CN103709096A - Urea type derivative used as nicotinamide ribose phosphate transferase inhibitor, as well as preparation method and application thereof - Google Patents

Urea type derivative used as nicotinamide ribose phosphate transferase inhibitor, as well as preparation method and application thereof Download PDF

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CN103709096A
CN103709096A CN201310723814.3A CN201310723814A CN103709096A CN 103709096 A CN103709096 A CN 103709096A CN 201310723814 A CN201310723814 A CN 201310723814A CN 103709096 A CN103709096 A CN 103709096A
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phenyl
picolyl
thiocarbamide
piperazinyl alkylsulfonyl
alkylsulfonyl
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CN103709096B (en
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缪朝玉
盛春泉
徐添颖
董国强
张赛龙
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Second Military Medical University SMMU
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention belongs to the technical field of medicines. The invention provides a urea type derivative and a pharmaceutically acceptable salt thereof. The general structural formula of the compound is as shown in formula (I) in the specification. As proved by pharmacological experiments, the compound or salt mentioned in the invention not only has quite high inhibition activity on nicotinamide ribose phosphate transferase but also has high antitumor activity in vitro. The invention further provides a preparation method of the derivative and the pharmaceutically acceptable salt thereof, as well as an application of the derivative and the pharmaceutically acceptable salt thereof to preparation of a nicotinamide ribose phosphate transferase inhibitor or antitumor drugs.

Description

A kind of carbamide derivative as Nampt inhibitor and preparation method thereof and application
Technical field
The invention belongs to medical technical field, be specifically related to a kind of carbamide derivative as Nampt inhibitor and preparation method thereof and preparing the antitumor application waiting in medicine.
Background technology
Nampt (nicotinamide phosphoribosyltransferase, Nampt) is called again Nampt (visfatin) or PBEF (PBEF).Nampt catalysis niacinamide (nicotinamide, NAM) generate nmn (nicotinaminde mononucleotide, NMN), the level of the essential energy matter NAD of regulation and control mammalian cell, it is the rate-limiting enzyme that NAD generates approach, in cell physiological activity, play vital effect (Galli, U., et al.Medicinal Chemistry of Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors, J Med Chem2013,56,6279-96.).Research shows, the generation of Nampt and tumour and develop closely relatedly has become a very important novel targets in antitumor drug research.First, tumour cell has very high NAD and consumes and metabolic rate, and tumor cell ratio normal cell is stronger to the dependency of NAD, is more easily subject to the impact of Nampt inhibitor, secondly, in tumour cell, NAD participates in the synthetic of the essential material of kinds of tumors as essential coenzyme, and, NAD can significantly reduce (the reactive oxygen species of active oxygen radical in environment, ROS) level, protection tumour cell (Cerna, D., et al.Inhibition of nicotinamide phosphoribosyltransferase (NAMPT) activity by small molecule GMX1778regulates reactive oxygen species (ROS)-mediated cytotoxicity in a p53-and nicotinic acid phosphoribosyltransferase1 (NAPRT1)-dependent manner, J.Biol.Chem.2012, 287, 22408-17, Vander Heiden, M.G., et al.Understanding the Warburg Effect:The Metabolic Requirements of Cell Proliferation.Science2009,324,1029-33.), in addition, Nampt plays important effect (Adya at angiogenesis, induction of vascular endothelial growth factor in generating, R., et al.Visfatin induces human endothelial VEGF and MMP-2/9production via MAPK and PI3K/Akt signalling pathways:novel insights into visfatin-induced angiogenesis, Cardiovasc Res2008,78,356-65.).These features show that Nampt is the important rate-limiting enzyme that tumour cell maintains NAD level, and exploitation Nampt inhibitor has become the new direction of antitumor drug research.
The Nampt inhibitor studies have reported that at present has FK866 (Hasmann, M., et al.FK866, ahighly specific noncompetitive inhibitor of nicotinamide phosphoribosyltransferase, represents a novel mechanism for induction of tumor cell apoptosis, Cancer Res2003, 63, 7436-42.) and CHS-828 (Hjarnaa, P.J., et al.CHS828, a novel pyridyl cyanoguanidine with potent antitumor activity in vitro and in vivo, Cancer Res1999, 59, 5751-7.), both have all entered clinical study.
In early-stage Study, contriver finds carbamide compounds MS735, its chemical structural formula is as shown in formula II, this compound shows good inhibition activity to Nampt, and applied for that (number of patent application is CN201110447488.9 to Chinese invention patent, denomination of invention is a kind of application of carbamide compounds, and application publication number is CN102670625A).But also there is the shortcomings such as poorly water-soluble in this compound.
Figure BDA0000445187100000021
Summary of the invention
The object of the invention is to find that a class is efficient, the novel Nampt antineoplastic compound of low toxicity, wide spectrum, a kind of carbamide derivative and pharmacy acceptable salt thereof are provided; Another object of the present invention is to provide the preparation method of this analog derivative and pharmacy acceptable salt thereof; The 3rd object of the present invention is to provide this analog derivative and the application of pharmacy acceptable salt in preparation Nampt inhibitor, antitumor drug thereof.
The present invention, by carbamide compounds MS735 being carried out to structural modification and skeleton transition, obtains a plurality of carbamide derivatives, suppresses active and extracorporeal anti-tumor cell-proliferation activity, all improve a lot and improve on water-soluble at Nampt.
A first aspect of the present invention, is to provide a kind of carbamide derivative and pharmacy acceptable salt thereof, the general structure of this compound as shown in the formula (I):
Figure BDA0000445187100000022
Wherein:
X is NH or O;
Y is S, NH or N-CN;
L is CO or SO 2;
It is arbitrary to (III) that R group is selected from (I):
(I) aniline or substituted aniline
On substituted aniline phenyl ring, substituting group can be positioned at ortho position, a position and the contraposition of phenyl ring, can be monosubstituted, can be also polysubstituted, and substituting group refers to:
D. halogen: F, Cl, Br, I
E.1-6 the straight or branched alkyl of carbon atom
The straight or branched alkyl of 1-6 carbon atom refers to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl;
F. cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy;
(II) benzylamine or alpha substituted benzylamine
On alpha substituted benzylamine phenyl ring, substituting group can be positioned at ortho position, a position and the contraposition of phenyl ring, can be monosubstituted, can be also polysubstituted, and substituting group refers to:
D. halogen: F, Cl, Br, I
E.1-6 the straight or branched alkyl of carbon atom
The straight or branched alkyl of 1-6 carbon atom refers to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl;
F. cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy;
(III) N-pyrrolidyl, N-morpholinyl, N-piperidyl, N-piperazinyl or
Figure BDA0000445187100000031
When X is N, when Y is S, R is not N-piperidyl;
R 1it is arbitrary to (G) that group is selected from (A):
(H) phenyl or substituted-phenyl
On substituted-phenyl phenyl ring, substituting group can be positioned at ortho position, a position and the contraposition of phenyl ring, can be monosubstituted, can be also polysubstituted, and substituting group refers to:
D. halogen: F, Cl, Br, I
E.1-6 the straight or branched alkyl of carbon atom
The straight or branched alkyl of 1-6 carbon atom refers to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl;
F. cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy;
(I) benzyl or substituted benzyl
On substituted benzyl phenyl ring, substituting group can be positioned at ortho position, a position and the contraposition of phenyl ring, can be monosubstituted, can be also polysubstituted, and substituting group refers to:
D. halogen: F, Cl, Br, I
E.1-6 the straight or branched alkyl of carbon atom
The straight or branched alkyl of 1-6 carbon atom refers to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl;
F. cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy;
(J) containing 1-2 the first heterocycle of heteroatomic 5-6
Heteroatoms refers to N, O, S;
(K) containing 1-2 heteroatomic 5-6 unit's heterocyclic methyl or containing 1-2 heteroatomic benzo 5-6
Unit's heterocyclic methyl
Heteroatoms refers to N, O, S;
(L) the straight or branched alkyl of 1-8 carbon atom
The straight or branched alkyl of a described 1-8 carbon atom refers to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl;
(M) straight or branched alkyl carbonyl or the carbalkoxy of 1-8 carbon atom
The straight or branched alkyl of a described 1-8 carbon atom refers to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl;
(N) cycloalkyl of 3-8 carbon atom
The cycloalkyl of a described 3-8 carbon atom refers to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group.
Described pharmacy acceptable salt, preferably: hydrochloride, hydrobromate, vitriol, acetate, lactic acid salt, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, tosic acid or mesylate;
Described pharmacy acceptable salt, does not contain crystal water, or contains the crystal water of one or more molecules, preferably contains the crystal water of 0.5-3.0 molecule.
Part preferred compound of the present invention includes, but are not limited to following:
1-[4-(4-tertbutyloxycarbonyl-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
1-(4-(1-piperazinyl alkylsulfonyl)-phenyl)-3-(3-picolyl) thiocarbamide
N-phenyl-4-[3-(3-picolyl) thioureido] benzsulfamide
1-[4-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
1-[4-(4-formyl radical-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
1-{4-[4-(2-pyridyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(4-benzyl-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
1-[4-(4-hexanaphthene-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
1-(3-picolyl)-3-[4-(1-pyrrolidyl alkylsulfonyl)-phenyl] thiocarbamide
N-benzyl-4-[3-(3-picolyl) thioureido] benzsulfamide
1-[4-(N-morpholine alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
2-(1-group-4 ethyl formate)-1-(3-picolyl)-3-[4-(1-piperdine sulfonyl)-phenyl] guanidine
1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) urea
1-[4-(1-piperdine sulfonyl)-phenyl]-3-(3-picolyl) urea
1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) thiocarbamide
[4-(1-piperidine formyl base)-phenyl] carboxylamine-3-pyridine methyl esters
[4-(1-piperdine sulfonyl)-phenyl] carboxylamine-3-pyridine methyl esters
1-[4-(1-piperdine sulfonyl)-phenyl]-3-(3-picolyl) guanidine
1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) guanidine
[4-(1-piperidine formyl base)-phenyl] amino bamic acid ethyl ester
2-cyano group-1-(3-picolyl)-3-[4-(1-tetramethyleneimine alkylsulfonyl)-phenyl] guanidine
1-{4-[4-(4-luorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(2,6-difluorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(3-luorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(2-luorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(4-methyl-benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(2-methyl-benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(3-methyl-benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(3-chlorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(2-chlorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(4-chlorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(4-bromobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(2-menaphthyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(4-trifluoromethyl benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(4-trifluoro-methoxybenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(4-normal-butyl benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(4-nitrobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(4-aminobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(2-1H-benzo [d] imidazoles)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(3-furylmethyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(3-thenyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(furfuryl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(2-thenyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(4-picolyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(3-picolyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(4-tolyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(2-picolyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide.
A second aspect of the present invention, is to provide the preparation method of above-mentioned carbamide derivative and pharmacy acceptable salt thereof.
The reaction process of the compounds of this invention is as follows:
Reaction process leads to method one:
Figure BDA0000445187100000061
Raw material I (10mmol) and raw material II (11mmol) are dissolved in to methylene dichloride (50mL), add triethylamine (1.5mL), room temperature reaction 2h.1M aqueous hydrochloric acid (50mL) and saturated aqueous common salt (50mL) washing for reaction solution, anhydrous sodium sulfate drying.Filter, organic phase concentrating under reduced pressure obtains intermediate III.
Intermediate III (10mmol) is dissolved in ethyl acetate (50mL), adds catalytic amount palladium charcoal, room temperature reaction 12h under hydrogen.Filter palladium charcoal, solvent evaporated obtains key intermediate IV.
Key intermediate IV (5mmol) is dissolved in methylene dichloride (50mL), add thiophosgene (or phosgene, 7.5mmol), room temperature (or 50 ℃) reaction 2h.Saturated sodium bicarbonate for reaction solution (50mL) and saturated aqueous common salt (50mL) washing, anhydrous sodium sulfate drying.Filter, solvent evaporated obtains intermediate V.The not purified ethanol (20mL) that is directly dissolved in of intermediate V, adds 3-aminomethyl-pyridine (5mmol), stirring at room 1h.Reaction solution is concentrated, and residue obtains target compound VI a through column chromatography purification.
Reaction process leads to method two:
Intermediate IV (1mmol) and compound VII (1mmol) are dissolved in to tetrahydrofuran (THF) (20mL), room temperature reaction 3h.Concentration of reaction solution, residue obtains target compound VI b through column chromatography purification.
Reaction process leads to method three:
Figure BDA0000445187100000072
Intermediate VIII (1mmol) is dissolved in to acetone (10mL), adds triethylamine (0.6mL), slowly drip compound IX (1.2mmol), stirring at room 2h.Then solvent evaporated, residue obtains target compound VI c through column chromatography purification.
Reaction process leads to method four:
Figure BDA0000445187100000073
Compound X (1mmol), EDC (0.76g, 2mmol), triethylamine (1.5mL) and cyanamide (0.8g, 20mmol) or ammoniacal liquor (2mL) are dissolved in to tetrahydrofuran (THF) (20mL), 50 ℃ of reaction 3h.Reaction solution adds water (100mL), and dichloromethane extraction (100mL * 3) merges organic phase, saturated common salt water washing (100mL), anhydrous sodium sulfate drying.Organic phase concentrating under reduced pressure, residue obtains target compound VI d through column chromatography purification.
The reaction process of described pharmacy acceptable salt is as follows:
Reaction process leads to method five:
Figure BDA0000445187100000081
Target product VI (0.1g) is dissolved in ethanol (10mL), adds the ethanolic soln (10mL) with HX heat, and room temperature reaction 3h has reacted rear suction filtration, washing, the dry salt XI that obtains.
Target product VI is that aforementioned target compound VI a is to VI d.
HX is hydrochloric acid, Hydrogen bromide, sulfuric acid, acetic acid, lactic acid, tartrate, tannic acid, Citric Acid, trifluoracetic acid, oxysuccinic acid, toxilic acid, succsinic acid, tosic acid or methylsulfonic acid etc.
The numerical value such as the interior weight of above bracket, volume, concentration, are optimum reaction condition, and those skilled in the art can rule of thumb be adjusted.
A third aspect of the present invention, is to provide the application in preparing Nampt inhibitor of above-mentioned carbamide derivative and pharmacy acceptable salt thereof.
Compound of the present invention was tested through active inhibition of Nampt, proved that majority of compounds has good Nampt and suppresses active.
The present invention also provides above-mentioned carbamide derivative and the application of pharmacy acceptable salt in preparing antitumor drug thereof.
Described tumour is liver cancer, lung cancer, intestinal cancer, ovarian cancer, prostate cancer, cancer of the stomach etc.
Compound of the present invention is tested through anti-tumor activity, proves that majority of compounds has better anti-tumor activity.
The present invention has opened up new approach for furtheing investigate and develop new texture type antitumor drug.
Embodiment
Below in conjunction with embodiment, the present invention is described in further detail, but enforcement of the present invention is not limited only to this.
Embodiment 1:1-[4-(4-tertbutyloxycarbonyl-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
4-(4-tertbutyloxycarbonyl-1-piperazinyl alkylsulfonyl) aniline (0.34g; 1mmol; logical method one is synthetic), thiophosgene (0.14g; 1.2mmol) with 3-aminomethyl-pyridine (0.11g; 1mmol) by synthetic 1-[4-(4-tertbutyloxycarbonyl-1-piperazinyl alkylsulfonyl)-phenyl of logical method one]-3-(3-picolyl) thiocarbamide; obtain white solid 0.21g, yield 41%.
1H?NMR(d-DMSO,600MHz)δ:1.34(s,9H),2.83-2.85(m,4H),3.37-3.39(m,4H),4.78(s,2H),7.37(dd,J=7.8Hz,4.8Hz,1H),7.65(d,J=9.0Hz,2H),7.76(d,J=7.8Hz,1H),7.80(d,J=9.0Hz,2H),8.47(dd,J=4.8Hz,1.2Hz,1H),8.57(d,J=1.8Hz,1H),8.61(s,1H),10.11(s,1H).ESI-MS(m/z):492.53[M+1].
Embodiment 2:1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
1-[4-(4-tertbutyloxycarbonyl-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g, 0.2mmol) is dissolved in methylene dichloride: trifluoracetic acid (2:1) 20mL, stirring at room 1h.Solvent evaporated, resistates adds saturated sodium bicarbonate (50mL), and ethyl acetate extraction (50mL * 3) merges organic phase, saturated aqueous common salt (50mL) washing, anhydrous sodium sulfate drying.Then concentrating under reduced pressure solvent, the separated (methylene dichloride: methyl alcohol=100:5) obtain white solid 0.06g, yield 75% of silica gel column chromatography.
1H?NMR(d-DMSO,600MHz)δ:2.70-2.73(m,8H),4.76(s,2H),7.36(dd,J=7.2Hz,4.8Hz,1H),7.60(d,J=8.7Hz,2H),7.75(d,J=7.8Hz,1H),7.85(d,J=8.7Hz,2H),8.46(m,1H),8.55(s,1H),9.20(s,1H),10.75(s,1H).ESI-MS(m/z):392.12[M+1].
Embodiment 3:N-phenyl-4-[3-(3-picolyl) thioureido] benzsulfamide
4-amino-N-phenyl benzenesulfonamides (0.25g, 1mmol, logical method one is synthetic), thiophosgene (0.14g, 1.2mmol) with 3-aminomethyl-pyridine (0.11g, 1mmol) by synthetic N-phenyl-4-[3-(3-picolyl) thioureido of logical method one] benzsulfamide, obtain white solid 0.16g, yield 39%.
1H?NMR(d-DMSO,600MHz)δ:4.75(d,J=5.3Hz,2H),7.00(t,J=7.3Hz,1H),7.10(d,J=7.8Hz,2H),7.22(t,J=7.8Hz,2H),7.35(dd,J=7.8Hz,4.6Hz,1H),7.66-7.69(m,4H),7.74(d,J=7.8Hz,1H),8.46(dd,J=4.8Hz,1.7Hz,1H),8.54-8.55(m,2H),9.98(s,1H),10.20(s,1H).ESI-MS(m/z):399.61[M+1].
Embodiment 4:1-[4-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
4-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl) aniline (0.25g; 1mmol; logical method one is synthetic), thiophosgene (0.14g; 1.2mmol) with 3-aminomethyl-pyridine (0.11g; 1mmol) by synthetic 1-[4-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl)-phenyl of logical method one]-3-(3-picolyl) thiocarbamide; obtain white solid 0.18g, yield 45%.
1H?NMR(d-DMSO,600MHz)δ:2.14(s,3H),2.35-2.36(m,4H),2.87-2.88(m,4H),4.79(s,2H),7.37(dd,J=7.8Hz,4.7Hz,1H),7.65(d,J=8.8Hz,2H),7.77(d,J=7.8Hz,1H),7.79(d,J=8.8Hz,2H),8.47(dd,J=4.7Hz,1.2Hz,1H),8.57(s,1H),8.58(s,1H),10.05(s,1H).ESI-MS(m/z):406.62[M+1].
Embodiment 5:1-[4-(4-formyl radical-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
4-(4-formyl radical-1-piperazinyl alkylsulfonyl) aniline (0.28g; 1mmol; logical method one is synthetic), thiophosgene (0.14g; 1.2mmol) with 3-aminomethyl-pyridine (0.11g; 1mmol) by synthetic 1-[4-(4-formyl radical-1-piperazinyl alkylsulfonyl)-phenyl of logical method one]-3-(3-picolyl) thiocarbamide; obtain white solid 0.14g, yield 33%.
1H?NMR(d-DMSO,600MHz)δ:1.93(s,3H),2.85-2.91(m,4H),3.48-3.51(m,4H),4.79(d,J=5.4Hz,2H),7.37(dd,J=7.8Hz,4.7Hz,1H),7.66(d,J=8.8Hz,2H),7.76(d,J=7.8Hz,1H),7.81(d,J=8.8Hz,2H),8.48(d,J=4.7Hz,1H),8.57(br?s,2H),10.06(s,1H).ESI-MS(m/z):434.44[M+1].
Embodiment 6:1-{4-[4-(2-pyridyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
4-[4-(2-pyridyl)-1-piperazinyl alkylsulfonyl] aniline (0.32g; 1mmol; logical method one is synthetic), thiophosgene (0.14g; 1.2mmol) with 3-aminomethyl-pyridine (0.11g; 1mmol) by synthetic 1-{4-[4-(2-the pyridyl)-1-piperazinyl alkylsulfonyl of logical method one]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.23g, yield 50%.
1H?NMR(d-DMSO,600MHz)δ:2.96(t,J=5.1Hz,4H),3.58(t,J=5.1Hz,4H),4.77(d,J=5.6Hz,2H),6.63(dd,J=7.1Hz,5.0Hz,1H),6.80(d,J=8.6Hz,1H),7.35-7.37(m,1H),7.49-7.52(m,1H),7.68(d,J=8.8Hz,2H),7.75(d,J=7.7Hz,1H),7.79(d,J=8.8Hz,2H),8.06-8.08(m,1H),8.46(dd,J=4.8Hz,1.7Hz,1H),8.56(d,J=1.7Hz,1H),8.59(m,1H),10.08(s,1H).ESI-MS(m/z):469.42[M+1].
Embodiment 7:1-[4-(4-benzyl-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
4-(4-benzyl-1-piperazinyl alkylsulfonyl) aniline (0.33g; 1mmol; logical method one is synthetic), thiophosgene (0.14g; 1.2mmol) with 3-aminomethyl-pyridine (0.11g; 1mmol) by synthetic 1-[4-(4-benzyl-1-piperazinyl alkylsulfonyl)-phenyl of logical method one]-3-(3-picolyl) thiocarbamide; obtain white solid 0.20g, yield 42%.
1H?NMR(d-DMSO,600MHz)δ:2.42-2.43(m,4H),2.89-2.91(m,4H),3.46(s,1H),4.80(d,J=6.0Hz,2H),7.21-7.23(m,3H),7.26-7.29(m,2H),7.37(dd,J=7.7Hz,4.7Hz,1H),7.64(d,J=8.9Hz,2H),7.76(d,J=7.7Hz,1H),7.80(d,J=8.9Hz,2H),8.48(dd,J=4.7Hz,1.3Hz,1H),8.58(br?s,2H),10.05(s,1H).ESI-MS(m/z):482.51[M+1].
Embodiment 8:1-[4-(4-hexanaphthene-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
4-(4-cyclohexyl-1-piperazinyl alkylsulfonyl) aniline (0.32g; 1mmol; logical method one is synthetic), thiophosgene (0.14g; 1.2mmol) with 3-aminomethyl-pyridine (0.11g; 1mmol) by synthetic 1-[4-(4-cyclohexyl-1-piperazinyl alkylsulfonyl)-phenyl of logical method one]-3-(3-picolyl) thiocarbamide; obtain white solid 0.21g, yield 44%.
1H?NMR(d-DMSO,600MHz)δ:1.02-1.18(m,6H),1.67-1.68(m,4H),2.20(s,1H),2.53-2.54(m,4H),2.84-2.85(m,4H),4.79(d,J=5.6Hz,2H),7.37(dd,J=7.8Hz,4.7Hz,1H),7.64(d,J=8.8Hz,2H),7.76(d,J=8.0Hz,1H),7.79(d,J=8.8Hz,2H),8.47(dd,J=4.7Hz,1.3Hz,1H),8.57(br?s,2H),10.05(s,1H).ESI-MS(m/z):474.71[M+1].
Embodiment 9:1-(3-picolyl)-3-[4-(1-pyrrolidyl alkylsulfonyl)-phenyl] thiocarbamide
4-(1-tetramethyleneimine alkylsulfonyl) aniline (0.23g; 1mmol; logical method one is synthetic), thiophosgene (0.14g; 1.2mmol) with 3-aminomethyl-pyridine (0.11g; 1mmol) by synthetic 1-(3-picolyl)-3-[4-(1-pyrrolidyl the alkylsulfonyl)-phenyl of logical method one] thiocarbamide; obtain white solid 0.18g, yield 48%.
1H?NMR(d-DMSO,600MHz)δ:1.65-1.67(m,4H),3.12-3.14(m,4H),4.79(d,J=5.7Hz,2H),7.37(dd,J=7.8Hz,4.8Hz,1H),7.72(d,J=8.8Hz,2H),7.76(d,J=7.8Hz,1H),7.79(d,J=8.8Hz,2H),8.47(dd,J=4.7Hz,1.2Hz,1H),8.54(s,1H),8.57(d,J=1.8Hz,1H),10.01(s,1H).ESI-MS(m/z):377.30[M+1].
Embodiment 10:N-benzyl-4-[3-(3-picolyl) thioureido] benzsulfamide
4-amino-N-benzyl benzsulfamide (0.26g, 1mmol, logical method one is synthetic), thiophosgene (0.14g, 1.2mmol) with 3-aminomethyl-pyridine (0.11g, 1mmol) by synthetic N-benzyl-4-[3-(3-picolyl) thioureido of logical method one] benzsulfamide, obtain white solid 0.19g, yield 40%.
1H?NMR(d-DMSO,600MHz)δ:3.97(d,J=6.3Hz,2H),4.79(d,J=5.6Hz,2H),7.22-7.25(m,3H),7.28-7.30(m,2H),7.38(dd,J=7.7Hz,4.6Hz,1H),7.70(d,J=8.8Hz,2H),7.74(d,J=8.8Hz,2H),7.77(d,J=7.8Hz,1H),8.04(t,J=6.3Hz,1H),8.48(dd,J=4.6Hz,1.5Hz,1H),8.54(s,1H),8.58(d,J=1.8Hz,1H),10.02(s,1H).ESI-MS(m/z):413.54[M+1].
Embodiment 11:1-[4-(N-morpholine alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide
4-(1-morpholine alkylsulfonyl) aniline (0.24g; 1mmol; logical method one is synthetic), thiophosgene (0.14g; 1.2mmol) with 3-aminomethyl-pyridine (0.11g; 1mmol) by synthetic 1-[4-(N-morpholine the alkylsulfonyl)-phenyl of logical method one]-3-(3-picolyl) thiocarbamide; obtain white solid 0.14g, yield 35%.
1H?NMR(d-DMSO,600MHz)δ:2.85(t,J=4.5Hz,4H),3.63(t,J=4.5Hz,4H),4.79(d,J=5.5Hz,2H),7.38(dd,J=7.9Hz,4.8Hz,1H),7.66(d,J=8.8Hz,2H),7.77(d,J=7.8Hz,1H),7.82(d,J=8.8Hz,2H),8.47(dd,J=4.6Hz,1.3Hz,1H),8.57(d,J=1.6Hz,1H),8.61(s,1H),10.12(s,1H).ESI-MS(m/z):393.51[M+1].
Embodiment 12:2-(1-group-4 ethyl formate)-1-(3-picolyl)-3-[4-(1-piperdine sulfonyl)-phenyl] guanidine
By different sulphur cyanato-ethyl formate (0.15g; 1.2mmol) with 3-aminomethyl-pyridine (0.13g; 1.2mmol) be dissolved in methylene dichloride; stirring at room 2h; add again 4-(1-tetramethyleneimine alkylsulfonyl) aniline (0.3g; 1.2mmol), EDC (0.48g, 2.4mmol) and triethylamine (1.7mL), 30 ℃ of reaction 38h.Concentrating under reduced pressure reaction solution, residue silica gel column chromatography (methylene dichloride: methyl alcohol=100:3) obtain white powder 0.1g, yield 20%.
1H?NMR(d-DMSO,600MHz)δ:1.13(t,J=6.6Hz,3H),1.33-1.37(m,2H),1.51-1.56(m,4H),2.82-2.87(m,4H),3.95-3.97(m,2H),4.61(s,2H),7.36-7.39(m,3H),7.57-66(m,3H),7.76(d,J=5.5Hz,1H),8.44-8.48(m,1H),8.57(s,1H),10.02(s,1H).ESI-MS(m/z):446.54[M+1].
Embodiment 13:1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) urea
4-(1-piperidine formyl base) aniline (0.20g; 1mmol; logical method one is synthetic), phosgene (0.12g; 1.2mmol) with 3-aminomethyl-pyridine (0.11g; 1mmol) by synthetic 1-[4-(1-piperidine formyl the base)-phenyl of logical method one]-3-(3-picolyl) urea; obtain white solid 0.13g, yield 39%.
1H?NMR(d-DMSO,600MHz)δ:1.44-1.49(m,4H),1.58-1.62(m,2H),3.40-3.44(m,4H),4.33(d,J=5.4Hz,2H),6.77(t,J=6.0Hz,1H),7.25(d,J=8.4Hz,2H),7.36(dd,J=7.8Hz,4.8Hz,1H),7.44(d,J=8.4Hz,2H),7.71(d,J=7.8Hz,1H),8.45(dd,J=7.8Hz,1.2Hz,1H),8.52(s,1H),8.82(s,1H).ESI-MS(m/z):339.61[M+1].
Embodiment 14:1-[4-(1-piperdine sulfonyl)-phenyl]-3-(3-picolyl) urea
4-(1-piperdine sulfonyl) aniline (0.24g; 1mmol; logical method one is synthetic), phosgene (0.12g; 1.2mmol) with 3-aminomethyl-pyridine (0.11g; 1mmol) by synthetic 1-[4-(1-the piperdine sulfonyl)-phenyl of logical method one]-3-(3-picolyl) urea; obtain white solid 0.16g, yield 44%.
1H?NMR(d-DMSO,600MHz)δ:1.34-1.35(m,2H),1.50-1.54(m,4H),2.81-2.84(m,4H),4.34(d,J=6.0Hz,2H),6.90(t,J=5.4Hz,1H),7.34-7.37(m,1H),7.56(d,J=8.4Hz,2H),7.62(d,J=8.4Hz,2H),7.70-7.72(m,1H),8.45(dd,J=4.8Hz,1.8Hz,1H),8.53(s,1H),9.16(s,1H).ESI-MS(m/z):335.55[M+1].
Embodiment 15:1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) thiocarbamide
4-(1-piperidine formyl base) aniline (0.20g; 1mmol; logical method one is synthetic), thiophosgene (0.14g; 1.2mmol) with 3-aminomethyl-pyridine (0.11g; 1mmol) by synthetic 1-[4-(1-piperidine formyl the base)-phenyl of logical method one]-3-(3-picolyl) thiocarbamide; obtain white solid 0.16g, yield 47%.
1H?NMR(d-DMSO,600MHz)δ:1.49-1.53(m,4H),1.60-1.63(m,2H),3.41-3.47(m,4H),4.78(d,J=5.4Hz,2H),7.33(d,J=8.4Hz,2H),7.37(d,J=5.4Hz,,1H),7.50(d,J=8.4Hz,2H),8.34(s,1H),8.46(dd,J=4.2Hz,1.2Hz,1H),8.56(s,1H),9.76(s,1H).ESI-MS(m/z):355.50[M+1].
Embodiment 16:[4-(1-piperidine formyl base)-phenyl] carboxylamine-3-pyridine methyl esters
4-(1-piperidine formyl base) aniline (0.20g; 1mmol; logical method one is synthetic) and chloroformic acid-3-pyridine methyl esters (0.21g; 1.2mmol) by synthetic [4-(the 1-piperidine formyl base)-phenyl] carboxylamine-3-pyridine methyl esters of logical method two; obtain white solid 0.19g, yield 58%.
1H?NMR(d-DMSO,600MHz)δ:1.45-1.49(m,4H),1.60-1.62(m,2H),3.40-3.45(m,4H),5.21(s,2H),7.30(d,J=8.4Hz,2H),7.42-7.44(m,1H),7.51(d,J=8.4Hz,2H),7.84-7.86(m,1H),8.55(dd,J=4.8Hz,1.8Hz,1H),8.66(s,1H),9.31(s,1H).ESI-MS(m/z):338.61[M-1].
Embodiment 17:[4-(1-piperdine sulfonyl)-phenyl] carboxylamine-3-pyridine methyl esters
4-(1-piperdine sulfonyl) aniline (0.24g; 1mmol; logical method one is synthetic) and chloroformic acid-3-pyridine methyl esters (0.21g; 1.2mmol) by synthetic [4-(the 1-piperdine sulfonyl)-phenyl] carboxylamine-3-pyridine methyl esters of logical method two; obtain white solid 0.22g, yield 60%.
1H?NMR(d-DMSO,600MHz)δ:1.34-1.35(m,2H),1.50-1.54(m,4H),2.82-2.84(m,4H),5.23(s,2H),7.44(dd,J=8.4Hz,4.8Hz,1H),7.65(d,J=8.4Hz,2H),7.68(d,J=8.4Hz,2H),7.87(d,J=7.8Hz,1H),8.56(s,1H),8.67(d,J=1.8Hz,1H),10.29(s,1H).ESI-MS(m/z):376.54[M+1].
Embodiment 18:1-[4-(1-piperdine sulfonyl)-phenyl]-3-(3-picolyl) guanidine
1-[4-(1-piperdine sulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (30mg; 0.077mmol), sodium periodate (20mg; 0.09mmol) and ammoniacal liquor (3mL) be dissolved in the mixing solutions of DMF (3mL) and water (3mL), 70 ℃ reaction 3h.Reaction solution adds water (10mL), and dichloromethane extraction (20mL * 3) merges organic phase, saturated common salt water washing (20mL), anhydrous sodium sulfate drying.Organic phase concentrating under reduced pressure, column chromatography purification obtains white solid 20mg, yield 71%.
1H?NMR(d-DMSO,300MHz)δ:1.22-1.24(m,2H),1.32-1.34(m,4H),2.79-2.82(m,4H),4.38(s,2H),5.54(br?s,2H),6.36(s,1H),6.92(d,J=6.6Hz,2H),7.36(dd,J=7.8Hz,4.8Hz,1H),7.47(d,J=8.7Hz,2H),7.74(d,J=7.8Hz,1H),8.44(dd,J=4.5Hz,1.5Hz,1H),8.53(d,J=1.5Hz,1H).ESI-MS(m/z):374.54[M+1].
Embodiment 19:1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) guanidine
1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) thiocarbamide (30mg; 0.084mmol), sodium periodate (20mg; 0.09mmol) and ammoniacal liquor (3mL) be dissolved in the mixing solutions of DMF (3mL) and water (3mL), 70 ℃ reaction 3h.Reaction solution adds water (10mL), and dichloromethane extraction (20mL * 3) merges organic phase, saturated common salt water washing (20mL), anhydrous sodium sulfate drying.Organic phase concentrating under reduced pressure, column chromatography purification obtains white solid 18mg, yield 64%.
1H?NMR(d-DMSO,300MHz)δ:1.29-1.34(m,2H),1.52-1.54(m,4H),2.79-2.83(m,4H),4.42(s,2H),5.55(br?s,2H),6.36(s,1H),7.03(d,J=7.8Hz,2H),7.35-7.39(m,1H),7.51(d,J=7.8Hz,2H),7.74(d,J=8.1Hz,1H),8.45-8.46(m,1H),8.55(s,1H).ESI-MS(m/z):338.44[M+1].
Embodiment 20:[4-(1-piperidine formyl base)-phenyl] amino bamic acid ethyl ester
4-(1-piperidine formyl base) aniline (0.20g; 1mmol, logical method one is synthetic) and thio-ethyl chloride (0.15g, 1.2mmol) by logical method two, synthesize [4-(1-piperidine formyl base)-phenyl] carboxylamine-3-pyridine methyl esters; obtain white solid 0.21g, yield 55%.
1H?NMR(CDCl 3,600MHz)δ:1.15(t,J=6.0Hz,3H),1.33-1.37(m,2H),1.51-1.56(m,4H),2.82-2.87(m,4H),3.95-3.97(m,2H),6.46(d,J=8.4Hz,2H),6.82(d,J=8.4Hz,2H).ESI-MS(m/z):293.41[M+1].
Embodiment 21:2-cyano group-1-(3-picolyl)-3-[4-(1-tetramethyleneimine alkylsulfonyl)-phenyl] guanidine
1-(3-picolyl)-3-[4-(1-pyrrolidyl alkylsulfonyl)-phenyl] thiocarbamide (0.1g; 0.26mmol), EDC (0.1g; 0.52mmol), triethylamine (0.37mL) and cyanamide (0.22g; 5.2mmol) be dissolved in tetrahydrofuran (THF) (20mL), 50 ℃ of reaction 24h.Concentrating under reduced pressure reaction solution, residue silica gel column chromatography (methylene dichloride: methyl alcohol=100:10) obtain white powder 0.04g, yield 40%.
1H?NMR(d-DMSO,600MHz)δ:1.64-1.66(m,4H),3.11-3.13(m,4H),4.50(d,J=5.8Hz,2H),7.39(dd,J=7.8Hz,4.7Hz,1H),7.45(d,J=8.6Hz,2H),7.73-7.75(m,3H),8.20(t,J=5.9Hz,1H),8.48(dd,J=4.6Hz,1.5Hz,1H),8.54(d,J=1.6Hz,1H),9.56(s,1H).ESI-MS(m/z):385.49[M+1].
Embodiment 22:1-{4-[4-(4-luorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 4-fluorobenzyl bromide (0.05mL; 0.38mmol) by synthetic 1-{4-[4-(4-the luorobenzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.056g, yield 43%.
1H?NMR(d-DMSO,600MHz)δ:2.38-2.45(m,4H),2.85-2.92(m,4H),3.44(s,2H),4.80(d,J=5.5Hz,2H),7.09(t,J=8.8Hz,2H),7.26(dd,J=8.6Hz,6.0Hz,2H),7.38(dd,J=7.9Hz,4.8Hz,1H),7.64(d,J=8.8Hz,2H),7.77(d,J=7.8Hz,1H),7.79(d,J=8.8Hz,2H),8.48(dd,J=4.7Hz,1.5Hz,1H),8.57(d,J=1.5Hz,1H),8.61(s,1H),10.11(s,1H).ESI-MS(m/z):500.55[M+1].
Embodiment 23:1-{4-[4-(2,6-difluorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 2; 6-bis-fluorobenzyl bromide (0.08g; 0.38mmol) by the synthetic 1-{4-[4-(2 of logical method three; 6-difluorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.06g, yield 48%.
1H?NMR(d-DMSO,300MHz)δ:2.43-2.45(m,4H),2.83-2.85(m,4H),3.54(s,2H),4.77(d,J=5.5Hz,2H),7.05(t,J=7.9Hz,2H),7.32-7.40(m,2H),7.59(d,J=8.6Hz,2H),7.74(d,J=8.6Hz,2H),8.46(d,J=4.4Hz,1H),8.55(s,1H),8.61(s,1H),10.08(s,1H).ESI-MS(m/z):518.59[M+1].
Embodiment 24:1-{4-[4-(3-luorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 3-fluorobenzyl bromide (0.05mL; 0.38mmol) by synthetic 1-{4-[4-(3-the luorobenzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.062g, yield 33%.
1H?NMR(d-DMSO,600MHz)δ:2.43-2.45(m,4H),2.89-2.92(m,4H),3.48(s,2H),4.80(d,J=5.4Hz,2H),7.03-7.08(m,3H),7.30-7.34(m,1H),7.38(dd,J=7.7Hz,4.7Hz,1H),7.64(d,J=8.8Hz,2H),7.77(dd,J=7.7Hz,1.7Hz,1H),7.79(d,J=8.8Hz,2H),8.48(dd,J=4.7Hz,1.6Hz,1H),8.57(d,J=2.0Hz,1H),8.62(br?s,1H),10.12(s,1H).ESI-MS(m/z):500.34[M+1].
Embodiment 25:1-{4-[4-(2-luorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 2-fluorobenzyl bromide (0.05mL; 0.38mmol) by synthetic 1-{4-[4-(2-the luorobenzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.082g, yield 68%.
1H?NMR(d-DMSO,600MHz)δ:2.42-2.48(m,4H),2.88-2.92(m,4H),3.51(s,2H),4.79(d,J=5.2Hz,2H),7.13(t,J=7.8Hz,2H),7.27-7.33(m,2H),7.38(dd,J=7.8Hz,4.8Hz,1H),7.64(d,J=8.6Hz,2H),7.77(d,J=8.1Hz,1H),7.80(d,J=8.6Hz,2H),8.48(d,J=3.7Hz,1H),8.57(s,1H),8.63(br?s,1H),10.12(s,1H).ESI-MS(m/z):500.63[M+1].
Embodiment 26:1-{4-[4-(4-methyl-benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 4-methyl benzyl bromine (0.05g; 0.25mmol) by synthetic 1-{4-[4-(4-the methyl-benzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.074g, yield 60%.
1H?NMR(d-DMSO,300MHz)δ:2.23(s,3H),2.24-2.42(m,4H),2.79-2.89(m,4H),3.38(s,2H),4.79(d,J=5.3Hz,2H),7.07-7.10(m,4H),7.37(dd,J=7.8Hz,4.8Hz,1H),7.61(d,J=8.6Hz,2H),7.74-7.79(m,3H),8.46(d,J=4.7Hz,1H),8.56(s,1H),8.62(br?s,1H),10.12(s,1H).ESI-MS(m/z):496.37[M+1].
Embodiment 27:1-{4-[4-(2-methyl-benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 2-methyl benzyl bromine (0.05g; 0.25mmol) by synthetic 1-{4-[4-(2-the methyl-benzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.07g, yield 57%.
1H?NMR(d-DMSO,300MHz)δ:2.21(s,3H),2.39-2.44(m,4H),2.81-2.87(m,4H),3.40(s,2H),4.77(d,J=5.4Hz,2H),7.06-7.12(m,4H),7.36(dd,J=7.7Hz,4.7Hz,1H),7.62(d,J=8.7Hz,2H),7.73-7.79(m,3H),8.46(d,J=4.0Hz,1H),8.56(s,1H),8.61(br?s,1H),10.11(s,1H).ESI-MS(m/z):496.68[M+1].
Embodiment 28:1-{4-[4-(3-methyl-benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 3-methyl benzyl bromine (0.05g; 0.25mmol) by synthetic 1-{4-[4-(3-the methyl-benzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.063g, yield 50%.
1H?NMR(d-DMSO,300MHz)δ:2.23(s,3H),2.34-2.43(m,4H),2.82-2.89(m,4H),3.39(s,2H),4.78(d,J=5.6Hz,2H),6.98-7.02(m,3H),7.14(t,J=7.6Hz,1H),7.37(dd,J=7.8Hz,4.8Hz,1H),7.63(d,J=8.6Hz,2H),7.74-7.78(m,3H),8.46(dd,J=4.7Hz,1.6Hz,1H),8.57(d,J=1.6Hz,1H),8.64(br?s,1H),10.15(s,1H).ESI-MS(m/z):496.54[M+1].
Embodiment 29:1-{4-[4-(3-chlorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 3-bromine chloride (0.05g; 0.25mmol) by synthetic 1-{4-[4-(3-the chlorobenzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.075g, yield 58%.
1H?NMR(d-DMSO,300MHz)δ:2.38-2.43(m,4H),2.83-2.90(m,4H),3.45(s,2H),4.78(d,J=5.4Hz,2H),7.18(t,J=6.3Hz,1H),7.27-7.30(m,3H),7.37(dd,J=7.8Hz,4.7Hz,1H),7.63(d,J=8.7Hz,2H),7.74-7.80(m,3H),8.46(dd,J=4.7Hz,1.3Hz,1H),8.56(d,J=1.5Hz,1H),8.62(br?s,1H),10.11(s,1H).ESI-MS(m/z):517.10[M+1].
Embodiment 30:1-{4-[4-(2-chlorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 2-bromine chloride (0.04mL; 0.25mmol) by synthetic 1-{4-[4-(2-the chlorobenzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.04g, yield 31%.
1H?NMR(d-DMSO,300MHz)δ:2.43-2.49(m,4H),2.82-2.92(m,4H),3.55(s,2H),4.78(d,J=5.4Hz,2H),7.23-7.28(m,2H),7.34-7.39(m,3H),7.63(d,J=8.7Hz,2H),7.74-7.80(m,3H),8.46(d,J=4.5Hz,1H),8.56(d,J=1.7Hz,1H),8.63(br?s,1H),10.13(s,1H).ESI-MS(m/z):517.13[M+1].
Embodiment 31:1-{4-[4-(4-chlorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 4-bromine chloride (0.05g; 0.25mmol) by synthetic 1-{4-[4-(4-the chlorobenzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.06g, yield 45%.
1H?NMR(d-DMSO,300MHz)δ:2.37-2.43(m,4H),2.82-2.89(m,4H),3.43(s,2H),4.78(d,J=5.4Hz,2H),7.23(d,J=8.4Hz,2H),7.32(d,J=8.4Hz,2H),7.37(dd,J=7.7Hz,4.8Hz,1H),7.63(d,J=8.7Hz,2H),7.74-7.80(m,3H),8.46(dd,J=4.7Hz,1.2Hz,1H),8.56(d,J=1.5Hz,1H),8.64(br?s,1H),10.14(s,1H).ESI-MS(m/z):517.11[M+1].
Embodiment 32:1-{4-[4-(4-bromobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 4-bromobenzyl bromine (0.07g; 0.25mmol) by synthetic 1-{4-[4-(4-the bromobenzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.065g, yield 45%.
1H?NMR(d-DMSO,300MHz)δ:2.36-2.43(m,4H),2.80-2.88(m,4H),3.42(s,2H),4.78(d,J=5.5Hz,2H),7.18(d,J=8.2Hz,2H),7.36(dd,J=8.8Hz,4.8Hz,1H),7.44(d,J=8.3Hz,2H),7.63(d,J=8.8Hz,2H),7.74-7.80(m,3H),8.47(dd,J=4.7Hz,1.4Hz,1H),8.56(s,1H),8.63(br?s,1H),10.13(s,1H).ESI-MS(m/z):561.56[M+1].
Embodiment 33:1-{4-[4-(2-menaphthyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 2-brooethyl naphthalene (0.06g; 0.25mmol) by synthetic 1-{4-[4-(2-the menaphthyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.063g, yield 46%.
1H?NMR(d-DMSO,300MHz)δ:2.84-2.93(m,4H),3.04-3.11(m,4H),3.62(s,2H),4.78(d,J=5.4Hz,2H),7.34-7.40(m,2H),7.44-7.47(m,2H),7.62(d,J=8.7Hz,2H),7.72-7.86(m,7H),8.47(d,J=4.1Hz,1H),8.56(s,1H),8.66(br?s,1H),10.17(s,1H).ESI-MS(m/z):532.77[M+1].
Embodiment 34:1-{4-[4-(4-trifluoromethyl benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 4-trifluoromethyl benzyl bromine (0.04mL; 0.25mmol) by synthetic 1-{4-[4-(4-the trifluoromethyl benzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.07g, yield 51%.
1H?NMR(d-DMSO,300MHz)δ:2.41-2.46(m,4H),2.81-2.91(m,4H),3.54(s,2H),4.78(d,J=5.5Hz,2H),7.18(d,J=8.2Hz,2H),7.36(dd,J=7.6Hz,4.7Hz,1H),7.45(d,J=7.8Hz,2H),7.61-7.64(m,4H),7.74-7.80(m,3H),8.47(d,J=3.5Hz,1H),8.56(d,J=1.5Hz,1H),8.62(br?s,1H),10.11(s,1H).ESI-MS(m/z):550.53[M+1].
Embodiment 35:1-{4-[4-(4-trifluoro-methoxybenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 4-trifluoromethoxy benzyl bromine (0.04mL; 0.25mmol) by synthetic 1-{4-[4-(4-the trifluoro-methoxybenzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.067g, yield 47%.
1H?NMR(d-DMSO,300MHz)δ:2.38-2.46(m,4H),2.82-2.89(m,4H),3.47(s,2H),4.78(d,J=5.5Hz,2H),7.24(d,J=8.1Hz,2H),7.35(d,J=8.1Hz,2H),7.38(d,J=5.4Hz,1H),7.63(d,J=8.6Hz,2H),7.74-7.80(m,3H),8.47(dd,J=4.6Hz,1.3Hz,1H),8.56(s,1H),8.63(br?s,1H),10.13(s,1H).ESI-MS(m/z):566.71[M+1].
Embodiment 36:1-{4-[4-(4-normal-butyl benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 4-normal-butyl benzyl bromine (0.05mL; 0.25mmol) by synthetic 1-{4-[4-(4-normal-butyl the benzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.07g, yield 52%.
1H?NMR(d-DMSO,300MHz)δ:0.86(t,J=7.4Hz,3H),1.21-1.29(m,4H),1.44-1.52(m,2H),2.35-2.42(m,4H),2.82-2.89(m,4H),3.39(s,2H),4.78(d,J=5.5Hz,2H),7.05-7.12(m,4H),7.34-7.38(m,1H),7.62(d,J=8.7Hz,2H),7.74-7.80(m,3H),8.46(d,J=4.3Hz,1H),8.56(s,1H),8.65(br?s,1H),10.17(s,1H).ESI-MS(m/z):538.66[M+1].
Embodiment 37:1-{4-[4-(4-nitrobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.22g; 0.56mmol), triethylamine (0.4mL) and 4-nitrobenzyl bromine (0.12g; 0.25mmol) by synthetic 1-{4-[4-(4-the nitrobenzyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.12g, yield 41%.
1H?NMR(d-DMSO,300MHz)δ:2.42-2.46(m,4H),2.85-2.92(m,4H),3.61(s,2H),4.78(d,J=5.4Hz,2H),7.37(dd,J=7.8Hz,4.7Hz,1H),7.52(d,J=8.7Hz,2H),7.63(d,J=8.7Hz,2H),7.76(d,J=7.8Hz,1H),7.82(d,J=8.7Hz,2H),8.13(d,J=8.7Hz,2H),8.47(dd,J=4.7Hz,1.4Hz,1H),8.56(d,J=2.1Hz,1H),8.68(br?s,1H),10.21(s,1H).ESI-MS(m/z):527.70[M+1].
Embodiment 38:1-{4-[4-(4-aminobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-{4-[4-(4-nitrobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide (50mg, 0.1mmol) is dissolved in ethyl acetate (10mL), adds catalytic amount palladium carbon, room temperature reaction 12h under hydrogen.Filter palladium carbon, evaporated under reduced pressure solvent, residue column chromatography obtains white solid 34mg, yield 72%.
1H?NMR(d-DMSO,600MHz)δ:2.43-2.48(m,4H),2.82-2.90(m,4H),3.71(s,2H),4.79(d,J=5.5Hz,2H),5.09(s,2H),7.36(dd,J=7.8Hz,4.7Hz,1H),7.52(d,J=8.8Hz,2H),7.63(d,J=8.8Hz,2H),7.77(d,J=7.8Hz,1H),7.88(d,J=8.6Hz,2H),8.13(d,J=8.6Hz,2H),8.47(dd,J=4.7Hz,1.4Hz,1H),8.56(s,1H),8.68(br?s,1H),10.19(s,1H).ESI-MS(m/z):497.71[M+1].
Embodiment 39:1-{4-[4-(2-1H-benzo [d] imidazoles)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 2-brooethyl-1H-benzo [d] imidazoles (0.05g; 0.25mmol) by synthetic 1-{4-[4-(2-1H-benzo [d] the imidazoles)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.098g, yield 76%.
1H?NMR(d-DMSO,600MHz)δ:2.54-2.55(m,4H),2.92-2.94(m,4H),3.73(s,2H),4.79(d,J=6.0Hz,2H),7.09-7.12(m,2H),7.37-7.39(m,1H),7.41-7.46(m,2H),7.66(d,J=8.9Hz,2H),7.77(dd,J=7.8Hz,1.7Hz,2H),7.81(d,J=8.9Hz,2H),8.47(dd,J=4.7Hz,1.6Hz,1H),8.57(d,J=1.7Hz,1H),8.62(br?s,1H),10.13(s,1H),12.17(s,1H).ESI-MS(m/z):522.63[M+1].
Embodiment 40:1-{4-[4-(3-furylmethyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 3-brooethyl furans (0.05mL) are by synthetic 1-{4-[4-(the 3-furylmethyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.065g, yield 55%.
1H?NMR(d-DMSO,600MHz)δ:2.52-2.61(m,4H),2.85-2.94(m,4H),3.39(s,2H),4.77(d,J=5.5Hz,2H),6.38(s,1H),7.36(dd,J=7.8Hz,4.6Hz,1H),7.57-7.63(m,4H),7.74(d,J=7.8Hz,1H),7.85(d,J=8.7Hz,2H),8.44(d,J=4.6Hz,1H),8.54(s,1H),8.83(t,J=5.5Hz,1H),10.44(s,1H).ESI-MS(m/z):472.62[M+1].
Embodiment 41:1-{4-[4-(3-thenyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 3-bromomethyl thiophene (0.05mL) are by synthetic 1-{4-[4-(3-the thenyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.06g, yield 49%.
1H?NMR(d-DMSO,600MHz)δ:2.55-2.62(m,4H),2.83-2.93(m,4H),3.41(s,2H),4.77(d,J=5.5Hz,2H),6.96(d,J=4.4Hz,1H),7.36(dd,J=7.7Hz,4.6Hz,2H),7.45(s,1H),7.62(d,J=8.5Hz,2H),7.74(d,J=7.7Hz,1H),7.80(d,J=8.5Hz,2H),8.44(dd,J=4.9Hz,1.6Hz,1H),8.55(d,J=2.2Hz,1H),8.72(s,1H),10.27(s,1H).ESI-MS(m/z):488.77[M+1].
Embodiment 42:1-{4-[4-(furfuryl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 2-brooethyl furans (0.05mL) are by synthetic 1-{4-[4-(the furfuryl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.07g, yield 59%.
1H?NMR(d-DMSO,600MHz)δ:2.47-2.52(m,4H),2.83-2.88(m,4H),3.68(s,2H),4.78(d,J=5.5Hz,2H),6.89-6.92(m,2H),7.33-7.39(m,2H),7.62(d,J=8.7Hz,2H),7.75(d,J=7.9Hz,1H),7.86(d,J=8.7Hz,2H),8.45(d,J=4.7Hz,1H),8.55(d,J=1.6Hz,1H),8.86(t,J=5.8Hz,1H),10.46(s,1H).ESI-MS(m/z):472.55[M+1].
Embodiment 43:1-{4-[4-(2-thenyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 2-bromomethyl thiophene (0.05mL) are by synthetic 1-{4-[4-(2-the thenyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.065g, yield 56%.
1H?NMR(d-DMSO,600MHz)δ:2.43-2.47(m,4H),2.83-2.89(m,4H),3.56(s,2H),4.78(d,J=5.5Hz,2H),6.27(d,J=3.0Hz,1H),6.35-6.37(m,1H),7.35(dd,J=7.7Hz,4.9Hz,1H),7.55(s,1H),7.62(d,J=8.7Hz,2H),7.75(d,J=7.7Hz,1H),7.82(d,J=8.7Hz,2H),8.45(d,J=3.5Hz,1H),8.55(s,1H),8.77(t,J=5.5Hz,1H),10.32(s,1H).ESI-MS(m/z):488.79[M+1].
Embodiment 44:1-{4-[4-(4-picolyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 4-picolyl thiophene (0.06mL) are by synthetic 1-{4-[4-(4-the picolyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.06g, yield 52%.
1H?NMR(d-DMSO,600MHz)δ:2.44-2.47(m,4H),2.88-2.92(m,4H),3.52(s,2H),4.79(d,J=5.7Hz,2H),7.26(d,J=5.9Hz,2H),7.37-7.39(m,1H),7.65(d,J=8.8Hz,2H),7.76-7.78(m,1H),7.81(d,J=8.8Hz,2H),8.46(dd,J=4.5Hz,1.3Hz,2H),8.47(d,J=4.7Hz,1.5Hz,1H),8.57(d,J=1.8Hz,1H),8.63(br?s,1H),10.15(s,1H).ESI-MS(m/z):483.37[M+1].
Embodiment 45:1-{4-[4-(3-picolyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 3-picolyl thiophene (0.06mL) are by synthetic 1-{4-[4-(3-the picolyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.065g, yield 57%.
1H?NMR(d-DMSO,600MHz)δ:2.45-2.48(m,4H),2.87-2.92(m,4H),3.54(s,2H),4.79(d,J=5.7Hz,2H),7.31(dd,J=7.8Hz,4.8Hz,1H),7.38(dd,J=7.8Hz,4.8Hz,1H),7.62-7.65(m,3H),7.75-7.77(m,1H),7.79-7.80(m,2H),8.43(d,J=1.6Hz,1H),8.44(dd,J=4.7Hz,1.4Hz,1H),8.47(dd,J=4.7Hz,1.4Hz,1H),8.57(d,J=1.8Hz,1H),8.64(br?s,1H),10.15(s,1H).ESI-MS(m/z):483.38[M+1].
Embodiment 46:1-{4-[4-(4-tolyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
4-[4-(4-tolyl)-1-piperazinyl alkylsulfonyl] aniline (0.32g; 1mmol; logical method one is synthetic), thiophosgene (0.14g; 1.2mmol) with 3-aminomethyl-pyridine (0.11g; 1mmol) by synthetic 1-{4-[4-(4-the tolyl)-1-piperazinyl alkylsulfonyl of logical method one]-phenyl }-3-(3-picolyl) thiocarbamide; obtain white solid 0.25g, yield 51%.
1H?NMR(d-DMSO,600MHz)δ:2.17(s,3H),2.98(t,J=4.8Hz,4H),3.12(t,J=4.8Hz,4H),4.78(d,J=5.4Hz,2H),6.79(d,J=8.4Hz,2H),7.00(d,J=8.4Hz,2H),7.35(dd,J=7.8Hz,4.8Hz,1H),7.68(d,J=9.0Hz,2H),7.75(d,J=7.8Hz,1H),7.80(d,J=9.0Hz,2H),8.44(dd,J=4.8Hz,1.8Hz,1H),8.55(d,J=1.2Hz,1H),8.60(br?s,1H),10.10(s,1H).ESI-MS(m/z):482.66[M+1].
Embodiment 47:1-{4-[4-(2-picolyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide
1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide (0.1g; 0.25mmol), triethylamine (0.05mL) and 2-picolyl thiophene (0.06mL) are by synthetic 1-{4-[4-(4-the picolyl)-1-piperazinyl alkylsulfonyl of logical method three]-phenyl }-3-(2-picolyl) thiocarbamide; obtain white solid 0.054g, yield 45%.
1H?NMR(d-DMSO,600MHz)δ:2.41-2.47(m,4H),2.84-2.92(m,4H),3.53(s,2H),4.75(d,J=5.5Hz,2H),7.23-7.25(m,2H),7.33-7.39(m,3H),7.66(d,J=8.8Hz,2H),7.77-7.82(m,3H),8.46(d,J=4.5Hz,1H),8.56(d,J=1.7Hz,1H),8.63(br?s,1H),10.19(s,1H).ESI-MS(m/z):482.77[M+1].
The structural formula of target compound 1-47 is as shown in table 1, numbers the equal corresponding target compound 1-47 of 1-47 and embodiment 1-47 in following table 1, table 2, table 3.
Table 1. part preferred compound of the present invention structural formula
Figure BDA0000445187100000231
Figure BDA0000445187100000241
Figure BDA0000445187100000251
Embodiment 48:1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide salt hydrochlorate
In 50mL round-bottomed flask; add 0.1g1-[4-(1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide; add the ethyl acetate solution 20mL of saturated hydrogenchloride to dissolve; room temperature reaction 3 hours, has reacted rear suction filtration, washing, dry 1-[4-(1-piperazinyl the alkylsulfonyl)-phenyl that obtains]-3-(3-picolyl) thiocarbamide salt hydrochlorate 0.06g.
Embodiment 49:N-phenyl-4-[3-(3-picolyl) thioureido] benzsulfamide succinate
In 50mL round-bottomed flask, add 0.2g N-phenyl-4-[3-(3-picolyl) thioureido] benzsulfamide, add ethanolic soln 20mL to dissolve, add hot succsinic acid ethanolic soln, room temperature reaction 3 hours, has reacted rear suction filtration, washing, dry N-phenyl-4-[3-(3-picolyl) thioureido that obtains] benzsulfamide succinate 0.12g.
Embodiment 50:1-[4-(4-benzyl-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide maleate
In 50mL round-bottomed flask; add 0.2g1-[4-(4-benzyl-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide; dissolve with ethanol; add hot toxilic acid ethanolic soln; room temperature reaction 3 hours, has reacted rear suction filtration, washing, dry 1-[4-(4-benzyl-1-piperazinyl alkylsulfonyl)-phenyl that obtains]-3-(3-picolyl) thiocarbamide maleate 0.1g.
Embodiment 51:1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) urea malate
In 50mL round-bottomed flask; add 0.2g1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) urea; dissolve with ethanol; add hot oxysuccinic acid ethanolic soln; room temperature reaction 3 hours, has reacted rear suction filtration, washing, dry 1-[4-(1-piperidine formyl the base)-phenyl that obtains]-3-(3-picolyl) urea malate 0.09g.
Embodiment 52:1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) guanidine tartrate
In 50mL round-bottomed flask; add 0.2g1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) guanidine; dissolve with ethanol; add hot oxysuccinic acid ethanolic soln; room temperature reaction 3 hours, has reacted rear suction filtration, washing, dry 1-[4-(1-piperidine formyl the base)-phenyl that obtains]-3-(3-picolyl) guanidine tartrate 0.13g.
Embodiment 53: the compounds of this invention suppresses the activity experiment of Nampt
Following enzyme refers to Nampt, can, purchased from Kang Tai bio tech ltd, also can prepare voluntarily.
1, the preparation of enzyme:
There is BL21 (DE3) the plysS cell of recombinant plasmid Nampt-pET28a+ to be inoculated in 2 * YT substratum (37 μ g/mL paraxin and 100 μ g/mL kantlex) conversion, 37 ℃ of joltings are spent the night, resuspended with 20 times of fresh cultures to original volume after collection thalline, 37 ℃ are cultured to the about 0.6-0.8 of OD600, under 0.5mM IPTG, 28 ℃ of conditions, induce 8h.Centrifugal collection thalline, and be resuspended in lysis buffer (20mM Tris-HCl pH8.0,300mM NaCl), add 0.1%Triton X-100,1%PMSF, 200W ultrasonic degradation cell, ultrasonic ls gap 9s, carries out 30min altogether.Lysate is drawn to supernatant liquor in 12000rpm, 4 ℃ of centrifugal 50min.This supernatant liquor and Ni-NTA post (purchased from QIAGEN company) on ice jolting hatch 2h, use successively again binding buffer(5mM imidazole, 0.5M NaCl, 20mMTris-Hcl, pH=7.5), wash buffer(10mM/20mM/40mM/60mM imidazole, 0.5M NaC1,20mM Tris-HC1, pH=7.5) wash away successively foreign protein, finally use Elution buffer (200mM imidazole, 0.5M NaCl, 20mM Tris-Hc1, PH=7.5) wash-out target protein, and carry out SDS-PAGE detection, by BCA method, measure protein concentration.
2, enzyme reaction system is 25 μ L, and wherein the final concentration of various components is: 50mM Tris-HCl (pH7.5), 0.02%BSA, 12mM MgC1 2, 2mM ATP, 0.4mM PRPP, 2mM DTT, 2 μ g/mL Nampt, 0.2uM NAM, DMSO and doubling dilution compound of the present invention.First the different concns solution of 0.5 μ L compound of the present invention is added on to 96 orifice plates, add again 20 μ L enzyme reaction mixing solutionss (the enzyme reaction component except substrate), after incubated at room 5min, add 4.5 μ L substrate NAM solution to start reaction, after 37 ℃ of reaction 15min, in 95 ℃ of heating 1min, stop enzyme reaction.
3, by reaction solution after cooled on ice, add successively 10 μ L20% methyl phenyl ketones and 2M KOH, after mixing on vortex mixed instrument in 0 ℃ effect 2min, add 45 μ L88% formic acid, hatch 10min for 37 ℃.
4, use microplate reader to measure the fluorescent value at excitation wavelength 382nm, emission wavelength 445nm place.
5, according to formula: E=R/ (1+ (C/IC 50) s(wherein E is enzymic activity to)+B, and C is compound concentration, R, IC 50, S, B be the parameter for the treatment of matching), in origin software, enzymic activity is carried out to matching to the curve of compound concentration, obtain the IC of compound 50.
The activity experiment that compound of the present invention suppresses Nampt the results are shown in Table 2.
Table 2. compound is to enzyme inhibition activity
Figure BDA0000445187100000271
Result shows that majority of compounds of the present invention has very strong Nampt and suppresses active, wherein compound 7 activity are the strongest, surpass MS735, compound 22,23,24,25,26,27,29 and 45 is suitable with MS735, overwhelming majority compound enzyme inhibition activity, in nmole level, shows the strong restraining effect to Nampt.
Embodiment 54: the experiment of the in-vitro multiplication of the compounds of this invention inhibition tumor cell
First we have carried out the primary dcreening operation of Cytostatic to tumor cell experiment to all synthetic compounds of the present invention, by the compound effects of gradient concentration in the cell strain of logarithmic phase 3 days, utilize srb assay to detect, cell strain is selected HepG2 (human liver cancer cell), HCT116 (people's colon-cancer cell), A549 (human lung adenocarcinoma epithelial cell).We are all less than 735 of 5 μ M to primary dcreening operation half-inhibition concentration IC50 on above 3 kinds of cell strains, 1,23,28,31,32,33, No. 34 compounds that in 35, No. 37 compounds and unorganized ferment screening active ingredients, optimum No. 7 compounds of performance and supposition have structural advantage carry out multiple sieve on HepG2 (human liver cancer cell), further confirm their half-inhibition concentration IC50 by less concentration gradient is set.Experimental result after multiple sieve is in Table 3.
1, by after the cell dissociation of logarithmic phase, blow and beat into single cell suspension, be inoculated in 96 well culture plates; 5x10 3cells/well, every hole substratum 200 microlitres, overnight incubation in 37 ℃, 5%CO2 incubator;
2, add the test-compound (hatching through blood plasma) of gradient concentration, in incubator, cultivate again 3 days.
3,10% Tricholroacetic Acid is fixed 1 hour.
4, with distilled water washing, after being dried, every hole adds 70 microlitre SRB solution (4mg/mL), room temperature dyeing 20 minutes, and 1% acetic acid washing, dry.
5, every hole adds 100 microlitre 10mM Tris-Base solution that SRB is dissolved.
6, microplate reader detects each hole OD value (detection wavelength: 515nm); Record result; By following formula, calculate inhibiting rate: inhibiting rate (%)=(OD contrast-OD administration)/OD contrast * 100%, and calculate IC 50.
Table 3. compound is to 72 hours inhibited proliferations of HepG2 cell lines
Figure BDA0000445187100000281
Figure BDA0000445187100000282
Experimental result demonstration, compound suppresses activity to liver cancer tumor line No. 1, No. 34 and is obviously better than MS735; It is active suitable with MS735 that 31,32,35,37 pairs of liver cancer tumor lines of compound suppress; It is not good that 7,23,28 pairs of liver cancer tumor lines of compound suppress activity.
Below the preferred embodiment of the invention is illustrated, but the invention is not limited to described embodiment, those of ordinary skill in the art also can make all modification being equal to or replacement under the prerequisite without prejudice to the invention spirit, and the modification that these are equal to or replacement are all included in the application's claim limited range.

Claims (9)

1. carbamide derivative and a pharmacy acceptable salt thereof, the general structure of this compound as shown in the formula (I):
Figure FDA0000445187090000011
Wherein:
X is NH or O;
Y is S, NH or N-CN;
L is CO or SO 2;
It is arbitrary to (III) that R group is selected from (I):
(I) aniline or substituted aniline
On substituted aniline phenyl ring, substituting group can be positioned at ortho position, a position and the contraposition of phenyl ring, can be monosubstituted, can be also polysubstituted, and substituting group refers to:
A. halogen: F, Cl, Br, I
B.1-6 the straight or branched alkyl of carbon atom
The straight or branched alkyl of 1-6 carbon atom refers to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl;
C. cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy;
(II) benzylamine or alpha substituted benzylamine
On alpha substituted benzylamine phenyl ring, substituting group can be positioned at ortho position, a position and the contraposition of phenyl ring, can be monosubstituted, can be also polysubstituted, and substituting group refers to:
A. halogen: F, Cl, Br, I
B.1-6 the straight or branched alkyl of carbon atom
The straight or branched alkyl of 1-6 carbon atom refers to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl;
C. cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy;
(III) N-pyrrolidyl, N-morpholinyl, N-piperidyl, N-piperazinyl or
Figure FDA0000445187090000021
When X is N, when Y is S, R is not N-piperidyl;
R 1it is arbitrary to (G) that group is selected from (A):
(A) phenyl or substituted-phenyl
On substituted-phenyl phenyl ring, substituting group can be positioned at ortho position, a position and the contraposition of phenyl ring, can be monosubstituted, can be also polysubstituted, and substituting group refers to:
A. halogen: F, Cl, Br, I
B.1-6 the straight or branched alkyl of carbon atom
The straight or branched alkyl of 1-6 carbon atom refers to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl;
C. cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy;
(B) benzyl or substituted benzyl
On substituted benzyl phenyl ring, substituting group can be positioned at ortho position, a position and the contraposition of phenyl ring, can be monosubstituted, can be also polysubstituted, and substituting group refers to:
A. halogen: F, Cl, Br, I
B.1-6 the straight or branched alkyl of carbon atom
The straight or branched alkyl of 1-6 carbon atom refers to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl;
C. cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy;
(C) containing 1-2 the first heterocycle of heteroatomic 5-6
Heteroatoms refers to N, O, S;
(D) contain 1-2 heteroatomic 5-6 unit's heterocyclic methyl or contain 1-2 the first heterocyclic methyl of heteroatomic benzo 5-6
Heteroatoms refers to N, O, S;
(E) the straight or branched alkyl of 1-8 carbon atom
The straight or branched alkyl of a described 1-8 carbon atom refers to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl;
(F) straight or branched alkyl carbonyl or the carbalkoxy of 1-8 carbon atom
The straight or branched alkyl of a described 1-8 carbon atom refers to: methyl, ethyl, propyl group, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl;
(G) cycloalkyl of 3-8 carbon atom
The cycloalkyl of a described 3-8 carbon atom refers to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, ring octyl group.
2. a kind of carbamide derivative according to claim 1 and pharmacy acceptable salt thereof, it is characterized in that, described pharmacy acceptable salt is hydrochloride, hydrobromate, vitriol, acetate, lactic acid salt, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, tosic acid or mesylate.
3. a kind of carbamide derivative according to claim 1 and pharmacy acceptable salt thereof, is characterized in that, described pharmacy acceptable salt does not contain crystal water, or contain the crystal water of one or more molecules.
4. a kind of carbamide derivative according to claim 3 and pharmacy acceptable salt thereof, is characterized in that, described pharmacy acceptable salt is containing the crystal water of 0.5-3.0 molecule.
5. a kind of carbamide derivative according to claim 1 and pharmacy acceptable salt thereof, is characterized in that, described carbamide derivative is
1-[4-(4-tertbutyloxycarbonyl-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide,
1-(4-(1-piperazinyl alkylsulfonyl)-phenyl)-3-(3-picolyl) thiocarbamide,
N-phenyl-4-[3-(3-picolyl) thioureido] benzsulfamide,
1-[4-(4-methyl isophthalic acid-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide,
1-[4-(4-formyl radical-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide,
1-{4-[4-(2-pyridyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-[4-(4-benzyl-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide,
1-[4-(4-hexanaphthene-1-piperazinyl alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide,
1-(3-picolyl)-3-[4-(1-pyrrolidyl alkylsulfonyl)-phenyl] thiocarbamide,
N-benzyl-4-[3-(3-picolyl) thioureido] benzsulfamide,
1-[4-(N-morpholine alkylsulfonyl)-phenyl]-3-(3-picolyl) thiocarbamide,
2-(1-group-4 ethyl formate)-1-(3-picolyl)-3-[4-(1-piperdine sulfonyl)-phenyl] guanidine,
1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) urea,
1-[4-(1-piperdine sulfonyl)-phenyl]-3-(3-picolyl) urea,
1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) thiocarbamide,
[4-(1-piperidine formyl base)-phenyl] carboxylamine-3-pyridine methyl esters,
[4-(1-piperdine sulfonyl)-phenyl] carboxylamine-3-pyridine methyl esters,
1-[4-(1-piperdine sulfonyl)-phenyl]-3-(3-picolyl) guanidine,
1-[4-(1-piperidine formyl base)-phenyl]-3-(3-picolyl) guanidine,
[4-(1-piperidine formyl base)-phenyl] amino bamic acid ethyl ester,
2-cyano group-1-(3-picolyl)-3-[4-(1-tetramethyleneimine alkylsulfonyl)-phenyl] guanidine,
1-{4-[4-(4-luorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(2,6-difluorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(3-luorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(2-luorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(4-methyl-benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(2-methyl-benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(3-methyl-benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(3-chlorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(2-chlorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(4-chlorobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(4-bromobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(2-menaphthyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(4-trifluoromethyl benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(4-trifluoro-methoxybenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide, 1-{4-[4-(4-normal-butyl benzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(4-nitrobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(4-aminobenzyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(2-1H-benzo [d] imidazoles)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(3-furylmethyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(3-thenyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(furfuryl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(2-thenyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(4-picolyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(3-picolyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide,
1-{4-[4-(4-tolyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide, or
1-{4-[4-(2-picolyl)-1-piperazinyl alkylsulfonyl]-phenyl }-3-(3-picolyl) thiocarbamide.
6. a preparation method for carbamide derivative as claimed in claim 1 and pharmacy acceptable salt thereof, its reaction process is selected from following reaction formula one to four, and the reaction process of described pharmacy acceptable salt also comprises reaction formula five:
Reaction formula one:
Figure FDA0000445187090000051
Raw material I and raw material II are dissolved in to methylene dichloride, add triethylamine, room temperature reaction; 1M aqueous hydrochloric acid and saturated common salt water washing for reaction solution, anhydrous sodium sulfate drying; Filter, organic phase concentrating under reduced pressure obtains intermediate III;
Intermediate III is dissolved in ethyl acetate, adds catalytic amount palladium charcoal, room temperature reaction 12h under hydrogen; Filter palladium charcoal, solvent evaporated obtains key intermediate IV;
Key intermediate IV is dissolved in methylene dichloride, adds thiophosgene or phosgene, room temperature or 50 ℃ of reaction 2h; Saturated sodium bicarbonate and saturated common salt water washing for reaction solution, anhydrous sodium sulfate drying; Filter, solvent evaporated obtains intermediate V; The not purified ethanol that is directly dissolved in of intermediate V, adds 3-aminomethyl-pyridine, stirring at room 1h; Reaction solution is concentrated, and residue obtains target compound VI a through column chromatography purification;
Reaction formula two:
Figure FDA0000445187090000052
Intermediate IV and compound VII are dissolved in to tetrahydrofuran (THF), room temperature reaction 3h; Concentration of reaction solution, residue obtains target compound VI b through column chromatography purification;
Reaction formula three:
Figure FDA0000445187090000061
Intermediate VIII is dissolved in to acetone, adds triethylamine, slowly drip compound IX, stirring at room 2h; Then solvent evaporated, residue obtains target compound VI c through column chromatography purification;
Reaction formula four:
Figure FDA0000445187090000062
Compound X, EDC, triethylamine and cyanamide are dissolved in to tetrahydrofuran (THF), 50 ℃ of reaction 3h; Reaction solution adds water, and dichloromethane extraction merges organic phase, saturated common salt water washing, anhydrous sodium sulfate drying; Organic phase concentrating under reduced pressure, residue obtains target compound VI d through column chromatography purification;
Reaction formula five:
Figure FDA0000445187090000063
Target product VI a is dissolved in ethanol to VI d is arbitrary, adds the ethanolic soln with HX heat, and room temperature reaction 3h has reacted rear suction filtration, washing, the dry salt XI that obtains;
Described HX is hydrochloric acid, Hydrogen bromide, sulfuric acid, acetic acid, lactic acid, tartrate, tannic acid, Citric Acid, trifluoracetic acid, oxysuccinic acid, toxilic acid, succsinic acid, tosic acid or methylsulfonic acid.
7. carbamide derivative and the application of pharmacy acceptable salt in preparing Nampt inhibitor thereof as described in as arbitrary in claim 1-5.
8. carbamide derivative and the application of pharmacy acceptable salt in preparing antitumor drug thereof as described in as arbitrary in claim 1-5.
9. carbamide derivative according to claim 8 and pharmacy acceptable salt thereof the application in preparing antitumor drug, is characterized in that, described tumour is liver cancer, lung cancer, intestinal cancer, ovarian cancer, prostate cancer, cancer of the stomach.
CN201310723814.3A 2013-12-24 2013-12-24 Urea type derivative used as nicotinamide ribose phosphate transferase inhibitor, as well as preparation method and application thereof Active CN103709096B (en)

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CN109293537A (en) * 2018-11-12 2019-02-01 中国药科大学 Sulfamide compound and its medical usage
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CN111454327A (en) * 2020-04-02 2020-07-28 中国人民解放军第二军医大学 NAMPT protein degradation targeting chimera and preparation method and application thereof

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