-2-morpholino aniline (9.6g) reacted 30 minutes down at 0 ℃ with sulfo-carbonyl chloride (5.7ml), at room temperature reacted 3 hours again, obtained buttery isothiocyanic acid 6-methyl-2-morpholino phenylester.
The isothiocyanic acid 6-methyl-2-morpholino phenylester (8.8g) and the ethanolic soln (60ml) of 33% ammonia were reacted 5 hours, obtain 1-(6-methyl-2-morpholino phenyl) thiocarbamide (9g), be a light yellow solid thing (m.p.199 ℃), with 1: 1 mixture recrystallization of ethyl acetate and hexane.
1-(6-methyl-2-morpholino phenyl) thiocarbamide (9g) and the mixture of methyl-iodide (2.5ml) in anhydrous propanone (100ml) in 90-95 ℃ of following reflux 2.5 hours, are obtained 2-methyl isophthalic acid-(6-methyl-2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate.
Preparation method B
In being chilled to 0 ℃ the mixture of sulfo-carbonyl chloride (4ml) and water (60ml), add N, two (2-methoxy ethyl) benzene-1 of N-, 2-diamines (7.5g) Zai diox (10
Table VII
Figure C9010329500861
Example G H I J NR 1R 2R 6R 7Mp (℃) note 1 68 3.8 2.7 45 8 morpholino Et H 107-109 (32) 169 2.8 2.6 35 10 morpholino Pr H 131-132 (32) 170 3.8 3 45 14 morpholino i-Pr H 121-122 (32) 171 5.7 5.2 65 7 morpholino Bu H 88-89 (32) 172 3.8 3.5 45 12 morpholino i-Bu H 136-138 (32) 173 7.5 7.8 90 14 morpholino amyl group H 72-74 (32) 174 3.8 3 50 8 morpholino pi-allyl H 126-128 (32) 175 3.8 3.1 45 5 morpholino CH2CH 2OH H 131-132 (44)
Table VII (continuing) example G H I J NR 1R 2R 6R 7Mp (℃) note 1 76 7.9 6.2 90 150 morpholino CH 2CH 2OH 3-Me 198-199 (45) (46) 177 3.8 3.8 45 9 morpholino CH 2CH 2OMe H 74-75 (32) 178 3.8 4.2 40 24 morpholino cyclohexyl H 189-189 (44) 179 5.7 6.75 70 12 morpholino CH 2Ph H 96-97 (32) 180 7.6 9.8 90 8 morpholino CH 2CH 2Ph H 106-108 (32) 181 11.4 8.3 150 24 morpholino CH 2CH 2NMe 2H 151 (47) 182 5.7 6 70 24 morpholino CH 2CHOHCH 2OH H 144-145 (44) 183 3.8 3.4 45 18 morpholino CH 2C (Me)=CH 2H 141-143 (48) 184 4.2 2.4 45 8 N (CH 2CH 2OMe) 2Me H 140-141 (39) (49) 185 3.0 2.2 30 40 N (CH 2CH 2OMe) 2CH 2CH 2OH H 110-111 (38) (49) 186 7.9 4.4 90 8 thia morpholino Me R 115-117 (32) (50) 187 5.4 3.3 70 10 1-pyrrolidinyl Me H 117-118 (32) (51) 188 3.9 3.5 45 8 thia morpholino Bu H 106-108 (32) (50) 189 7.8 4.4 90 75 morpholino Me 3-Me 120-121 (52) (46) 190 9.8 5.9 115 12 morpholino Me 4-Me 122-123 (32) (53)
Table VII (continuing) example G H I J NR 1R 2R 6R 7Mp (℃) note 1 91 7.2 6.4 90 24 1-pyrrolidyl CH 2CH 2OH H 166-167 (38) (51) 192 3.7 3.1 45 32 1-methyl isophthalic acid-CH 2CH 2OH H 81 (32) (54)
Pyrrolidinyl 193 5.9 5.2 75 12 morpholino Bu 4-Me 114-116, (32) 194 7.5 3.6 750 24 piperidino H H 163, (38), (55) 195 7.5 5.5 90 14 piperidino Me H 75-76, (41), (32), (55) 196 5.9 3.4 70 70 piperidino Me 3-Me 86-87, (56), (32), (57) 197 2.8 2.2 40 24 thia morpholino CH2CH 2OH H 99-101 (58) (50) 198 3.7 3.1 45 18 piperidino-(1-position only) CH 2CH 2OH H 105-107 (32) (55) 199 5.6 5.3 65 39 morpholino (CH 2) 3OH H 139-140 (44) 200 5.9 3.4 70 70 morpholino CH 2CH (OH) Me H 147-148 (44) 201 7.6 8 90 23 morpholino CH 2CH (OH) Et H 112-113 (56) 202 3.8 3.9 45 14 morpholino CH 2C (OH) Me 2H 132-133 (44) ml) solution in.Make the temperature of mixture rise to room temperature, and this mixture was stirred 4 hours.Add frozen water (50ml), (3 * 20ml) extract this mixture with ether.Extraction liquid water (50ml) and salt solution (50ml) washing obtain a kind of resistates after drying and the evaporation, in 45 ℃ of following vacuum (100m/Hg) heating, obtain buttery isothiocyanic acid 2-(two (2-methoxy ethyl) amino) phenylester.
In the mixture that is chilled to 10 ℃ isothiocyanic acid 2-(two (2-methoxy ethyl) amino) phenylester (7.5g) and ethanol (10ml), with the saturated ethanolic soln (40ml) that added ammonia in 40 minutes.This mixture was stirred 8 hours down in 0 ℃, or else added cooling and stirring 16 hours.Steam then and desolventize, resistates carries out chromatography purification on silicagel column, with 1: 4 mixture wash-out of ethyl acetate and hexane, use 1: 1 mixture wash-out of ethyl acetate and hexane more earlier, obtain 1-(2-(two (2-methoxy ethyl) amino) phenyl) thiocarbamide (m.p.118-119 ℃).
With 1-(2-two (2-methoxy ethyl) amino) phenyl) mixture of thiocarbamide (5g), methyl-iodide (1.4ml) and acetone (25ml) heated 2 hours down in 40 ℃.Obtain a kind of resistates except that after desolvating, obtain 2-methyl isophthalic acid-(2-(two (2-methoxy ethyl) amino) phenyl)-2-sulfo-pseudo-urea hydriodate (m.p.111-112 ℃) after the development that adds diethyl ether.
Preparation method C
In the mixture that is chilled to 0 ℃ sulfo-carbonyl chloride (8.77ml) and water (120ml), with adding the 2-thia morpholino aniline (solution in the 14.6g) Zai diox (10ml) in 15 minutes.Stirring this mixture makes its temperature rise to room temperature.Then this mixture was stirred 4 hours and add frozen water (200ml).(2 * 100ml) extract this mixture with ether, extraction liquid washes (50ml) earlier with water again with salt washing (100ml), obtain a kind of resistates after steaming desolventizes, after 2 hours, obtain isothiocyanic acid 2-thia morpholino phenylester (m.p.55-56 ℃) in 40-45 ℃ of following vacuum (100mmHg) heating.
Under 10 ℃, in the mixture of assorted morpholino phenylester (14g) of isothiocyanic acid 2-alkali and ethanol (40ml), add the aqueous solution (100ml) of 25% ammonia.This mixture was stirred 24 hours down in 30 ℃, be chilled to 10 ℃ then.Filter and collect 1-(2-thia morpholino phenyl) thiocarbamide, wash (100ml) after drying (m.p.170-171 ℃) with water.
The mixture of 1-(2-thia morpholino phenyl) thiocarbamide (12.6g), methyl-iodide (7.1g) and acetone (60ml) was heated 2.5 hours down in 90-95 ℃.Steaming desolventizes, and with resistates vacuum (5mmHg) drying, obtains 2-methyl isophthalic acid-(2-thia morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (m.p.176-177 ℃).
Preparation method D
In the mixture of 2-(1-pyrrolidyl) aniline (10.6g) and methylene dichloride (30ml), with 30 minutes adding isothiocyanic acid benzoyl esters (10ml).Then this mixture was stirred 4 hours down in 30 ℃.Steaming desolventizes, resistates vacuum (5mmHg) dry 30 minutes and the development that adds diethyl ether.Filter and collect 3-benzoyl-1-(2-(1-pyrrolidyl) phenyl) thiocarbamide, with ether washing and dry (m.p.172-173 ℃).
The mixture of 3-benzoyl-1-(2-(1-pyrrolidyl) phenyl) thiocarbamide (18.1g), sodium hydroxide (5g) and water (50ml) was heated 4 hours down in 90-95 ℃.Add ice, and then add 50% aqueous hydrochloric acid.Mixture is filtered, and filtrate is handled to pH8 with saturated sodium bicarbonate solution.Filter and collect 1-(2-(1-pyrrolidyl) phenyl) thiocarbamide, wash after drying (m.p.185-186 ℃) with water.
With the mixture heating up of 1-(2-(1-pyrrolidyl) phenyl) thiocarbamide (12.2g), acetone (100ml) and methyl alcohol (20ml) to 90-95 ℃.Add methyl-iodide (8.36g), this mixture heating up was refluxed 3 hours.Steaming desolventizes and obtains a kind of resistates, will obtain 2-methyl isophthalic acid-(2-(1-pyrrolidyl) phenyl)-2-sulfo-pseudo-urea hydriodate (m.p.139-141 ℃) after its vacuum (5mmHg) drying.
Preparation method E
5-methyl in the Shi diox (80ml)-2-morpholino aniline (20g) reacted 30 minutes down at 0 ℃ with water (200ml), at room temperature reacted 2 hours again, obtained isothiocyanic acid 5-methyl-2-morpholino phenylester (m.p.91-92 ℃).
The isothiocyanic acid 5-methyl-2-morpholino phenylester (15g) and the ethanolic soln of 33% ammonia were reacted under room temperature 48 hours, obtain 1-(5-methyl-2-morpholino phenyl) thiocarbamide, be light yellow solid (m.p.181-182 ℃).
1-(5-methyl-2-morpholino phenyl) thiocarbamide (14g), methyl-iodide (7.9g) mixture heating up in methyl alcohol (50ml) was refluxed 2 hours, obtain 2-methyl isophthalic acid-(5-methyl-2-morpholino phenyl)-2-sulfo-pseudo-urea iodate, be light yellow solid, m.p.157-159 ℃.
Preparation method F
The mixture of 2-methyl isophthalic acid-(2-aminophenyl) tetramethyleneimine (9.1g), isothiocyanic acid benzoyl ester (9.2g) and methylene dichloride (100ml) was stirred under room temperature 8 hours, and place and spend the night.Except that desolvating and developing, obtain 1-benzoyl-3-(2-methyl isophthalic acid-pyrrolidyl) phenyl with ether) thiocarbamide (m.p.105-106 ℃).
With 1-benzoyl-3-(2-(2-methyl isophthalic acid-pyrrolidyl) phenyl) thiocarbamide (9g), sodium hydroxide (1g; the ball shape) and the mixture of water (10ml) in 90-95 ℃ of down heating 48 hours; obtain 1-(2-(2-methyl isophthalic acid-pyrrolidyl) phenyl) thiocarbamide (m.p.145-148 ℃); on silica gel, carry out column chromatography purification, make eluent with 1: 1 mixture of ethyl acetate and hexane.
1-(2-(2-methyl isophthalic acid-pyrrolidyl) phenyl) thiocarbamide (3.4g) and the mixture of methyl-iodide (2.1g) in acetone (60ml) were heated 3 hours down in 90-95 ℃, obtain 2-methyl isophthalic acid-(2-methyl isophthalic acid-pyrrolidyl) phenyl except that after desolvating)-2-sulfo-pseudo-urea hydriodate (3.7g), be thickness oily matter.
Preparation method G
In the mixture that is chilled to 0 ℃ sulfo-carbonyl chloride (10.2ml) and water (200ml), with adding the solution of 2-piperidino-(1-position only) aniline (17.6g) in diox (100ml) in 25 minutes.Make the temperature of mixture rise to room temperature, and mixture was stirred 4 hours.Add ice (200g) and water (200ml), (6 * 50ml) extract with ether with mixture.Extraction liquid is merged and water (100ml) and salt solution (100ml) washing, obtain resistates after drying and the evaporation, on silicagel column, carry out chromatography purification, use the hexane wash-out, obtain buttery isothiocyanic acid 2-piperidino-(1-position only) phenyl ester.
In the mixture that is chilled to 10 ℃ isothiocyanic acid 2-piperidino-(1-position only) phenyl ester (12g) and ethanol (25ml), add the aqueous solution (60ml) of 25% ammonia.Mixture stirred 24 hours down at 30 ℃, was chilled to 10 ℃ then.Filter and collect 1-(2-piperidino-(1-position only) phenyl) thiocarbamide, wash with water and dry (m.p.143-145 ℃).
The mixture of 1-(2-piperidino-(1-position only) phenyl) thiocarbamide (10.1g), methyl-iodide (5.35g) and methyl alcohol (50ml) was heated 2 hours down in 50-55 ℃.Steaming desolventizes, and resistates vacuum (5mmHg) drying obtains 2-methyl isophthalic acid-(2-piperidino-(1-position only) phenyl)-2-sulfo-pseudo-urea hydriodate (m.p.160-162 ℃).
Preparation method H
6-methyl-2-piperidino-(1-position only) aniline (6.4g) in diox (20ml) and the water (65ml) was reacted 30 minutes down in 0 ℃ with sulfo-carbonyl chloride (5.7g), under room temperature, reacted 2 hours again, obtain buttery isothiocyanic acid 6-methyl-2-piperidino-(1-position only) phenyl and twist ester.
25% ammonia soln (65ml) in different sulfuric acid 6-methyl-2-piperidino-(1-position only) phenyl ester and the ethanol (20ml) was reacted 8 hours under room temperature, obtain 1-(6-methyl-2-piperidino-(1-position only) phenyl) thiocarbamide, be light yellow solid (m.p.197-198 ℃).
Mixture heating up in anhydrous methanol (100ml) refluxed 3 hours with 1-(6-methyl-2-piperidino-(1-position only) phenyl) thiocarbamide (7g) and methyl-iodide (4.38g), obtain 2-methyl isophthalic acid-(6-methyl-2-piperidino-(1-position only) phenyl)-2-sulfo-pseudo-urea hydriodate, be light yellow solid (m.p.204-205 ℃).
Example 203
With 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (3.8g, as preparation as described in the example 166), the 2-methyl isophthalic acid, the mixture heating up of 2-quadrol (2.2g) and ethanol (45ml) refluxed 8 hours, obtain a kind of solids, with obtaining 4-(2-(4-methyl-2-imidazolidine subunit amino) phenyl) morpholine (m.p.173-174 ℃) after the re-crystallizing in ethyl acetate.
Example 204
With 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (7.6g, as preparation as described in the example 166), 1,2-dimethyl-1, the mixture heating up of 2-quadrol (5.3g) and ethanol (90ml) refluxed 70 hours, obtain a kind of solids, with obtaining 4-(2-(4,5-dimethyl-2-imidazolidine subunit amino) phenyl) morpholine (m.p.142-143 ℃) after the re-crystallizing in ethyl acetate.
Example 205
Make 1 in the oxyethane that produces by ethylene chlorhydrin (36g) and the ball shape potassium hydroxide (20g) in the methyl alcohol (60ml) and the methyl alcohol (50ml), 2-dimethyl-1,2-quadrol (22.6g) is in-15 ℃ of reactions down, obtain N-(2-hydroxyethyl)-1,2-dimethyl-1, the 2-quadrol is colourless liquid (b.p.89-91 ℃ (1mmHg)).
Make 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea (12.5g) and N-(2-hydroxyethyl) 1,2-dimethyl-1, the mixture of 2-quadrol (8g) in dehydrated alcohol (150ml) was in 90-95 ℃ of following reflux 6 days, obtain a kind of dark-brown oily matter, on neutral alumina (250g), carry out column chromatography purification, 1: 9 mixture with methylene dichloride and hexane is made eluent, (2-(4 to obtain 4-, 5-dimethyl-1-(2-hydroxyethyl)-2-imidazolidine subunit amino) morpholine phenyl), for colorless solid (m.p.108-109 ℃), use the hexane recrystallization.
Example 206
With 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (3.8g, as preparation as described in the example 166), N '-sec.-propyl-2-methyl isophthalic acid, the mixture heating up of 2-propylene diamine (3.95g) and ethanol (45ml) refluxed 28 hours, obtain a kind of oily matter, on the neutral alumina post, carry out column chromatography purification, make eluent with methylene dichloride.Gained oily matter (1.5g) is dissolved in the methyl alcohol (10ml), and adding fumaric acid (0.5g), obtain 4-(2-(1-sec.-propyl-4,4-dimethyl-2-imidazolidine subunit amino) phenyl) morpholine list fumarate (m.p.206-208 ℃), with 1: 3 mixture recrystallization of methyl alcohol and ether.
Example 207
With 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (3.8g, as system preparation as described in the example 166), the mixture heating up backflow of 3-methylamino-propylamine (2.6g) and dehydrated alcohol (40ml) 6 hours, obtain a kind of solids, obtain 4-(2-(1-methyl perhydro pyrimidine-2-subunit amino) phenyl) morpholine (m.p.138-139 ℃) with the ether recrystallization.
Example 208
With 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (7.6g) and 1, the mixture heating up of 4-diaminobutane (5.3g) in ethanol (150ml) refluxed 60 hours, obtain a kind of white solid (m.p.135 ℃), use re-crystallizing in ethyl acetate.This solids (2.7g) is dissolved in the methyl alcohol (20ml), obtains 2-(2-morpholino phenylimino) 1 after handling with fumaric acid, 3-Diazesuberane fumarate (m.p.220-222 ℃) is with 1: 1 mixture recrystallization of methyl alcohol and ether.
Example 209
The mixture of 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (1g), dimethylamine (ethanolic soln of 1ml 33%) and ethanol (2ml) was kept under room temperature 48 days.Then this mixture is put in the ice bath and cooled off.Filter to isolate the solids of gained, handle with sodium hydroxide dilute aqueous soln (5ml), (2 * 50ml) extract the gained mixture with methylene dichloride.Extraction liquid salt water washing obtains 1 after dry and steaming desolventizes, and 1-dimethyl-2-(2-morpholino phenyl) guanidine (m.p.143-144 ℃) is used the hexane recrystallization.
Example 210
The solution of 4-(2-aminophenyl) morpholine (5.3g) in methylene dichloride (25ml) is handled with Trapex (3.2g), to stir 36 hours under this mixture room temperature, obtain 1-(2-morpholino phenyl)-3-methylthiourea (m.p.115-116 ℃), with 4: 1 mixture recrystallizations of ethyl acetate and hexane.
Mixture heating up in acetone (30ml) refluxed 4 hours with 1-(2-morpholino phenyl)-3-methylthiourea (5g) and methyl-iodide (2.8g), obtain 2-methyl isophthalic acid-(2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate (m.p.163-164 ℃), with 1: 3 mixture recrystallization of methyl alcohol and ether.
With the mixture of the ethanol solution (40ml) of 2-methyl isophthalic acid-(2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate (3.9g) and 33% methylamine in 50-55 ℃ of heating 28 hours down, obtain 1,3-dimethyl-2-(2-morpholino phenyl) guanidine is with hexane recrystallization (m.p.137-138 ℃).
Example 211
2-methyl isophthalic acid-(2-morpholino the phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate (3.9g is as preparation as described in the example 210) and the mixture of dimethylamine (25ml 33% ethanolic soln) were kept under room temperature 25 days.Obtain a resistates except that after desolvating, on alumina column, carry out chromatography purification, make eluent with 1: 49 mixture of methyl alcohol and methylene dichloride.The gained solids is dissolved in the methyl alcohol, handles with fumaric acid, obtain 1,3,3-trimethylammonium-2-(2-morpholino phenyl) guanidine list fumarate (m.p.192-194 ℃) is with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 212
Make isothiocyanic acid 2-morpholino phenylester (3.3g) and the ethamine reaction that generates by ethylamine hydrochloride (12.18g) and sodium methylate (generating) by sodium (3.5g) and methyl alcohol (100ml), obtain 1-ethyl-3-(2-morpholino phenyl) thiocarbamide (m.p.118-120 ℃), with 1: 1 mixture recrystallization of ethyl acetate and hexane.
Mixture heating up in acetone (25ml) refluxed 4 hours with 1-ethyl-3-(2-morpholino phenyl) thiocarbamide (3.2g) and methyl-iodide (2g), obtain 2-methyl-3-ethyl-1-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate, for light yellow solid (m.p.170-172 ℃), use acetone recrystallization.
With the mixture of the ethanol solution (250ml) of 2-methyl-3-ethyl-1-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (6g) and 33% methylamine earlier 45 ℃ of heating 24 hours down, at room temperature placed again 14 days, obtain 1-ethyl-2-(2-morpholino phenyl)-3-methylguanidine, for colorless solid (m.p.118-119 ℃), use the hexane recrystallization.
Example 213
In ethanol (300ml), add sodium (23g), make the alcohol sodium solution and the ethylamine hydrochloride reaction that obtain, resulting ethylamine solution and 2-methyl-3-ethyl-1-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (6g, put forth energy as system as described in the example 212) at room temperature stirred together 30 days, obtain 1,3-diethyl-2-(2-morpholino phenyl) guanidine (m.p.101-102 ℃) is used the hexane recrystallization.
Example 214
Make 4-(2-(1-(2-the hydroxyethyl)-2-imidazolidine subunit amino) phenyl) morpholine (3g in the methylene dichloride (20ml), as preparation as described in the example 175) with diacetyl oxide (0.86g) reaction, obtain 4-(2-(1-(2-acetoxyl group ethyl)-2-imidazolidine subunit amino) phenyl) morpholine (m.p.89-91 ℃), use the hexane recrystallization.
Example 215
In the presence of anhydrous triethylamine (2ml) and 4-Dimethylamino pyridine (50mg), make 4-(2-(1-(2-the hydroxyethyl)-2-imidazolidine subunit amino) phenyl) morpholine (2.9g in the methylene dichloride (60ml), as preparation as described in the example 175) with benzoyl oxide (2.4g) reaction, obtain a kind of oily matter, on alumina column, carry out chromatography purification, make eluent with methylene dichloride, obtain 4-(2-(1-(2-benzoyloxy ethyl)-2-imidazolidine subunit amino) phenyl) morpholine (m.p.92-94 ℃), with 1: 1 mixture recrystallization of ethyl acetate and hexane.
Example 216
The solution of 4-(2-aminophenyl) morpholine (5.8g) in methylene dichloride (60ml) is handled with n-butyl isothiocyanate (5g), and this mixture stirred under room temperature 4 days, obtain 1-normal-butyl-3-(2-morpholino phenyl) thiocarbamide, be light yellow solid (m.p.105 ℃).
Mixture heating up in acetone (25ml) refluxed 4 hours with 1-normal-butyl-3-(2-morpholino phenyl) thiocarbamide (5.8g) and methyl-iodide (3.1g), obtain 2-methyl-3-normal-butyl-1-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate, be colorless solid (m.p.154-156 ℃).
With the mixture of the ethanol solution (200ml) of 2-methyl-3-normal-butyl-1-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (4.0g) and 33% methylamine earlier 45 ℃ of heating 24 hours down, at room temperature placed again 21 days, and obtained buttery 1-normal-butyl-2-(2-morpholino phenyl)-3-methylguanidine; Handle the methanol solution (25ml) of this oily matter with fumaric acid (0.7g), obtain the colorless solid thing, 1: 1 mixture recrystallization with methyl alcohol and ether obtains 1-normal-butyl-2-(2-morpholino phenyl)-3-methylguanidine list fumarate (m.p.170-172 ℃).
Example 217
With 2-methyl isophthalic acid-(2-piperidino-(1-position only)) phenyl)-mixture of 2-sulfo-pseudo-urea hydriodate (7.5g puts forth energy preparation as described in the method G as system), 2-methoxyethyl amine (2ml) and ethanol (40ml) stirred under room temperature 20 days.Obtain a resistates except that after desolvating, it is dissolved in the methyl alcohol and with fumaric acid handles, obtain 1-(2-methoxyethyl)-2-(2-piperidino-(1-position only) phenyl) guanidine hemifumarate (m.p.218-220 ℃), with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 218
With 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (1.7g, put forth energy as system as described in the example 166), the mixture of 2-methylthio group ethamine (1.8g) and ethanol (25ml) is in 90-95 ℃ of heating 22 hours down, obtain 1-(2-methylmercaptoethyl)-2-(2-morpholino phenyl) guanidine (m.p.115-116 ℃), use the hexane recrystallization.
Example 219
The mixture of 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (7.6g), 2-methoxyethyl amine (2ml) and ethanol (45ml) was stirred under room temperature 14 days, obtain 1-(2-methoxy ethyl)-2-(2-morpholino phenyl) guanidine (m.p.125-128 ℃), with 1,2-glycol dimethyl ether recrystallization, be translated into fumarate (m.p.136-138 ℃), with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 220
The mixture of 2-methyl isophthalic acid-(2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate (7.8g as example 210 as described in preparation), Tri N-Propyl Amine (1.3g) and ethanol (50ml) was stirred under room temperature 45 days, obtain an oily matter, on the neutral alumina post, carry out chromatography purification, make eluent with 1: 99 mixture of methyl alcohol and methylene dichloride.The oily matter of gained is dissolved in the methyl alcohol and with fumaric acid handles affairs, obtain 1-n-propyl-2-morpholino phenyl-3-methylguanidine list fumarate (m.p.187-188 ℃), with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 221
With 2-methyl isophthalic acid-(2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate (3.9g, as preparation as described in the example 210), the mixture of 2-methoxyethyl amine (0.82g) and ethanol (25ml) preserved three months under room temperature, obtain an oily matter, it is dissolved in the methyl alcohol and with fumaric acid handles, obtain 1-methyl-2-(2-morpholino phenyl)-3-(2-methoxy ethyl) guanidine list fumarate (m.p.158-160 ℃), with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 222
With the mixture of 2-methyl isophthalic acid-(2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate (7.86g is as preparation as described in the example 210), cyclopentamine (2.9g), anhydrous sodium carbonate (6.36g) and ethanol (100ml) the stainless steel high pressure vessel heating that places 110 ℃ of oil baths 24 hours.With the reaction mixture cooling, filter the rear section except that desolvating.In resistates impouring ice, gained mixture dichloromethane extraction.With the extraction liquid drying, filter and remove and desolvate, obtain a resistates, handle with fumaric acid, obtain 1-cyclopentyl-2-(2-morpholino phenyl)-3-methylguanidine list fumarate (m.p.220 ℃), with 1: 1 mixture recrystallization of methyl alcohol and ether.
Example 223
With 2-methyl isophthalic acid-(2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate 3.9g, as preparation as described in the example 210), the mixture heating up of pyrrolidone (1ml) and ethanol (40ml) refluxed for 2 weeks, obtain an oily matter, on the neutral alumina post, carry out chromatography purification, 1: 1 mixture wash-out with methylene dichloride and hexane, use 1: 9 mixture wash-out of methyl alcohol and methylene dichloride again, obtain N-methyl-N '-(2-morpholino phenyl) tetramethyleneimine-1-carbonamidine, be translated into its single fumarate (m.p.168-171 ℃), use the propan-2-ol recrystallization.
Example 224
With 2-methyl isophthalic acid-(2-morpholino phenyl)-3-ethyl-2-sulfo-pseudo-urea hydriodate (10g, as preparation as described in the example 212), the mixture of n-Butyl Amine 99 (2.7g) and propyl carbinol (75ml) is in 90-95 ℃ of heating 172 hours, obtain 1-normal-butyl-2-(2-morpholino phenyl)-3-ethyl guanidine, convert it into its single fumarate (m.p.159-160 ℃), with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 225
5-chloro-2-morpholino aniline (2.8g) and n-butyl isothiocyanate (1.5g) were reacted 60 days under room temperature in ethanol (20ml), obtain 1-normal-butyl-3-(5-chloro-2-morpholino phenyl) thiocarbamide (m.p.150-152 ℃).
The mixture heating up of 1-normal-butyl-3-(5-chloro-2-morpholino phenyl) thiocarbamide (2.6g), methyl-iodide (1.4g) and acetone (20ml) was refluxed 3 hours, obtain 2-methyl isophthalic acid-(5-ammonia-2-morpholino phenyl)-3-normal-butyl-2-sulfo-pseudo-urea hydriodate (m.p.130-132 ℃).
The mixture of the second (10ml) of 2-methyl isophthalic acid-(5-chloro-2-morpholino phenyl)-3-butylidene-2-sulfo-pseudo-urea hydriodate (3.4g) and 33% methylamine put in the encloses container under room temperature, preserved 8 months, obtain 1,3-dimethyl-2-(5-chloro-2-morpholino phenyl) guanidine (m.p.145-146 ℃) is used the hexane recrystallization.In this reaction, the fourth amino and the methylthio group of raw material are replaced by methylamino-.
Example 226
Trapex (6.3g) in 1-(2-aminophenyl) tetramethyleneimine (10g) and the methylene dichloride (45ml) was reacted 4 days under room temperature, obtain 1-methyl-3-(2-(1-pyrrolidyl) phenyl) thiocarbamide (m.p.125-126 ℃).
The mixture heating up of 1-methyl-3-(2-(1-pyrryl) phenyl) thiocarbamide (18.5g), methyl-iodide (12.3g) and acetone (100ml) was refluxed 2.5 hours, obtain 2-methyl isophthalic acid-(2-(1-pyrrolidyl) phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate (m.p.161-162 ℃).
The mixture of 2-methyl isophthalic acid-(2-(1-pyrrolidyl) phenyl)-3-methyl-2-sulfo-pseudo-urea iodate (14.7g), allylamine (4.45g) and ethanol (65ml) was preserved under room temperature 50 days, reflux is 20 hours then, the oily matter that obtains is handled with fumaric acid, obtain 1-allyl group-2-(2-(1-pyrrolidyl) phenyl)-3-methylguanidine list fumarate (m.p.162-163 ℃), with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 227
The solution of 4-(2-amino-4-aminomethyl phenyl) morpholine (5.7g) in methylene dichloride (30ml) is handled with Trapex (2.8g), and this reaction mixture preserved under room temperature 6 days, obtain 1-methyl-3-(5-methyl-2-morpholino phenyl) thiocarbamide, be colorless solid (m.p.107 ℃).
Mixture heating up in acetone (60ml) refluxed 4 hours with 1-methyl-3-(5-methyl-2-morpholino phenyl) thiocarbamide (6.4g) and methyl-iodide (3.8g), obtain 2-methyl isophthalic acid-(5-methyl-2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate, be light yellow solid (m.p.160-161 ℃).
The mixture of the ethanol solution (250ml) of 2-methyl isophthalic acid-(5-methyl-2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate (6g) and 33% methylamine was kept under room temperature 21 days, obtain buttery 1,3-dimethyl-2-(5-methyl-2-morpholino phenyl) guanidine, it is dissolved in the methyl alcohol (60ml) also with fumaric acid (1.7g) processing, obtain 1,3-dimethyl-2-(5-methyl-2-morpholino phenyl) guanidine fumarate (1.2g), be colorless solid, with 1: 1 mixture recrystallization (m.p.201-202 ℃) of methyl alcohol and ether.
Example 228
With 2-methyl isophthalic acid-(5-methyl-2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate (8.4g, as preparation as described in the example 227), N-(2-hydroxyethyl)-1, the mixture heating up of 2-quadrol (6.8ml) and ethanol (80ml) refluxed 30 hours, the oily matter that obtains is handled with fumaric acid in methyl alcohol, obtains 4-(2-(1-(2-hydroxyethyl)-2-imidazolidine subunit amino)-4-aminomethyl phenyl) morpholine sesqui fumarate (m.p.135-136 ℃).
Example 229
With 2-methyl isophthalic acid-(2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea (4g, make by example 210 described hydriodates), the mixture of potassium hydroxide (1.7g), n-amylamine (2.1g), lead acetate trihydrate (5.8g) and ethanol (20ml) is in 90-95 ℃ of heating 40 minutes down, the oily matter hexane extraction that obtains, obtain 1-methyl-2-(2-morpholino phenyl)-3-n-pentyl guanidine, be translated into its single fumarate (m.p.148-149 ℃).3: 5 mixture recrystallizations with methyl alcohol and ether.
Example 230
The mixture of 2-methyl isophthalic acid-(5-methyl-2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate (12.2g makes as described in example 227), n-Butyl Amine 99 (2.4g) and ethanol (80ml) was preserved 4 months under room temperature.Add lead acetate trihydrate (9g) then, mixture heating up was refluxed 1 hour, obtain 1-normal-butyl-2-(5-methyl-2-morpholino phenyl)-3-methylguanidine, be translated into its single fumarate (m.p.150 ℃), with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 231
Trapex (4.7g) in 6-methyl-2-morpholino aniline (8.75g) and the methylene dichloride (50ml) was reacted 4 days under the greenhouse, obtain N-methyl-N '-(6-methyl-2-morpholino phenyl) thiocarbamide (m.p.182-183 ℃).
The mixture heating up of N-methyl-N '-(6-methyl-2-morpholino phenyl) thiocarbamide (11.5g), methyl-iodide (6.75g) and acetone (100ml) was refluxed 2.5 hours, obtain 2-methyl isophthalic acid-(6-methyl-2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate (m.p.187-188 ℃).
The mixture of 2-methyl isophthalic acid-(6-methyl-2-morpholino phenyl)-3-methyl-2-sulfo-pseudo-urea hydriodate (17.8g), n-Butyl Amine 99 (6.4g) and ethanol (60ml) was preserved under room temperature 60 days.Add potassium hydroxide (2.2g), add lead acetate trihydrate (7.6g) then, this mixture heating up was refluxed 5 hours, obtain 1-normal-butyl-2-(6-methyl-2-morpholine methyl)-3-methylguanidine, be translated into its single fumarate (m.p.203-204 ℃), with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 232
Make isothiocyanic acid N-(the 2-morpholino methyl) ester (4g) in the ethanol (10ml) recall alcoholic solution (15ml) 15 ℃ of following reactions 4 hours, obtain 1,1-dimethyl-3-(2-morpholino phenyl) thiocarbamide (m.p.150-152 ℃) with 33% of 33% dimethylamine.
With 1, the mixture heating up of 1-dimethyl-3-(2-morpholino phenyl) thiocarbamide (7.5g), methyl-iodide (1.7ml) and acetone refluxed 2 hours, obtained 2-methyl isophthalic acid-(2-morpholino phenyl)-3,3-dimethyl-2-sulfo-pseudo-urea (m.p.162-163 ℃).
With 2-methyl isophthalic acid-(2-morpholino phenyl)-3, the saturated ethanolic soln (100ml) of 3-dimethyl-2-sulfo-pseudo-urea hydriodate (2g), ammonia and the mixture of pyridine (10ml) place airtight stainless steel high pressure vessel to heat 19 hours down in 90-95 ℃.Remove pyridine under reduced pressure, resistates suspends in water.Filter and collect 1,1-dimethyl-2-(morpholino phenyl) guanidine (m.p.142-143 ℃) washes with water, dry back hexane recrystallization.
Example 233
The ethanolic soln (5ml) of 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (3.8g), 33% dimethylamine and the mixture of pyridine (25ml) were heated 6 hours down in 80 ℃.Remove pyridine under reduced pressure, resistates is handled with mixture of ice and water, obtains 1, and 1-dimethyl-2-(2-morpholino phenyl) guanidine (m.p.142-144 ℃) is used the hexane recrystallization.
Example 234
The ethanolic soln (5ml) of 2-methyl isophthalic acid-(2-morpholino phenyl)-2-sulfo-pseudo-urea hydriodate (3.8g), 33% dimethylamine and the mixture of triethylamine (25ml) were heated 8 hours down in 80 ℃.Remove triethylamine under reduced pressure, resistates is handled with mixture of ice and water, obtains 1, and 1-dimethyl-2-(2-morpholino phenyl) guanidine (m.p.141-143 ℃) is used the hexane recrystallization.
Example 235-241
Prepare the listed formula I compound of Table VIII with the following method: with R 14Be methyl and R 15Formula XVI thiocarbamide (Ag), potassium hydroxide (Bg), formula H for H 2NR 0The mixture of amine (Cg), lead acetate trihydrate (Dg) and ethanol (Eml) 90-95 ℃ of down heating F hour, obtain a kind of oily matter, it is dissolved in the methyl alcohol and with fumaric acid handles, obtain single fumarate of formula I compound.The fusing point of single fumarate provides under " m.p. " hurdle, and the used solvent of this salt of recrystallization is pointed out by following note.
The note of Table VIII
(59) salt recrystallizing methanol.
(60) preparation method of thiocarbamide raw material is: make 4-(2-amino-4-fluorophenyl)
Trapex (2.6g) in quinoline (6g) and the methylene dichloride (50ml)
At room temperature reacted 25 days, and obtained 1-methyl-3-(5-fluoro-2-morpholine
For phenyl) thiocarbamide (m.p.145-148 ℃).
(61) free alkali carries out chromatography purification on the neutral alumina post, washes with methylene dichloride
Take off agent.
(62) preparation method of thiocarbamide raw material is: make 4-(2-amino-4-methylthio group phenyl)
Trapex in morpholine (9.5g) and the methylene dichloride (100ml)
(3.1g) at room temperature react 30 days, obtain 1-methyl-3-(5-first sulphur
Base-2-morpholino phenyl) thiocarbamide (m.p.132-133 ℃).
(63) salt 1: 2 mixture recrystallization of methyl alcohol and ether.
(64) salt propan-2-ol recrystallization.
Table VIII Example A B C D E F NR 1R 2R 6R 7Mp (℃) note 2 35 5.4 2.2 2.2 7.4 40 2 morpholino n-Bu 4-F 212 (decomposition) (59) (60) 236 5.9 2.24 2.2 7.6 60 1.5 morpholino n-Bu 4-SMe 120-122 (61) (62) (63) 237 5 2.2 2.9 7.6 50 2 morpholino i-Bu H 157-158 (64) 238 2.5 1.1 1 3.7 20 2 morpholino s-Bu H 170 (decomposition) (63) 239 5 2.2 2.93 7.6 50 3.5 morpholino t-Bu H 182-184 (63) 240 5 2.2 2.3 7.6 50 4.5 morpholino allyl H 189-190 (63) 241 3.9 1.64 2.1 5.5 50 2.5 thia morpholino n-Bu H 162-163 (59)
Example 242
(12g) is Yu the sulfo-carbonyl chloride (8.6g) in diox (30ml) and the water (100ml) descends reaction 30 minutes in 0 ℃ to make 2-morpholino-5-5-trifluoromethylaniline, at room temperature reacted again 2 hours, obtain a resistates, obtain isothiocyanic acid 2-morpholino-5-trifluoromethyl ester with dichloromethane extraction, be yellow oil.
The ethanolic soln (50ml) of isothiocyanic acid 2-morpholino-5-trifluoromethyl ester (12g) and 33% ammonia in the ethanol (20ml) was at room temperature reacted 2 hours, obtain 1-(2-morpholino-5-trifluoromethyl) thiocarbamide (m.p.196-197 ℃).
With the mixture of ethanolic soln (5.6ml), lead acetate trihydrate and the ethanol (40ml) of 1-(2-morpholino-5-trifluoromethyl) thiocarbamide (6.1g), potassium hydroxide (2.2g), 33% dimethylamine in 90-95 ℃ of heating 2 hours down, obtain 1,1-dimethyl-2-(2-morpholino-5-trifluoromethyl) guanidine (m.p.132-135 ℃), use re-crystallizing in ethyl acetate, and be translated into its fumarate (m.p.228-230 ℃), with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 243
(2g) is Yu the sulfo-carbonyl chloride (1.15ml) in diox (2ml) and the water (25ml) descends reaction 30 minutes in 0 ℃ to make 5-cyano group-2-morpholino aniline, under room temperature, reacted 2 hours again, obtain a resistates, with obtaining buttery isothiocyanic acid 5-cyano group-2-morpholino phenylester behind the dichloromethane extraction.
The aqueous solution (1ml) of isothiocyanic acid 5-cyano group-2-morpholino phenylester (2.5g) and 2% ammonia in the ethanol (10ml) was reacted 3 hours under room temperature, obtain 1-(5-cyano group-2-morpholino phenyl) thiocarbamide (m.p.193-194 ℃).
The mixture heating up of ethanolic soln (15ml), lead acetate trihydrate and the ethanol (25ml) of 1-(5-cyano group-2-morpholino phenyl) thiocarbamide (5.2g), salt of wormwood (8.3g), 33% dimethylamine was refluxed 3 hours, obtain 1,1-dimethyl-2-(3-cyano group-2-morpholino phenyl) guanidine (m.p.125-127 ℃), be translated into its single fumarate (m.p.223-225 ℃ (decomposition)), use recrystallizing methanol.
Example 244
With 1, the mixture heating up of 1-dimethyl-3-(2-morpholino phenyl) thiocarbamide (2.65g is as preparation as described in the example 232), Tri N-Propyl Amine (1.6ml), lead acetate trihydrate (3.8g), potassium hydroxide (1.2g) and ethanol (25ml) refluxed 4 hours.Add a certain amount of Tri N-Propyl Amine (1.6ml) again, the mixture reheat refluxed 8 hours.This reaction mixture generates a kind of resistates, with extracted with diethyl ether it.The extraction liquid activated carbon decolorizing, filter and remove desolvate after, stay the solids of next viscosity, it is dissolved in the methyl alcohol (10ml) and with fumaric acid handles, obtain 1,3-di-2-(2-morpholino phenyl) guanidine hemifumarate (m.p.212-214 ℃) is with 1: 2 mixture recrystallization of methyl alcohol and ether.
Example 245
With 1,1-dimethyl-3-(2-morpholino phenyl) thiocarbamide (2.65g, as preparation as described in the example 232), the mixture of saturated ethanolic soln (25ml), potassium hydroxide (1.12g) and the ethanol (20ml) of lead acetate trihydrate (3.8g), ammonia placed in the airtight stainless steel high pressure vessel, in 90-95 ℃ of heating 5 hours.Reaction mixture is filtered and the collection solids, use washing with alcohol.Washings is added in the filtrate, and evaporation reduces volume.Add ice and also filter and collect the gained solid, wash with water and drying after, obtain 1,1-dimethyl-2-(2-morpholino phenyl) guanidine (m.p.141-142 ℃) is used the hexane recrystallization.
Example 246-269
With the formula VII compound (K gram) of hydrochloride form and the formula NC-NR in the meta-cresol (Mml) 5R 6Compound (L gram) obtained the compound that Table I X lists in 90-95 ℃ of following reacting by heating N hour.
The note note (32) of Table I X, (38), (44) and (45) have the given meaning in front.(65) be reflected under 110 ℃ and carry out.(66) product is separated with its single fumarate, and with methyl alcohol and ether 1: 1
The mixture recrystallization.(67) be reflected at and carried out under 90-95 ℃ 8 hours, under 115-120 ℃, carry out again
4 hours.(68) be reflected under 120-125 ℃ and carry out.(69) reaction mixture heated 9 hours down in 90-95 ℃, added under 120 ℃ again
Heat 21 hours.(70) reaction mixture generates a kind of oily matter, uses the ebullient hexane extraction, obtains trip
From alkali, be translated into its single fumarate, with methyl alcohol and ether 1: 3
The mixture recrystallization.(71) reaction mixture generates a kind of oily matter, and it is free to obtain buttery with hexane extraction
Alkali carries out chromatography purification on the neutral alumina post, use following wash-out successively
Agent: 1: 1 mixture of hexane, methylene dichloride and hexane, methylene dichloride, first
1: 99 mixture of pure and mild methylene dichloride is converted into the alkali that obtains its list
Fumarate is with 2: 7 mixture recrystallizations of methyl alcohol and ether.
Table I X Example K L M N NR 1R 2R 5R 6R 7Mp (℃) note 2 46 6.4 1.8 25 3.5 morpholino H H H 189 (44) 247 19.2 9.45 80 5 morpholino Me Me H 215-216 (45) 248 7.4 5.5 25 5.5 morpholino Me Me 4-Me 122-123 (32) 249 10.8 5 45 10 morpholino Me Me 3-Me 230-231 (45) (65) 250 7.3 3.54 50 42 morpholino Me Me 5-Cl 152 (44) 251 7.2 3.54 50 50 morpholino Me Me 6-Cl 190-192 (45) 252 6.3 2.7 25 18 morpholino Me Me 4-OMe 220 (45) 253 6.8 4.25 40 18 morpholino Me Me 4-SMe 220 (decomposition) (45) 254 5.7 2.93 25 6 morpholino Me Me 5-Me 225-226 (45)
Table I X (continuing) example K L M N NR 1R 2R 5R 6R 7Mp (℃) note 2 55 4.9 2.1 25 9 morpholino Me Me 4-Et 217-218 (45) 256 5.4 5.4 40 20 morpholino Me Me 4-CH 2SMe 198-200, (38) 257 8.6 5.9 30 15 morpholino Et Et H 193-194, (45) 258 8.6 6.7 40 8 morpholino Me Bu H 187-188, (45) 259 8.1 8.8 50-morpholinoes, (CH 2) 2OMe (CH 2) 2OMe H 160-162 (66) (67) 260 6.5 5 20 7 morpholino-(CH 2) 2O (CH 2) 2-H 202-203 (45) 261 10.2 6.8 40 12 morpholino-(CH 2) 4-H 237-238, (45) 262 10.6 5.25 30 16 piperidino Me Me H 189-190, (68), (45) 263 8.2 4.3 40 pyrrolidinyl Me Me H 201-202, (45), (69) 264 4.6 2.1 25 1 thia morpholino Me Me H 209-210, (45) 265 4.5 2.3 50 6 NMe2Me Me H 188 (70) 266 4.33 1.75 10 8 N (Me) CH 2CH 2OMe Me Me H 162-163 (71) 267 11.38 3.52 20 8 4-methyl isophthalic acids-Me Me H 205-206 (38)
Piperazinyl 268 7 5.5 25 10 piperidino-(1-position only)s-(CH 2) 2O (CH 2) 2-H 208-209 (68) (45) 269 7.5 5.8 25 13 morpholino-(CH 2) 5-H 216-217 (45)
Example 270
With 4-(2-aminophenyl) morpholine hydrochloride (2.1g) and N, N-dimethyl cyanamide (7ml) heating 12 hours under 165-170 ℃ and nitrogen.Reaction mixture is cooled to 10 ℃, filters the collecting precipitation thing,, add 40% aqueous sodium hydroxide solution and stir with recalling the ether washing.Gained mixture dichloromethane extraction, extraction liquid is also dry with the salt water washing.Obtain a resistates except that after desolvating, obtain 1 with the hexane recrystallization, 1-dimethyl-2-(2-morpholino phenyl) guanidine (m.p.144-145 ℃).
Example 271
With 4-(2-amino-4-methoxycarbonyl phenyl) morpholine (2.7g), N, the mixture of N-dimethyl cyanamide (1g) and meta-cresol (15ml) heated 10 hours down in 90-95 ℃.Add ice, and adding 2N hydrochloric acid is acidified to pH4 with reaction mixture, gained mixture extracted with diethyl ether.The cooling water layer adds solid sodium bicarbonate and alkalizes to pH8, uses dichloromethane extraction then.Extraction liquid is dry also except that after desolvating, obtain an oily resistates, chromatography purification on the neutral alumina post is with 1: 99 mixture wash-out of methyl alcohol and methylene dichloride, obtain 1,1-dimethyl-2-(5-carbometoxyl-2-morpholino phenyl) guanidine (m.p.152-154 ℃).
Example 272
1-(2-morpholino phenyl) thiocarbamide (10.6g) is suspended in the boiling water (80ml), adds the solution of potassium hydroxide (25.2g) in hot water (70ml).With mixture heating up to 90 ℃, add the hot solution of lead acetate trihydrate (17.5g) in water (80ml) of some equal portions, this mixture heating up was refluxed 10 minutes, be cooled to room temperature again.Mixture is filtered, and filtrate is acidified with acetic acid to pH6.The formed solids of filtering separation washes with water, uses re-crystallizing in ethyl acetate, obtains N-(2-morpholino phenyl) cyanamide (m.p.175-176 ℃).
With N-(2-morpholino phenyl) cyanamide (2g) with ethanolic soln (15ml) reflux of 33% dimethylamine 4 hours.With this mixture cooling, steaming desolventizes, and obtains a resistates, and it is suspended in 20% aqueous sodium hydroxide solution then.(3 * 25mn) extract this suspension, and extraction liquid washes with water, uses the salt water washing again, after the dry also evaporation, obtain 1, and 1-dimethyl-2-(2-morpholino base) guanidine (m.p.142-143 ℃) is used the hexane recrystallization with methylene dichloride.
Example 273-285
With with example 272 described similar fashion, with N-(2-morpholino phenyl) ammonia, nitrile (Pg) and formula HNR 5R 6Amine (Qg) and ethanol (Rml) together reflux T hour the time, obtain the listed compound of Table X.
The note of Table X
Note (32), (38), (44) and (45) have the given meaning in front.
(72) make reactant with the ethanolic soln (25ml) of 33% methylamine.
(73) be reflected under 90-95 ℃ and carry out.
(74) product is separated with its single fumarate, uses mix in 2: 3 of methyl alcohol and ether
The compound recrystallization.
(75) product 1: 1 mixture recrystallization of hexane and ethyl acetate.
(76) reaction was at room temperature carried out 2 hours, carried out under 90-95 ℃ 20 minutes again.
(77) product 3: 7 mixture recrystallizations of ethyl acetate and hexane.
(78) reaction was at room temperature carried out 4 hours, and then reflux 4 hours.
Table X Example p Q R T R 5R 6Mp, (℃) note 2 73 2.5 2 H Me 171-172, (72), (73), (74) 274 2 1.3 15 1 H Et 103-105, (75) 275 2 2.2 15 3 H Bu 114-116, (44), (73) 276 2 3.4 20 Me Et 130-132, (76), (32) 277 46 25 1 Me CH2CH 2SMe 230 (decomposition) (45) (73) 278 3 4.6 30 1.25 Me CH 2CH 2OMe 192-193 (38) 279 2 2.2 10 1.5 Me allyl groups 125 (73) (77) 280 4 6.2 30 1.5 Et CH 2CH 2OMe 168-170 (38) 281 4 2.5 25 2 allyl group allyl group 188-190 (73) (38)
Table X (continuing) example P Q R T R 5R 6Mp (℃) note 2 82 55 50 2-(CH 2) 2NMe (CH 2) 2-146-147 (32) 283 2 1.7 20 6-CH 2CHMeOCHMeCH 2-175-177 (44) 284 4 4.1 40 3-(CH 2) 2CHMe (CH 2) 2-133-135 (32) 285 3 22 40-(CH 2) 2S (CH 2) 2-148-150 (32) (78)
Example 286
(8.5g) is Yu the sulfo-carbonyl chloride (4.6ml) in diox (25ml) and the water (100ml) descends reaction 30 minutes in 0 ℃ to make 4-(2-amino-4-chloro-phenyl-) morpholine, under room temperature, reacted 3 hours again, obtain isothiocyanic acid 5-chloro-2-morpholino phenylester, be light yellow solid (m.p.86-87 ℃).
The isothiocyanic acid 5-chloro-2-morpholino phenylester (10g) and the ethanolic soln (60ml) of 33% ammonia were reacted 14 hours under room temperature, obtain 1-(5-chloro-2-morpholino phenyl) thiocarbamide, be light yellow solid (m.p.174-175 ℃).
The mixture heating up that will be suspended in 1-(5-chloro-2-morpholino phenyl) thiocarbamide (5.97g), the lead acetate trihydrate (8.75g) in the water (40ml) and the potassium hydroxide (12.6g) in the water (35ml) in the water (40ml) refluxed 15 minutes, obtain N-(5-chloro-2-morpholino phenyl) cyanamide, be white solid (m.p.305-308 ℃).
With with example 27 described similar modes, with ethanolic soln (6ml) reflux of (5-chloro-2-morpholino phenyl) cyanamide (2.3g) of the N-in the ethanol (10ml) and 33% dimethylamine 4 hours, obtain 1,1-dimethyl-2-(5-chloro-2-morpholino phenyl) guanidine (m.p.135-138 ℃), be translated into its single fumarate (m.p.223-225 ℃) then, use recrystallizing methanol.
Example 287
(mixture in 5.2g) Zai diox (20ml) and the water (40ml) stirred 15 minutes down in 0 ℃ with 5-fluoro-2-morpholino aniline (6g) and sulfo-carbonyl chloride, at room temperature stirred 1 o'clock, obtain a resistates, with obtaining an oily matter behind the dichloromethane extraction, on 100-200 order silicagel column, carry out chromatography purification, 1: 9 mixture with ethyl acetate and hexane is made eluent, obtains oily matter isothiocyanic acid 5-fluoro-2-morpholino phenylester.
The isothiocyanic acid 5-fluoro-2-morpholino phenylester (5.8g) and the ethanolic soln (30ml) of 33% ammonia were reacted 3 hours under room temperature, obtain 1-(5-fluoro-2-morpholino phenyl) thiocarbamide, be white solid (m.p.195-196 ℃).
The mixture heating up that will be suspended in 1-(5-fluoro-2-morpholino phenyl) thiocarbamide (5.1g), the lead acetate trihydrate (7.95g) in the water (36ml) and the potassium hydroxide (11.45g) in the water (32ml) in the water (36.5ml) refluxed 25 minutes, obtain N-(5-fluoro-2-morpholino phenyl) cyanamide, be white solid (m.p.168-170 ℃).
With with example 286 described similar modes, with ethanolic soln (6ml) reflux of (5-fluoro-2-morpholino phenyl) cyanamide (2.2g) of the N-in the ethanol (10ml) and 33% dimethylamine 2 minutes, obtain 1,1-dimethyl-2-(5-fluorine 2-morpholino phenyl) guanidine (m.p.137-138 ℃), use the hexane recrystallization, and be converted into its fumarate (m.p.222-224 ℃), use recrystallizing methanol.
Example 288
(9.4g) is Yu the sulfo-carbonyl chloride (6ml) in diox (50ml) and the water (200ml) descends reaction 30 minutes in 0 ℃ to make 3-methyl-2-morpholino aniline, under room temperature, reacted 2 hours again, the product dichloromethane extraction that obtains, obtain isothiocyanic acid 3-methyl-2-morpholino phenylester, be red oil.
The isothiocyanic acid 3-methyl-2-morpholino phenylester in the ethanol (5ml) and the saturated ethanolic soln (60ml) of ammonia were reacted 4 hours under room temperature, obtain 1-(3-methyl-2-morpholino phenyl) thiocarbamide (m.p.178-179 ℃).
The mixture that will be suspended in 1-(3-methyl-2-morpholino phenyl) thiocarbamide in the water (40ml), the lead acetate trihydrate (9g) in the water (40ml), the potassium hydroxide (13.5g) in the water (35ml) is in 90-95 ℃ of heating 1 hour down, obtain N-(3-methyl-2-morpholino phenyl) cyanamide (m.p.137-138 ℃), use re-crystallizing in ethyl acetate.
With with example 286 described similar modes, with ethanolic soln (3.5ml) reflux of (3-methyl-2-morpholino phenyl) cyanamide (2.5g) of the N-in the ethanol (8ml) and 33% dimethylamine 1 hour.The ethanolic soln (3.5ml) that adds a certain amount of 33% dimethylamine again, this mixture reheat was refluxed 1 hour, obtain 1,1-dimethyl-2-(3-methyl-2-morpholino phenyl) guanidine (m.p.100 ℃), use the hexane recrystallization, be translated into its single fumarate (m.p.180 ℃), with 1: 1 mixture recrystallization of methyl alcohol and ether.
Example 289
(4.7g) is Yu the sulfo-carbonyl chloride (2.9ml) in diox (25ml) and the water (75ml) descends reaction 30 minutes in 0 ℃ to make 4-methoxyl group-2-morpholino aniline, under room temperature, reacted 3 hours again, the resistates dichloromethane extraction that obtains obtains buttery isothiocyanic acid 4-methoxyl group-2-morpholino phenylester.
The isothiocyanic acid 4-methoxyl group-2-morpholino phenyl (4.1g) and the saturated ethanolic soln (30ml) of ammonia were reacted 24 hours under room temperature, obtain 1-(4-methoxyl group-2-morpholino phenyl) thiocarbamide (m.p.175 ℃).
The mixture that will be suspended in 1-(4-methoxyl group-2-morpholino phenyl) thiocarbamide (3.8g), the lead acetate trihydrate (5.7g) in the water (26ml) and the potassium hydroxide (8.4g) in the water (24ml) in the water (26ml) heated 20 minutes down in 90-95 ℃, obtained N-(4-methoxyl group-2-morpholino phenyl) cyanamide.
The mixture heating up of the ethanolic soln (2.5ml) of N-(4-methoxyl group-2-morpholino phenyl) cyanamide (1.9g) and 33% dimethylamine was refluxed 15 minutes, obtain 1,1-dimethyl-2-(4-methoxyl group-2-morpholino phenyl) guanidine (m.p.135 ℃) is used the hexane recrystallization.
Example 290
With 5-isobutyl--2-morpholino anilinechloride (4.1g), N, the mixture of N-dimethyl cyanamide (1.77g) and meta-cresol (15ml) was in 90-95 ℃ of heating 6 hours, the hot hexane extraction of resulting resistates, use activated carbon decolorizing, on alumina column, carry out chromatography purification, with 2: 98 mixture wash-outs of methyl alcohol and methylene dichloride.Products therefrom 1: 3 crystalline mixture of ethyl acetate and hexane.Remove by filter the initial precipitation thing, filtrate is evaporated to dried, the resistates that obtains obtains 1,1-dimethyl-2-(5-isobutyl--2-morpholino phenyl) guanidine with 1: 3 mixture recrystallization of ethyl acetate and hexane.
Example 291
In the solution of yellow soda ash (3.75g) in water (25ml), add Textone (5.6g), cuprous chloride (0.2g), cupric chloride dihydrate (0.34g).Mixture is cooled to 20 ℃, with the solution of 15 minutes adding N-(2-morpholino phenyl) thiocarbamides (6g) in methylene dichloride (45ml).Temperature is brought up to 40 ℃ and when keeping this level 4.5.Add entry (100ml) and methylene dichloride (200ml), mixture was stirred 10 minutes.Tell organic layer, the water layer washed with dichloromethane.Merge organic layer and also dry with the salt water washing.Obtain a resistates except that after desolvating, add 20% aqueous sodium hydroxide solution (100ml) and stir, in steam bath, heat, filter then.Filtrate is washed with ether, is acidified with acetic acid to pH4, and uses dichloromethane extraction.Extraction liquid salt water washing, dry also removing desolvated, and the gained resistates carries out chromatography purification on silicagel column, use the hexane wash-out, adds ethyl acetate (until 30%) gradually to improve polarity in hexane.N-(2-morpholino phenyl) cyanamide (m.p.175-176 ℃).
The mixture heating up of the ethanolic soln (12ml) of N-(2-morpholino phenyl) cyanamide (1.5g) and 33% dimethylamine was refluxed 4 hours.Obtain a resistates except that after desolvating, to wherein adding methylene dichloride (100ml) and salt solution (50ml).Mixture was stirred 5 minutes, tell organic layer and dry.Obtain 1 except that after desolvating, 1-dimethyl-2-(2-morpholino phenyl) guanidine (m.p.144-145 ℃) is used the hexane recrystallization.
Example 292
1 of the free alkali form that will obtain by the product of example 253; 1-dimethyl-2-(5-methylthio group-2-morpholino phenyl) guanidine (1.3g), sodium metaperiodate (1g), methyl alcohol (10ml) and water (4ml) were preserved 20 hours under room temperature; obtain 1; 1-dimethyl-2-(5-methanesulfinyl-2-morpholino phenyl) guanidine (m.p.160-161 ℃) is used re-crystallizing in ethyl acetate.
Example 293
At aqueous sodium carbonate (3.75g yellow soda ash, 25ml), in the mixture that is stirring of Textone (5.6g), cuprous chloride (0.2g), cupric chloride dihydrate (0.34g) and benzyl trimethyl ammonium chloride (0.6g), with adding the solution of 1-methyl-2-(2-morpholino phenyl) thiocarbamides (6.2g) in methylene dichloride (30ml) in 15 minutes.The gained mixture was stirred 2 hours, adds Textone (2.4g) and benzyl trimethyl ammonium chloride 6.4g then), this mixture was stirred 1.5 hours.Add methylene dichloride (200ml) and water (50ml), (2 * 100ml) extract water layer with methylene dichloride.Combining extraction liquid is also used the salt water washing, dry and filtration.Obtain a resistates except that after desolvating, on silica gel, carry out chromatography purification, use 1: 4 mixture of ethyl acetate and hexane to make eluent again with hexane earlier, obtain N-methyl-N '-(2-morpholino phenyl) carbodiimide (m.p.67-68 ℃).
With N-methyl-N ' ,-(2-morpholino phenyl) carbodiimide (1g), n-Butyl Amine 99 (0.5g) and the mixture of propyl carbinol (5ml) in 90-95 ℃ of down heating 4 hours.After steaming desolventizes, resistates is dissolved in methylene dichloride (100ml), the washing of gained solution with water, dry and filtration, obtain 1-normal-butyl-2-(2-morpholino phenyl)-3-methylguanidine except that after desolvating, be translated into its single fumarate (m.p.178-179 ℃).
Example 294 to 300
With with example 2 described similar fashion; The product of following example is converted into their fumarate, and with shown in solvent recrystallization: the initial example recrystallization solvent of example fumarate fusing point (℃) 294 133 1: 2 methyl alcohol: ether 173-175295 134 1: 2 methyl alcohol: ether 183-184296 167 2: 1 methyl alcohol: ether 192-193297 175 1: 1 methyl alcohol: ether 159-160298 200 propan-2-ol 142-143299 201 1: 1 methyl alcohol: ether 151-152300 204 1: 2 methyl alcohol: ether 170-171
Example 301
The mixture of 2-morpholino anilinechloride (19.2g), meta-cresol (80ml) and diformazan cyanamide (9.45g) was heated 5 hours down in 100 ℃, it is joined in the mixture of 40% aqueous sodium hydroxide solution (300ml) and ice (300g) after the cooling.Add entry (300ml), the solid of filtering separation gained washes with water and it is dissolved in the methylene dichloride.Solution is dry also except that after desolvating, and the resistates that obtains hexane recrystallization obtains 1,1-dimethyl-2-(2-morpholino phenyl) guanidine (m.p.142-143 ℃).
Example 302-304
The product that makes example 175,248 and 300 obtains following compounds and uses recrystallizing methanol respectively with its free alkali form and reaction of L (+) tartrate in methyl alcohol.
(302.4-2-(1-(2-hydroxyethyl)-2-imidazolidine subunit amino) phenyl)
Morpholine list tartrate (m.p.147-148 ℃).
303 1,1-dimethyl-2-(5-methyl-2-morpholino phenyl) guanidine list winestone
Hydrochlorate (m.p.183-184 ℃).
304 1,1-dimethyl-2-(2-morpholino phenyl) guanidine list tartrate (m.
p.184-185℃)。
Example 305 and 306
Make methyl alcohol and excess acetyl chloride 30 minutes, the hydrogenchloride that obtains respectively with the reaction of the product of example 248 and 301, obtain following product.Product is with the solvent recrystallization that provides in the bracket.
305 1,1-dimethyl-2-(5-methyl-2-morpholino phenyl) guanidine list hydrochloric acid
Salt (m.p.161-162 ℃) (1: 1 mixture of Virahol and ether).
306 1,1-dimethyl-2-(2-morpholino base) guanidine mono-hydrochloric salts (m.p.
200-201 ℃) (Virahol).
Example 307
Make example 301 products and strong sulfuric acid response in the acetone, obtain 1,1-dimethyl-2-(2-morpholino phenyl) guanidine Hemisulphate (m.p.234-235 ℃) is with 1: 1 mixture recrystallization of methyl alcohol and ether.
Example 308
Make rub example 301 products reaction in acid (pamoi cacid) and the pyridine of handkerchief, obtain 1,1-dimethyl-2-(2-morpholino phenyl) guanidine half handkerchief hydrochlorate (m.p.158-160 ℃) that rubs.
Example 309
With 1 in the benzene (40ml), 4-(2-aminobenzyl) morpholine (3.8g) in 3-dimethyl-2 imidazolidone (4.6g), the benzene (20ml) and the mixture of phosphoryl chloride (3.6ml) heated 20 hours down in 65-70 ℃, (2-(1 to obtain 4-, 3-dimethyl-2-imidazolidine subunit amino) benzyl) morpholine (m.p.56-58 ℃) is used the hexane recrystallization.
Example 310
With 1 in the benzene (100ml), the mixture of (2-amino-4-benzyl chloride base) morpholine (13.6g) of the 4-in 3-dimethyl-2-imidazolidone (10.95g), the benzene (50ml) and phosphoryl chloride (8.8ml) heated 8 hours down at 60-65 ℃, the oily matter that obtains carries out column chromatography purification on alumina column, make eluent with following solvent successively: 1: 1 mixture, the methylene dichloride of 9: 1 mixtures, hexane and the methylene dichloride of hexane, hexane and methylene dichloride.Products therefrom (3.2g) is dissolved in the methyl alcohol (50ml), handle with fumaric acid (1.2g), obtain 4-(4-chloro-2-(1,3-dimethyl-2-imidazolidine subunit amino) benzyl) morpholine list fumarate (m.p.169-170 ℃), with 1: 1 mixture recrystallization of methyl alcohol and ether.
Example 311
With 4-(2-aminobenzyl) morpholine dihydrochloride (10.6g) and N, the mixture of N-dimethyl cyanamide (4.2g) in meta-cresol (40ml) heated 13 hours down at 90-95 ℃, obtain a kind of solids (m.p.120-121 ℃), its part (2g) is dissolved in the methyl alcohol (15ml).After fumaric acid (0.9g) processing, obtain N, N-dimethyl-N '-(2-morpholino aminomethyl phenyl) guanidine list fumarate (m.p.164-165 ℃) uses the propan-2-ol recrystallization.
Example 312
The mixture of 4-(2-aminobenzyl) morpholine dihydrochloride (6.8g), 4-cyano group morpholine (4.3g) and meta-cresol was heated 12 hours at 90-95 ℃, obtain N-(2-morpholino aminomethyl phenyl) morpholine-4-amidine (m.p.118-119 ℃), use the hexane recrystallization, be translated into its two fumarates (m.p.166-167 ℃) then, use the propan-2-ol recrystallization.
Example 313
The application of explanation The compounds of this invention in pharmaceutical compositions in the narration below.In the narration, term " active compound " refers to any compound of the present invention in this section, particularly as any compound of the final product of one of previous examples.
A) glue Nang agent
During the preparation capsule, with the lactose disaggregation and the mixing of 10 parts of heavy active compounds and 240 parts of weights.With this mixture hard gelatin capsule of packing into, contained active compound is the part of a unitary dose or a unitary dose in each capsule.
B) tablet
Prepare tablet by following ingredients.
Active compound 10 lactose 190 W-Gums 22 polyvinylpyrrolidones 10 Magnesium Stearates 3 of parts by weight such as example 1 preparation
With active compound, lactose and a part of starch disaggregation and mixing, the ethanolic soln of gained mixture and polyvinylpyrrolidone is made particle.Dried particle is mixed with Magnesium Stearate and remaining starch.Then this mixture is put and be pressed into tablet in the tabletting machine, contained active compound is the part of a unitary dose or a unitary dose in every.
C) enteric coated tablet
Prepare tablet with the method described in above-mentioned (b).With 20% acetate terephthaldehyde acid cellulose and 3% diethyl terephthalate at ethanol: the solution in the methylene dichloride (1: 1), in a usual manner tablet is carried out enteric coating.
D) suppository
During preparation suppository, 100 parts of heavy active compounds are mixed in the triglyceride level suppository base of 1300 parts of weights, this mixture is made suppository, every dose contains the treatment effective amount of actives.

Claims (11)

1. the method for a preparation I compound or its pharmacologically acceptable salt
Figure C9010329500021
N=0 or 1 wherein;
R 1And R 2Identical or different, for: (a) contain the aliphatic group of 1 to 3 carbon atom, described aliphatic group can be replaced by methoxyl group; (b) contain the cycloalkyl of 3 to 7 carbon atoms; Or (c) R 1And R 2Forming one with the nitrogen-atoms that they connected can substituted formula II heterocycle; R wherein 3Represent H or contain the alkyl of 1 to 3 carbon atom; B represents the alkylidene group of 2 to 4 carbon atoms, the middle nitrogen that can be inserted with oxygen, sulphur, sulfinyl or can be contained the alkyl replacement of 1 to 3 carbon atom of this alkylidene group, described alkylidene group can be replaced by one or more alkyl that contain 1 to 3 carbon atom, and perhaps the substituting group on two adjacent carbonss of this alkylidene group forms a phenyl ring; Perhaps B represents the alkenylene of 3 carbon atoms;
R 3For containing the straight or branched alkyl of 1 to 7 carbon atom, or contain the cycloalkyl of 3 to 7 carbon atoms, or the group of formula III;
Figure C9010329500031
R wherein 4And R ' 4Identical or different, for H or contain the alkyl of 1 to 4 carbon atom;
R 5Be the straight or branched aliphatic group of H or 1 to 4 carbon atom, described aliphatic group can be replaced by methoxyl group;
R 6For: (a) H; (b) the straight or branched aliphatic group of 1 to 6 carbon atom, this group can be replaced by following group: hydroxyl or its acylated derivatives, contain 1 to 3 carbon atom alkoxyl group, contain 1 to 3 carbon atom alkylthio, can be by alkylating amino, contain the carbocylic radical or the cyano group of 3 to 77 carbon atoms; Or its condition of cycloalkyl ring that (c) contains 3 to 7 carbon atoms is to work as NR 1R 2Be dialkyl amido and R 3R when being the group of formula III 4, R 4', R 5Or R 6In at least one be not hydrogen;
Or R 3Group and R 5The heterocycle that group forms formula IV with carbon atom that they connected and nitrogen-atoms;
Figure C9010329500032
R wherein 6Limit as the front; R 9And R 10Identical or different, be the alkyl of H or 1 to 4 carbon atom that can be replaced by methoxyl group; D is the oxygen ethylidene, Sauerstoffatom wherein with have a R 9And R 10The carbon atom keyed jointing of group, perhaps D is the alkylidene group of 2 to 5 carbon atoms, this alkylidene group can be replaced by the alkyl of one or more 1 to 3 carbon atom;
Perhaps R 3Group and R 5The heterocycle that their carbon atoms that connected of group and nitrogen-atoms form formula V together;
Figure C9010329500041
R wherein 6As previously mentioned, R 11For H or contain the alkyl of 1 or 2 carbon atom; E is the alkylidene group of 2 to 4 carbon atoms, and this alkylidene group can be replaced by one or more alkyl that contain 1 to 3 carbon atom;
Perhaps R 5And R 6Form the heterocycle of formula VI with the nitrogen-atoms that they connected; Wherein G is the alkylidene group of 4 or 5 carbon atoms, the middle nitrogen that can insert oxygen, sulphur or can be contained the alkyl replacement of 1 to 3 carbon atom of this alkylidene group, and described alkylidene group can be replaced by one or more alkyl that contain 1 to 3 carbon atom;
R 7Represent H or one or more dispensable substituting group, these substituting groups are selected from: halogen, contain 1 to 4 carbon atom and alkyl, the alkoxyl group that contains 1 to 3 carbon atom, the alkylthio that contains 1 to 3 carbon atom, the alkyl sulfinyl that contains 1 to 3 carbon atom that can be replaced by methylthio group, contain the alkane alkylsulfonyl of 1 to 3 carbon atom, contain carbalkoxy, trifluoromethyl or the cyano group of 2 or 3 carbon atoms altogether;
Described method comprises; In the presence of condensing agent, make aminophenyl compound and the formula R of formula VII 3CONR 5R 6Acid amides or urea reaction.
2. the method for preparation I compound according to claim 1, its Chinese style VII compound
Figure C9010329500052
React with following compound:
A) in the presence of condensing agent, with the lactone reaction of formula VII;
Figure C9010329500053
B) with the reaction of formula IX compound: R wherein 12For chlorine ,-O-POCl 2,-O-SOCl ,-OCOCl or-OSO 2Ph, B -Be a negatively charged ion, as halogen ion or POCl 4 -
C) with the reaction of formula X compound:
Figure C9010329500062
R wherein 13Be alkyl, B -Be a negatively charged ion such as fluoroboric acid root or methyl-sulfuric acid root;
D) work as R 6During for H, in the presence of SULPHURYL CHLORIDE, react with the ketoxime of formula XI; Or
Figure C9010329500063
E) in the presence of condensing agent, with the urea of formula XII, reaction;
3. according to the method for claim 1 or 2, wherein condensing agent is to be selected from phosphoryl chloride, thionyl chloride, carbonyl chloride, phosphorus pentachloride or benzene sulfonyl chloride.
4. the side of preparation I compound according to claim 1, wherein R 3And R 5Form the ring shown in the formula V with carbon atom and nitrogen-atoms that they connected, described method comprises: make wherein R 14And R 15For the formula XIII compound of H or arbitrarily selectively with its form of salt and the diamine reactant of formula XIV;
R 11NHENHR 6 XIV
5. the method for preparation I compound according to claim 1, wherein R 3Be 1 to 7 carbon atom the straight or branched alkyl or or the cycloalkyl of 3 to 7 carbon atoms, group NR 5R 6Be NH 2, described method comprises: make formula VII compound or with the form of its salt
With formula R 3The cyano compound reaction of CN, this reaction also can be carried out in the presence of aluminum chloride.
6. preparation I compound method according to claim 1, wherein R 3Group is NH 2, described method comprises, makes formula VII compound or with the form of its salt
Figure C9010329500082
With formula R 5-R 6The cyanamide compounds reaction of NCN.
7. the method for preparation I compound according to claim 1, wherein R 3Group is NH 2, described method comprises, makes formula XV compound and formula NHR 5R 6Amine reaction.
8. the method for preparation I compound according to claim 1, wherein R 3Be a formula III group, R in this group 4Be alkyl, R 4' be H or alkyl, described method comprises, makes wherein R 14Be R 4Group and R 15Be R 4The formula XIII compound of ' group With formula HN 5R 6Amine reaction, this reaction can be carried out in the presence of alkali, also can carry out in the presence of potassium hydroxide and aluminum acetate.
9. the method for preparation I compound according to claim 1, wherein R 3Be the formula III group, R in this group 4Be alkyl, R 4' for H or this method of alkyl comprise, make thiocarbamide and the formula HNR of formula XVI 5R 6Amine reaction, reaction can be carried out in the presence of alkali and aluminum acetate R wherein 14Be R 4Group, R 15Be R 4' group.
10. the method for the described preparation I compound of root root claim 1, wherein R 3Be the formula III group, R in this group 4Be alkyl, R 4' be H, R 5Be H, described method comprises, makes carbodiimide and the formula H of formula XVII 2NR 6Amine reaction;
Figure C9010329500093
11. the method for preparation I compound according to claim 1, n=0 wherein, NR 1R 2Be morpholino, thia morpholino, 1-pyrrolidyl or piperidino-(1-position only), described method comprises, makes the reaction of formula XVIII compound and dibasic formula XIX compound:
K (CH 2) 2L (CH 2) 2K XIX wherein K is a leavings group, L is respectively-O-,-S-, direct key or-CH 2-.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0017484A1 (en) * 1979-04-03 1980-10-15 Fujisawa Pharmaceutical Co., Ltd. 2-Imidazoline derivatives, process for the preparation thereof and the pharmaceutical composition of the same
US4414211A (en) * 1978-09-18 1983-11-08 Mcneilab, Inc. Heterocyclic derivatives of guanidine
EP0233461A2 (en) * 1986-01-13 1987-08-26 American Cyanamid Company 4,5,6-Substituted-2-pyrimidinamines

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4414211A (en) * 1978-09-18 1983-11-08 Mcneilab, Inc. Heterocyclic derivatives of guanidine
EP0017484A1 (en) * 1979-04-03 1980-10-15 Fujisawa Pharmaceutical Co., Ltd. 2-Imidazoline derivatives, process for the preparation thereof and the pharmaceutical composition of the same
EP0233461A2 (en) * 1986-01-13 1987-08-26 American Cyanamid Company 4,5,6-Substituted-2-pyrimidinamines

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