CN103709096B - 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 PDFInfo
- Publication number
- CN103709096B CN103709096B CN201310723814.3A CN201310723814A CN103709096B CN 103709096 B CN103709096 B CN 103709096B CN 201310723814 A CN201310723814 A CN 201310723814A CN 103709096 B CN103709096 B CN 103709096B
- Authority
- CN
- China
- Prior art keywords
- picolyl
- phenyl
- thiourea
- piperazinylsulfonyl
- benzyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 0 O=S(c(cc1)ccc1NC(*Cc1cccnc1)=S)(N1CCCCC1)=O Chemical compound O=S(c(cc1)ccc1NC(*Cc1cccnc1)=S)(N1CCCCC1)=O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/40—Acylated substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/60—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
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—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
- C07D295/16—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
- 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
- C07D295/182—Radicals derived from carboxylic acids
- C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- C07D405/02—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- 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
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
Technical field
The invention belongs to pharmaceutical technology field is and in particular to a kind of urea as Nampt inhibitor
Analog derivative and preparation method thereof with preparing the application in the medicines such as antitumor.
Background technology
Nampt (nicotinamide phosphoribosyltransferase, nampt) and
Referred to as Nampt (visfatin) or front b cell clone enhancer (pbef).Nampt is catalyzed nicotiamide
(nicotinamide, nam) generates nicotinamide mononucleotide. (nicotinaminde mononucleotide, nmn), and regulation and control are fed
The level of the required energy matter nad of newborn zooblast, is the rate-limiting enzyme of nad constructive ways, play in cellular physiological events to
Close important effect (galli, u., et al.medicinal chemistry of nicotinamide
Phosphoribosyltransferase (nampt) inhibitors, j med chem2013,56,6279-96.).Research table
Bright, nampt is closely related with the occurrence and development of tumor, has become as a very important new target in antitumor drug research
Point.First, tumor cell has very high nad and consumes and metabolic rate, and tumor cell ratio normal cell is to the dependency of nad more
By force it is easier to be affected by nampt inhibitor;Secondly, in tumor cell, nad participates in kinds of tumors as necessary coenzyme
The synthesis of required material, and, nad can significantly reduce (the reactive oxygen of reactive oxygen free radical in environment
Species, ros) level, protect tumor 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.);Additionally,
Nampt plays an important role (adya, r., et in angiogenesiss, induction of vascular endothelial growth factor generate
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 that tumor cell maintains
The important rate-limiting enzyme of nad level, exploitation nampt inhibitor has become the new direction of antitumor drug research.
The nampt inhibitor that 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
) and chs-828 (hjarnaa, p.j., et al.chs828, a novel pyridyl res2003,63,7436-42.
Cyanoguanidine with potent antitumor activity in vitro and in vivo, cancer
Res1999,59,5751-7.), both of which has been enter into clinical research.
In early-stage Study, inventor finds carbamide compounds ms735, shown in its chemical structural formula such as formula (), this change
Compound shows preferable inhibitory activity to Nampt, and has applied for Chinese invention patent (patent application
Number it is cn201110447488.9, a kind of invention entitled application of carbamide compounds, application publication number is
cn102670625a).But, the shortcomings of also there is poorly water-soluble in this compound.
Content of the invention
It is an object of the invention to finding, a class is efficient, low toxicity, wide spectrum new Nampt is anti-swells
Tumor compound, provides a kind of carbamide derivative and its pharmaceutically acceptable salt;It is a further object of the present invention to provide such spreads out
Biology and its preparation method of pharmaceutically acceptable salt;The third object of the present invention is to provide this analog derivative and its pharmaceutically
Acceptable salt is preparing nampt inhibitor, the application in antitumor drug.
The present invention, by carrying out structural modification and skeleton transition to carbamide compounds ms735, obtains multiple carbamide derivatives,
Nampt inhibitory activity and extracorporeal anti-tumor cell-proliferation activity, water solublity all improve a lot and improves.
A first aspect of the present invention, is to provide a kind of carbamide derivative and its pharmaceutically acceptable salt, this compound
General structure such as formula is (i) shown:
Wherein:
X is nh or o;
Y is s, nh or n-cn;
L is co or so2;
It is arbitrary to () that r group is selected from ():
() aniline or substituted aniline
Substituted aniline benzene ring substituents can be located at ortho position, meta and the para-position of phenyl ring, can be monosubstituted or
Polysubstituted, substituent group refers to:
D. halogen: f, cl, br, i
E.1-6 the straight or branched alkyl of individual carbon atom
The straight or branched alkyl of 1-6 carbon atom refers to: methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, uncle
Butyl, n-pentyl, isopentyl, tertiary pentyl, n-hexyl;
F. cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, ethyoxyl, propoxyl group, different
Propoxyl group, butoxy;
() benzylamine or alpha substituted benzylamine
Alpha substituted benzylamine benzene ring substituents can be located at ortho position, meta and the para-position of phenyl ring, can be monosubstituted or
Polysubstituted, substituent group refers to:
D. halogen: f, cl, br, i
E.1-6 the straight or branched alkyl of individual carbon atom
The straight or branched alkyl of 1-6 carbon atom refers to: methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, uncle
Butyl, n-pentyl, isopentyl, tertiary pentyl, n-hexyl;
F. cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, ethyoxyl, propoxyl group, different
Propoxyl group, butoxy;
() n- pyrrolidinyl, n- morpholinyl, n- piperidyl, n- piperazinyl or
When x is n, when y is s, r is not n- piperidyl;
r1It is arbitrary that group is selected from (a) to (g):
(h) phenyl or substituted-phenyl
Substituted-phenyl benzene ring substituents can be located at ortho position, meta and the para-position of phenyl ring, can be monosubstituted or
Polysubstituted, substituent group refers to:
D. halogen: f, cl, br, i
E.1-6 the straight or branched alkyl of individual carbon atom
The straight or branched alkyl of 1-6 carbon atom refers to: methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, uncle
Butyl, n-pentyl, isopentyl, tertiary pentyl, n-hexyl;
F. cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, ethyoxyl, propoxyl group, different
Propoxyl group, butoxy;
(i) benzyl or substituted benzyl
Substituted benzyl benzene ring substituents can be located at ortho position, meta and the para-position of phenyl ring, can be monosubstituted or
Polysubstituted, substituent group refers to:
D. halogen: f, cl, br, i
E.1-6 the straight or branched alkyl of individual carbon atom
The straight or branched alkyl of 1-6 carbon atom refers to: methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, uncle
Butyl, n-pentyl, isopentyl, tertiary pentyl, n-hexyl;
F. cyano group, cyano methyl, amino, nitro, trifluoromethyl, trifluoromethoxy, methoxyl group, ethyoxyl, propoxyl group, different
Propoxyl group, butoxy;
J () contains 1-2 heteroatomic 5-6 circle heterocycles
Hetero atom refers to n, o, s;
K () contains 1-2 heteroatomic 5-6 circle heterocycles methyl or containing 1-2 heteroatomic benzo 5-6
Circle heterocycles methyl
Hetero atom refers to n, o, s;
The straight or branched alkyl of (l) 1-8 carbon atom
The straight or branched alkyl of 1-8 described carbon atom refers to: methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl
Base, the tert-butyl group, n-pentyl, isopentyl, tertiary pentyl, n-hexyl, n-heptyl, n-octyl;
The straight or branched alkyl carbonyl of (m) 1-8 carbon atom or alkoxy carbonyl group
The straight or branched alkyl of 1-8 described carbon atom refers to: methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl
Base, the tert-butyl group, n-pentyl, isopentyl, tertiary pentyl, n-hexyl, n-heptyl, n-octyl;
The cycloalkyl of (n) 3-8 carbon atom
The cycloalkyl of 3-8 described carbon atom refers to: cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring are pungent
Base.
Described pharmaceutically acceptable salt, be preferably: hydrochlorate, hydrobromate, sulfate, acetate, lactate,
Tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-methyl benzenesulfonic acid or first
Sulfonate;
Described pharmaceutically acceptable salt, without water of crystallization, or the water of crystallization containing one or more molecules, preferably
Water of crystallization containing 0.5-3.0 molecule.
Part preferred compound of the present invention includes, but are not limited to following:
1- [4- (4- tertbutyloxycarbonyl -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea
1- (4- (1- piperazinylsulfonyl)-phenyl) -3- (3- picolyl) thiourea
N- phenyl -4- [3- (3- picolyl) ghiourea group] benzsulfamide
1- [4- (4- methyl isophthalic acid-piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea
1- [4- (4- formoxyl -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea
1- { 4- [4- (2- pyridine radicals) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- [4- (4- benzyl -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea
1- [4- (4- hexamethylene -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea
1- (3- picolyl) -3- [4- (1- pyrrolidinyl sulfonyl)-phenyl] thiourea
N- benzyl -4- [3- (3- picolyl) ghiourea group] benzsulfamide
1- [4- (n- morpholine sulfonyl)-phenyl] -3- (3- picolyl) thiourea
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) thiourea
[4- (1- piperidine formyl base)-phenyl] carbamic acid -3- picolyl
[4- (1- piperdine sulfonyl)-phenyl] carbamic acid -3- picolyl
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] aminothio Ethyl formate
2- cyano group -1- (3- picolyl) -3- [4- (1- pyrrolidine sulfonyl)-phenyl] guanidine
1- { 4- [4- (4- luorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (2,6- difluorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (3- luorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (2- luorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (4- methyl-benzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (2- methyl-benzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (3- methyl-benzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (3- chlorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (2- chlorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (4- chlorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (4- bromobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (2- menaphthyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (4- trifluoromethyl benzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (4- trifluoro-methoxybenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (4- normal-butyl benzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (4- nitrobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (4- aminobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (2-1h- benzo [d] imidazoles) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (3-furylmethyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (3- thenyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (furfuryl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (2- thenyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (4- picolyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (3- picolyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (4- tolyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- { 4- [4- (2- picolyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea.
A second aspect of the present invention, is the preparation method providing above-mentioned carbamide derivative and its pharmaceutically acceptable salt.
The reaction process of the compounds of this invention is as follows:
Reaction process leads to method one:
Raw material (10mmol) and raw material (11mmol) are dissolved in dichloromethane (50ml), add triethylamine (1.5ml),
Room temperature reaction 2h.Reactant liquor is washed with 1m aqueous hydrochloric acid solution (50ml) and saturated aqueous common salt (50ml), anhydrous sodium sulfate drying.Cross
Filter, organic faciess are concentrated under reduced pressure to give intermediate.
Intermediate (10mmol) is dissolved in ethyl acetate (50ml), adds catalytic amount palladium charcoal, and hydrogen at room temperature reacts 12h.
Filter palladium charcoal, solvent evaporated obtains key intermediate.
Key intermediate (5mmol) is dissolved in dichloromethane (50ml), adds thiophosgene (or phosgene, 7.5mmol), room temperature
(or 50 DEG C) react 2h.Reactant liquor is washed with saturated sodium bicarbonate (50ml) and saturated aqueous common salt (50ml), and anhydrous sodium sulfate is done
Dry.Filter, solvent evaporated obtains intermediate.Intermediate is not purified to be directly dissolved in ethanol (20ml), adds 3- aminomethyl
Pyridine (5mmol), is stirred at room temperature 1h.Reactant liquor concentrates, and residue obtains target compound a through column chromatography purification.
Reaction process leads to method two:
Intermediate (1mmol) and compound (1mmol) are dissolved in oxolane (20ml), room temperature reaction 3h.Concentrate
Reactant liquor, residue obtains target compound b through column chromatography purification.
Reaction process leads to method three:
Intermediate (1mmol) is dissolved in acetone (10ml), adds triethylamine (0.6ml), be slowly added dropwise compound
(1.2mmol), 2h is stirred at room temperature.Then solvent evaporated, residue obtains target compound c through column chromatography purification.
Reaction process leads to method four:
By compound (1mmol), edc (0.76g, 2mmol), triethylamine (1.5ml) and cyanamide (0.8g, 20mmol)
Or ammonia (2ml) is dissolved in oxolane (20ml), 50 DEG C of reaction 3h.Reactant liquor adds water (100ml), and dichloromethane extracts (100ml
× 3), organic faciess, saturated common salt water washing (100ml), anhydrous sodium sulfate drying are merged.Organic faciess concentrating under reduced pressure, residue warp
Column chromatography purification obtains target compound d.
The reaction process of described pharmaceutically acceptable salt is as follows:
Reaction process leads to method five:
Target product (0.1g) is dissolved in ethanol (10ml), adds the ethanol solution (10ml) with hx heat, room temperature reaction
3h, has reacted rear sucking filtration, has washed, is dried to obtain salt.
Target product is preceding aim compound a to d.
Hx is hydrochloric acid, hydrobromic acid, sulphuric acid, acetic acid, lactic acid, tartaric acid, tannic acid, citric acid, trifluoracetic acid, malic acid, horse
Come sour, succinic acid, p-methyl benzenesulfonic acid or methanesulfonic acid etc..
The numerical value such as weight, volume, concentration in above bracket, is optimum reaction condition, and those skilled in the art can basis
Experience is adjusted.
A third aspect of the present invention, is to provide above-mentioned carbamide derivative and its pharmaceutically acceptable salt preparing nicotinoyl
Application in amine ribose phosphate transferase inhibitor.
The compound of the present invention is through the experiment of nampt activity suppression it was demonstrated that majority of compounds has preferable nampt suppression
Activity.
Present invention also offers above-mentioned carbamide derivative and its pharmaceutically acceptable salt are in preparing antitumor drug
Application.
Described tumor is hepatocarcinoma, pulmonary carcinoma, intestinal cancer, ovarian cancer, carcinoma of prostate, gastric cancer etc..
The compound of the present invention is tested it was demonstrated that majority of compounds has preferable anti-tumor activity through anti-tumor activity.
The present invention is further investigation and exploitation new construction types of anti-tumor medicine opens new approach.
Specific embodiment
With reference to embodiment, the present invention is described in further detail, but the enforcement of the present invention is not limited only to this.
Embodiment 1:1- [4- (4- tertbutyloxycarbonyl -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea
4- (4- tertbutyloxycarbonyl -1- piperazinylsulfonyl) aniline (0.34g, 1mmol, logical method one synthesizes), thiophosgene
(0.14g, 1.2mmol) and 3- aminomethyl-pyridine (0.11g, 1mmol) press logical method one synthesis 1- [4- (4- tertbutyloxycarbonyl -1- piperazine
Piperazine base sulfonyl)-phenyl] -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea
1- [4- (4- tertbutyloxycarbonyl -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g,
0.2mmol) it is dissolved in dichloromethane: trifluoracetic acid (2:1) 20ml, 1h is stirred at room temperature.Solvent evaporated, residue adds unsaturated carbonate hydrogen
Sodium (50ml), ethyl acetate extracts (50ml × 3), merges organic faciess, and saturated aqueous common salt (50ml) washs, and anhydrous sodium sulfate is done
Dry.Then concentrating under reduced pressure solvent, silica gel column chromatography separates (dichloromethane: methanol=100:5) and obtains white solid 0.06g, yield
75%.
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) ghiourea group] benzsulfamide
4- amino-n- phenyl benzenesulfonamides (0.25g, 1mmol, logical method one synthesizes), thiophosgene (0.14g, 1.2mmol) and
3- aminomethyl-pyridine (0.11g, 1mmol) presses logical method one synthesis n- phenyl -4- [3- (3- picolyl) ghiourea group] 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-piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea
4- (4- methyl isophthalic acid-piperazinylsulfonyl) aniline (0.25g, 1mmol, logical method one synthesizes), thiophosgene (0.14g,
1.2mmol) and 3- aminomethyl-pyridine (0.11g, 1mmol) press logical method one synthesis 1- [4- (4- methyl isophthalic acid-piperazinylsulfonyl)-
Phenyl] -3- (3- picolyl) thiourea, 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- formoxyl -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea
4- (4- formoxyl -1- piperazinylsulfonyl) aniline (0.28g, 1mmol, logical method one synthesizes), thiophosgene (0.14g,
1.2mmol) press logical method one and synthesize 1- [4- (4- formoxyl -1- piperazinyl sulphonyl with 3- aminomethyl-pyridine (0.11g, 1mmol)
Base)-phenyl] -3- (3- picolyl) thiourea, 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- pyridine radicals) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
4- [4- (2- pyridine radicals) -1- piperazinylsulfonyl] aniline (0.32g, 1mmol, logical method one synthesizes), thiophosgene
(0.14g, 1.2mmol) and 3- aminomethyl-pyridine (0.11g, 1mmol) press logical method one synthesis 1- { 4- [4- (2- pyridine radicals) -1- piperazine
Piperazine base sulfonyl]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea
4- (4- benzyl -1- piperazinylsulfonyl) aniline (0.33g, 1mmol, logical method one synthesizes), thiophosgene (0.14g,
1.2mmol) and 3- aminomethyl-pyridine (0.11g, 1mmol) press logical method one synthesis 1- [4- (4- benzyl -1- piperazinylsulfonyl) -
Phenyl] -3- (3- picolyl) thiourea, 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- hexamethylene -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea
4- (4- cyclohexyl -1- piperazinylsulfonyl) aniline (0.32g, 1mmol, logical method one synthesizes), thiophosgene (0.14g,
1.2mmol) press logical method one and synthesize 1- [4- (4- cyclohexyl -1- piperazinyl sulphonyl with 3- aminomethyl-pyridine (0.11g, 1mmol)
Base)-phenyl] -3- (3- picolyl) thiourea, 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- pyrrolidinyl sulfonyl)-phenyl] thiourea
4- (1- pyrrolidine sulfonyl) aniline (0.23g, 1mmol, logical method one synthesizes), thiophosgene (0.14g, 1.2mmol)
Press logical method one synthesis 1- (3- picolyl) -3- [4- (1- pyrrolidinyl sulphonyl with 3- aminomethyl-pyridine (0.11g, 1mmol)
Base)-phenyl] thiourea, 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) ghiourea group] benzsulfamide
4- amino-n- benzyl benzsulfamide (0.26g, 1mmol, logical method one synthesizes), thiophosgene (0.14g, 1.2mmol) and
3- aminomethyl-pyridine (0.11g, 1mmol) presses logical method one synthesis n- benzyl -4- [3- (3- picolyl) ghiourea group] 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 sulfonyl)-phenyl] -3- (3- picolyl) thiourea
4- (1- morpholine sulfonyl) aniline (0.24g, 1mmol, logical method one synthesizes), thiophosgene (0.14g, 1.2mmol) and
3- aminomethyl-pyridine (0.11g, 1mmol) presses logical method one synthesis 1- [4- (n- morpholine sulfonyl)-phenyl] -3- (3- picolyl)
Thiourea, obtains 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
Different sulfur cyanato- Ethyl formate (0.15g, 1.2mmol) and 3- aminomethyl-pyridine (0.13g, 1.2mmol) are dissolved in two
Chloromethanes, are stirred at room temperature 2h, add 4- (1- pyrrolidine sulfonyl) aniline (0.3g, 1.2mmol), edc (0.48g,
2.4mmol) with triethylamine (1.7ml), 30 DEG C of reaction 38h.Concentrating under reduced pressure reactant liquor, residue silica gel column chromatography (dichloromethane:
Methanol=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 synthesizes), phosgene (0.12g, 1.2mmol) and 3-
Aminomethyl-pyridine (0.11g, 1mmol) presses logical method one synthesis 1- [4- (1- piperidine formyl base)-phenyl] -3- (3- picolyl)
Urea, obtains 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 synthesizes), phosgene (0.12g, 1.2mmol) and 3-
Aminomethyl-pyridine (0.11g, 1mmol) presses logical method one synthesis 1- [4- (1- piperdine sulfonyl)-phenyl] -3- (3- picolyl)
Urea, obtains 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) thiourea
4- (1- piperidine formyl base) aniline (0.20g, 1mmol, logical method one synthesizes), thiophosgene (0.14g, 1.2mmol) and
3- aminomethyl-pyridine (0.11g, 1mmol) presses logical method one synthesis 1- [4- (1- piperidine formyl base)-phenyl] -3- (3- picolyl)
Thiourea, obtains 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] carbamic acid -3- picolyl
4- (1- piperidine formyl base) aniline (0.20g, 1mmol, logical method one synthesizes) and chloro-carbonic acid -3- picolyl
(0.21g, 1.2mmol) synthesizes [4- (1- piperidine formyl base)-phenyl] carbamic acid -3- picolyl by logical method two, obtains white
Color 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] carbamic acid -3- picolyl
4- (1- piperdine sulfonyl) aniline (0.24g, 1mmol, logical method one synthesizes) and chloro-carbonic acid -3- picolyl
(0.21g, 1.2mmol) synthesizes [4- (1- piperdine sulfonyl)-phenyl] carbamic acid -3- picolyl by logical method two, obtains white
Color 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) thiourea (30mg, 0.077mmol), sodium metaperiodate
(20mg, 0.09mmol) and ammonia (3ml) are dissolved in dmf (3ml) and the mixed solution of water (3ml), 70 DEG C of reaction 3h.Reactant liquor
Add water (10ml), and dichloromethane extracts (20ml × 3), merges organic faciess, saturated common salt water washing (20ml), anhydrous sodium sulfate is done
Dry.Organic faciess 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) thiourea (30mg, 0.084mmol), sodium metaperiodate
(20mg, 0.09mmol) and ammonia (3ml) are dissolved in dmf (3ml) and the mixed solution of water (3ml), 70 DEG C of reaction 3h.Reactant liquor
Add water (10ml), and dichloromethane extracts (20ml × 3), merges organic faciess, saturated common salt water washing (20ml), anhydrous sodium sulfate is done
Dry.Organic faciess 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] aminothio Ethyl formate
4- (1- piperidine formyl base) aniline (0.20g, 1mmol, logical method one synthesizes) and thio-ethyl chloride (0.15g,
1.2mmol) synthesize [4- (1- piperidine formyl base)-phenyl] carbamic acid -3- picolyl by logical method two, obtain white solid
0.21g, yield 55%.
1h nmr(cdcl3,600mhz)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- pyrrolidine sulfonyl)-phenyl] guanidine
1- (3- picolyl) -3- [4- (1- pyrrolidinyl sulfonyl)-phenyl] thiourea (0.1g, 0.26mmol), edc
(0.1g, 0.52mmol), triethylamine (0.37ml) and cyanamide (0.22g, 5.2mmol) are dissolved in oxolane (20ml), 50 DEG C
Reaction 24h.Concentrating under reduced pressure reactant liquor, residue silica gel column chromatography (dichloromethane: methanol=100:10) obtains 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (4- luorobenzyl) -1- piperazinyl sulphur with 4- fluorobenzyl bromide (0.05ml, 0.38mmol)
Acyl group]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl)
Thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (2,6- difluorobenzyl) -1- piperazine with 2,6- bis- fluorobenzyl bromide (0.08g, 0.38mmol)
Piperazine base sulfonyl]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (3- luorobenzyl) -1- piperazinyl sulphur with 3- fluorobenzyl bromide (0.05ml, 0.38mmol)
Acyl group]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (2- luorobenzyl) -1- piperazinyl sulphur with 2- fluorobenzyl bromide (0.05ml, 0.38mmol)
Acyl group]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) sulfur
Urea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (4- methyl-benzyl) -1- piperazinyl with 4- methyl benzyl bromine (0.05g, 0.25mmol)
Sulfonyl]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) sulfur
Urea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (2- methyl-benzyl) -1- piperazinyl with 2- methyl benzyl bromine (0.05g, 0.25mmol)
Sulfonyl]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) sulfur
Urea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (3- methyl-benzyl) -1- piperazinyl with 3- methyl benzyl bromine (0.05g, 0.25mmol)
Sulfonyl]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (3- chlorobenzyl) -1- piperazinyl sulphonyl with 3- bromine chloride (0.05g, 0.25mmol)
Base]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (2- chlorobenzyl) -1- piperazinyl sulphur with 2- bromine chloride (0.04ml, 0.25mmol)
Acyl group]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (4- chlorobenzyl) -1- piperazinyl sulphonyl with 4- bromine chloride (0.05g, 0.25mmol)
Base]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (4- bromobenzyl) -1- piperazinyl sulphonyl with 4- bromobenzyl bromine (0.07g, 0.25mmol)
Base]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (2- menaphthyl) -1- piperazinyl sulphur with 2- bromomethyl naphthalene (0.06g, 0.25mmol)
Acyl group]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- pyridine first
Base) thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (4- trifluoromethyl benzyl with 4- trifluoromethyl benzyl bromine (0.04ml, 0.25mmol)
Base) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- pyridine first
Base) thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (4- trifluoromethoxy with 4- trifluoromethoxy benzyl bromine (0.04ml, 0.25mmol)
Benzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl)
Thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (4- normal-butyl benzyl) -1- with 4- normal-butyl benzyl bromine (0.05ml, 0.25mmol)
Piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) sulfur
Urea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.22g, 0.56mmol), triethylamine
(0.4ml) press logical method three and synthesize 1- { 4- [4- (4- nitrobenzyl) -1- piperazinyl with 4- nitrobenzyl bromine (0.12g, 0.25mmol)
Sulfonyl]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) sulfur
Urea
1- { 4- [4- (4- nitrobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea (50mg,
0.1mmol) it is dissolved in ethyl acetate (10ml), adds catalytic amount palladium carbon, hydrogen at room temperature reacts 12h.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- piperazinylsulfonyl]-phenyl } -3- (3- pyridine first
Base) thiourea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (2-1h- benzene with 2- bromomethyl -1h- benzo [d] imidazoles (0.05g, 0.25mmol)
And [d] imidazoles) -1- piperazinylsulfonyl]-phenyl -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) sulfur
Urea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (3-furylmethyl) -1- piperazinyl sulphonyl with 3- bromomethyl furan (0.05ml)
Base]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) sulfur
Urea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (3- thenyl) -1- piperazinyl sulphonyl with 3- bromomethyl thiophene (0.05ml)
Base]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) sulfur
Urea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (furfuryl) -1- piperazinyl sulphonyl with 2- bromomethyl furan (0.05ml)
Base]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) sulfur
Urea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (2- thenyl) -1- piperazinyl sulphonyl with 2- bromomethyl thiophene (0.05ml)
Base]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) sulfur
Urea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (4- picolyl) -1- piperazinyl sulphonyl with 4- picolyl thiophene (0.06ml)
Base]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) sulfur
Urea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (3- picolyl) -1- piperazinyl sulphonyl with 3- picolyl thiophene (0.06ml)
Base]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea
4- [4- (4- tolyl) -1- piperazinylsulfonyl] aniline (0.32g, 1mmol, logical method one synthesizes), thiophosgene
(0.14g, 1.2mmol) and 3- aminomethyl-pyridine (0.11g, 1mmol) press logical method one synthesis 1- { 4- [4- (4- tolyl) -1- piperazine
Piperazine base sulfonyl]-phenyl } -3- (3- picolyl) thiourea, 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- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) sulfur
Urea
1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea (0.1g, 0.25mmol), triethylamine
(0.05ml) press logical method three and synthesize 1- { 4- [4- (4- picolyl) -1- piperazinyl sulphonyl with 2- picolyl thiophene (0.06ml)
Base]-phenyl } -3- (2- picolyl) thiourea, 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].
As shown in table 1, in table 1 below, table 2, table 3, numbering 1-47 all corresponds to targeted to the structural formula of target compound 1-47
Compound 1-47 and embodiment 1-47.
Table 1. part preferred compound structural formula of the present invention
Embodiment 48:1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiouronium hydrochloride
In 50ml round-bottomed flask, add 0.1g1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) sulfur
Urea, adds the ethyl acetate solution 20ml dissolving of saturation hydrogen chloride, room temperature reaction 3 hours, has reacted rear sucking filtration, washing, drying
Obtain 1- [4- (1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiouronium hydrochloride 0.06g.
Embodiment 49:n- phenyl -4- [3- (3- picolyl) ghiourea group] benzsulfamide succinate
In 50ml round-bottomed flask, add 0.2g n- phenyl -4- [3- (3- picolyl) ghiourea group] benzsulfamide, plus
Enter ethanol solution 20ml dissolving, add the succinic acid ethanol solution of heat, room temperature reaction 3 hours, reacted rear sucking filtration, washing, done
Dry obtain n- phenyl -4- [3- (3- picolyl) ghiourea group] benzsulfamide succinate 0.12g.
Embodiment 50:1- [4- (4- benzyl -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea maleic acid
Salt
In 50ml round-bottomed flask, add 0.2g1- [4- (4- benzyl -1- piperazinylsulfonyl)-phenyl] -3- (3- pyridine
Methyl) thiourea, ethanol dissolves, and adds the maleic acid ethanol solution of heat, room temperature reaction 3 hours, has reacted rear sucking filtration, washing, has done
Dry obtain 1- [4- (4- benzyl -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea 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,
Ethanol dissolves, and adds the malic acid ethanol solution of heat, room temperature reaction 3 hours, has reacted rear sucking filtration, washed, be dried to obtain 1- [4-
(1- piperidine formyl base)-phenyl] -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,
Ethanol dissolves, and adds the malic acid ethanol solution of heat, room temperature reaction 3 hours, has reacted rear sucking filtration, washed, be dried to obtain 1- [4-
(1- piperidine formyl base)-phenyl] -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, is purchased from Kang Tai bio tech ltd, also can be voluntarily
Preparation.
1st, the preparation of enzyme:
Bl21 (de3) the plyss cell that conversion is had recombiant plasmid nampt-pet28a+ is inoculated in 2 × yt culture medium (37
μ g/ml chloromycetin and 100 μ g/ml kanamycin) in, 37 DEG C of shakings are overnight, fresh with 20 times of original volumes after collects thalline
Culture medium is resuspended, cultivates to od600 about 0.6-0.8 for 37 DEG C, induces 8h under the conditions of 0.5mm iptg, 28 DEG C.Bacterium is collected by centrifugation
Body, 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, carry out 30min altogether.By lysate in 12000rpm, 4 DEG C from
Heart 50min Aspirate supernatant.This supernatant and ni-nta post (purchased from qiagen company) shake incubation 2h on ice, then use successively
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 foreign protein successively, finally use
Elution buffer (200mm imidazole, 0.5m nacl, 20mm tris-hc1, ph=7.5) eluting destination protein, and
Carry out sds-page detection, measure protein concentration with bca method.
2nd, enzyme reaction system is 25 μ l, wherein various components final concentration of: 50mm tris-hcl (ph7.5), 0.02%
Bsa, 12mm mgc12, 2mm atp, 0.4mm prpp, 2mm dtt, 2 μ g/ml nampt, 0.2um nam, dmso and multiple proportions dilute
The compound of the present invention releasing.First the variable concentrations solution of the compound of the 0.5 μ l present invention is added on 96 orifice plates, adds 20 μ l
Enzyme reaction mixed solution (the enzyme reaction component in addition to substrate), after incubated at room 5min, adds 4.5 μ l substrate nam solution
To start reaction, after 37 DEG C of reaction 15min, terminate enzyme reaction in 95 DEG C of heating 1min.
3rd, by reactant liquor after cooled on ice, sequentially add 10 μ l20% 1-Phenylethanone .s and 2m koh, vortex mixed instrument mixes
Act on 2min after 0 DEG C, add 45 μ l88% formic acid, 37 DEG C of incubation 10min.
4th, use the fluorescent value at microplate reader mensure excitation wavelength 382nm, launch wavelength 445nm.
5th, according to formula: e=r/ (1+ (c/ic50)s) (wherein e is enzymatic activity to+b, and c is compound concentration, r, ic50, s, b be
Treat the parameter of matching), in origin software, enzymatic activity is fitted to the curve of compound concentration, obtains compound
ic50.
The compound of the present invention suppresses the activity experiment of Nampt to the results are shown in Table 2.
Table 2. compound is to enzyme inhibition activity
Result shows that the majority of compounds of the present invention has very strong Nampt inhibitory activity, its
Middle compound 7 activity is the strongest, more than ms735, compound 22,23,24,25,26,27,29 and 45, absolutely big portion suitable with ms735
Differentiation compound enzyme inhibition activity, in nanomole level, shows the high inhibition effect to Nampt.
Embodiment 54: the compounds of this invention suppresses the experiment of the in-vitro multiplication of tumor cell
We have carried out the primary dcreening operation of Cytostatic to tumor cell experiment to all synthesis compounds of the present invention first, with ladder
The compound effects of degree concentration, in the cell strain 3 days of exponential phase, are detected, cell strain selects hepg2 using srb method
(human liver cancer cell), hct116 (people's colon-cancer cell), a549 (human lung adenocarcinoma epithelial cell).We are in above 3 kinds of cell strains
Upper primary dcreening operation half-inhibition concentration ic50 is respectively less than 5 μm of 735,1,23,28,31,32,33,35, No. 37 compound and in vitro enzyme activity
Property screening in show No. 7 compounds of optimum and speculate there are No. 34 compounds of structural advantage (human liver cancer is thin in hepg2
Born of the same parents) on carry out secondary screening, further confirm that their half-inhibition concentration ic50 by arranging less Concentraton gradient.After secondary screening
Experimental result is shown in Table 3.
1st, by after the cell dissociation of exponential phase, blow and beat into single cell suspension, be inoculated in 96 well culture plates;5x103Carefully
Born of the same parents/hole, 200 microlitres of every hole culture medium, 37 DEG C, overnight incubation in 5%co2 incubator;
2nd, add the test-compound (being incubated through blood plasma) of gradient concentration, incubator is further cultured for 3 days.
3rd, 10% trichloroacetic acid fixes 1 hour.
4th, washed with distilled water, after being dried, 70 microlitres of srb solution (4mg/ml) of every hole addition, room temperature dyeing 20 minutes, 1%
Acetic acid washs, and is dried.
5th, every hole adds 100 microlitres of 10mm tris-base solution so that srb is dissolved.
6th, microplate reader detection each hole od value (Detection wavelength: 515nm);Record result;Calculate suppression ratio by following equation: suppression
Rate (%) processed=(od comparison-od administration)/od comparison × 100%, and calculate ic50.
Table 3. compound is to human hepatoma cell strain hepg272 hour inhibited proliferation
Experimental result shows, compound 1, No. 34 ms735 is substantially better than to hepatic carcinoma strain inhibitory activity;Compound
31st, 32,35,37 pairs of hepatic carcinoma strain inhibitory activity are suitable with ms735;7,23,28 pairs of hepatic carcinoma strain inhibitory activity of compound
Not good.
Below the preferred embodiment to the invention is illustrated, but the invention be not limited to described
Embodiment, those of ordinary skill in the art also can make without prejudice on the premise of the invention spirit a variety of equivalent
Modification or replacement, these equivalent modifications or replacement are all contained in the application claim limited range.
Claims (5)
1. a kind of carbamide derivative and its pharmaceutically acceptable salt are it is characterised in that described carbamide derivative is
1- [4- (4- tertbutyloxycarbonyl -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea,
1- (4- (1- piperazinylsulfonyl)-phenyl) -3- (3- picolyl) thiourea,
1- [4- (4- methyl isophthalic acid-piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea,
1- [4- (4- formoxyl -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea,
1- { 4- [4- (2- pyridine radicals) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- [4- (4- benzyl -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea,
1- [4- (4- hexamethylene -1- piperazinylsulfonyl)-phenyl] -3- (3- picolyl) thiourea,
1- { 4- [4- (4- luorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (2,6- difluorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (3- luorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (2- luorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (4- methyl-benzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (2- methyl-benzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (3- methyl-benzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (3- chlorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (2- chlorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (4- chlorobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (4- bromobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (2- menaphthyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (4- trifluoromethyl benzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (4- trifluoro-methoxybenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (4- normal-butyl benzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (4- nitrobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (4- aminobenzyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (2-1h- benzo [d] imidazoles) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (3-furylmethyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (3- thenyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (furfuryl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (2- thenyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (4- picolyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (3- picolyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea,
1- { 4- [4- (4- tolyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea, or
1- { 4- [4- (2- picolyl) -1- piperazinylsulfonyl]-phenyl } -3- (3- picolyl) thiourea.
2. a kind of carbamide derivative according to claim 1 and its pharmaceutically acceptable salt are it is characterised in that described
Pharmaceutically acceptable salt is hydrochlorate, hydrobromate, sulfate, acetate, lactate, tartrate, tannate, citric acid
Salt, trifluoroacetate, malate, maleate, succinate, p-methyl benzenesulfonic acid or mesylate.
3. a kind of carbamide derivative as claimed in claim 1 or 2 and its pharmaceutically acceptable salt are preparing nicotiamide phosphoric acid
Application in phosphoribosynltransferase inhibitor.
4. a kind of carbamide derivative as claimed in claim 1 or 2 and its pharmaceutically acceptable salt are preparing antitumor drug
In application.
5. carbamide derivative according to claim 4 and its pharmaceutically acceptable salt answering in preparing antitumor drug
With it is characterised in that described tumor be hepatocarcinoma, pulmonary carcinoma, intestinal cancer, ovarian cancer, carcinoma of prostate, gastric cancer.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310723814.3A CN103709096B (en) | 2013-12-24 | 2013-12-24 | Urea type derivative used as nicotinamide ribose phosphate transferase inhibitor, as well as preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201310723814.3A CN103709096B (en) | 2013-12-24 | 2013-12-24 | Urea type derivative used as nicotinamide ribose phosphate transferase inhibitor, as well as preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN103709096A CN103709096A (en) | 2014-04-09 |
CN103709096B true CN103709096B (en) | 2017-01-18 |
Family
ID=50402488
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201310723814.3A Active CN103709096B (en) | 2013-12-24 | 2013-12-24 | Urea type derivative used as nicotinamide ribose phosphate transferase inhibitor, as well as preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN103709096B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104557863B (en) * | 2014-12-18 | 2017-03-15 | 中国科学院广州生物医药与健康研究院 | A kind of new Nampt inhibitor and its synthetic method and application |
CN109293537A (en) * | 2018-11-12 | 2019-02-01 | 中国药科大学 | Sulfamide compound and its medical usage |
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 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102186822A (en) * | 2008-08-29 | 2011-09-14 | 顶标公司 | Novel urea and thiourea derivatives |
CN102869261A (en) * | 2010-03-01 | 2013-01-09 | 瑞科西有限公司 | Compounds and therapeutic uses thereof |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007008541A2 (en) * | 2005-07-08 | 2007-01-18 | Kalypsys, Inc. | Cellular cholesterol absorption modifiers |
-
2013
- 2013-12-24 CN CN201310723814.3A patent/CN103709096B/en active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102186822A (en) * | 2008-08-29 | 2011-09-14 | 顶标公司 | Novel urea and thiourea derivatives |
CN102869261A (en) * | 2010-03-01 | 2013-01-09 | 瑞科西有限公司 | Compounds and therapeutic uses thereof |
Non-Patent Citations (1)
Title |
---|
Structure-Based Identification of Ureas as Novel Nicotinamide Phosphoribosyltransferase (Nampt) Inhibitors;Xiaozhang Zheng et al.;《Journal of Medicinal Chemistry》;20130425;第56卷;4921-4937 * |
Also Published As
Publication number | Publication date |
---|---|
CN103709096A (en) | 2014-04-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN106916101B (en) | NAMPT/HDAC double-target inhibitor and preparation method thereof | |
US7338950B2 (en) | Amide compounds as ion channel ligands and uses thereof | |
EP1663204B1 (en) | C-kit modulators and methods of use | |
ES2402362T3 (en) | Proton-pump inhibitor | |
US20150353538A1 (en) | Compounds and therapeutic uses thereof | |
US20110065734A1 (en) | Novel bifunctional compounds which inhibit protein kinases and histone deacetylases | |
MX2007001119A (en) | Substituted propenyl piperazine derivatives as novel inhibitors of histone deacetylase. | |
NO319209B1 (en) | Aryl and heteroaryl substituted urea compounds and pharmaceutical compositions comprising these | |
CN101370791A (en) | Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase | |
TW200417546A (en) | New compounds | |
CN106588885A (en) | 2-substituted aromatic ring-pyrimidine derivative, and preparation and application thereof | |
US20130317027A1 (en) | Compounds and therapeutic uses thereof | |
Sun et al. | Design, synthesis and biological evaluation of pyrimidine-based derivatives as VEGFR-2 tyrosine kinase inhibitors | |
Ono et al. | Design and synthesis of selective CDK8/19 dual inhibitors: Discovery of 4, 5-dihydrothieno [3′, 4′: 3, 4] benzo [1, 2-d] isothiazole derivatives | |
CN103709096B (en) | Urea type derivative used as nicotinamide ribose phosphate transferase inhibitor, as well as preparation method and application thereof | |
Chimenti et al. | Exploring 4-substituted-2-thiazolylhydrazones from 2-, 3-, and 4-acetylpyridine as selective and reversible hMAO-B inhibitors | |
CA2802130A1 (en) | Cyanoquinoline derivatives | |
JP2023036991A (en) | Amine-substituted heterocyclic compounds as ehmt2 inhibitors, salts thereof, and methods of synthesis thereof | |
CN103450152A (en) | Anti-tumor medicine in double-aryl urea structure based on indazole, indole, azaindazole or azaindole | |
Shan et al. | Expanding the structural diversity of diarylureas as multi-target tyrosine kinase inhibitors | |
CN109796439A (en) | A kind of hydroxyproline class peptide derivant and its preparation method and application | |
US20090247590A1 (en) | Indane amides | |
KR101732989B1 (en) | Inhibitor compounds of 11-beta-hydroxysteroid dehydrogenase type 1 | |
TW200540161A (en) | 4-Amino-5-cyanopyrimidine derivatives | |
Martinez-Gonzalez et al. | Pyrido [2, 3-b][1, 5] benzoxazepin-5 (6H)-one derivatives as CDK8 inhibitors |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant |