CN104860900A - Thiazole compounds, and preparation method and application thereof in pharmacy - Google Patents

Thiazole compounds, and preparation method and application thereof in pharmacy Download PDF

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Publication number
CN104860900A
CN104860900A CN201410062371.2A CN201410062371A CN104860900A CN 104860900 A CN104860900 A CN 104860900A CN 201410062371 A CN201410062371 A CN 201410062371A CN 104860900 A CN104860900 A CN 104860900A
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base
nitrothiazole
dichloropyridine
sulfo
compound
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孙宏斌
宋洁梅
陈超
王锦政
温小安
顾伟
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China Pharmaceutical University
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China Pharmaceutical University
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Priority to CN201410062371.2A priority Critical patent/CN104860900A/en
Priority to PCT/CN2014/090466 priority patent/WO2015127797A1/en
Publication of CN104860900A publication Critical patent/CN104860900A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/58—Nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D277/36—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

The invention relates to thiazole compounds, and a preparation method and a use thereof in pharmacy, and discloses the compounds represented by the general formula I and the general formula II or nitrogen oxides, pharmaceutically acceptable salts or solvates thereof, and a preparation method and an application thereof in pharmacy, especially an application in resisting tumor. Pharmacodynamic experiment results indicate that the compounds represented by the formula I and the formula II have the antitumor effect, and especially have the effect on resisting human multiple myeloma cells. Therefore, the compounds can be used for preparation of drugs for preventing or treating tumor related diseases.

Description

Thiazole compound, its preparation method and the purposes in pharmacy thereof
Technical field
The present invention relates to pharmacy field, be specifically related to thiazole compound, its preparation method and the application in preparation prevention or treatment tumor disease medicine thereof.Please the preference of (application number 201310061162.1, the applying date: on 02 27th, 2013, invention and created name: thiazole compound, its preparation method and its purposes in pharmacy) in patent application claims Chinese patent.
Background technology
Malignant tumour is the major disease of serious threat human health.Tumour be that to exchange the wrong responses of the signal such as ganglion cell's growth, differentiation, function and apoptosis be feature with cell self.Think now that most tumors is that the change of several genes and rear raw environment causes.Even if the tumour of same type, its malignant cell group kind is also different, has different hereditary changes, and changes along with advancing of disease.At present, the antitumor drug used clinically comprises cytotoxic drug, kinase inhibitor, proteasome inhibitor, hdac inhibitor, hedgehog inhibitor etc.
Heterogeneous ring compound containing thiazole ring has the biological activity of wide spectrum, as effects such as local anaesthesia, anticonvulsion, antiviral, antibacterial, antitumor and desinsections.The antitumor drug gone on the market is as just contained thiazole ring in the structure of Dasatinib.Thiazole ring in Dasatinib is connected with other parts for amino by 2, and this is the conventional strategy of many thiazole compounds, and reason is that thiazolamine fragment easily obtains, and synthesis is simple, and 2 give the activation of electric base after, thiazole has higher reactive behavior.Amino (the US20130317218A1 that many thiazolium compoundss with anti-tumor activity all dissociate containing 2 or replace, WO2013082324A1, CN102964343A, US20120225880A1, CN102070556A, WO2010083246A1, U S20050234033A1, WO2005035541A1, WO2004074283A1, WO2000075120A1).Other 2 donor residuess also comprise the sulfydryl (Bioorg Med Chem.21 (24): 7648-54) and methylene radical (Bioorg MedChem.20 (7): 2316-22) etc. of replacement.In addition, have benefited from developing rapidly of heterocycle linked reaction, the anti-tumor small molecular that thiazole 2,4 and 5 digit pairs are associated with aromatic group all has report, as 2 (WO2011137219A1, EP2606889A1), 4 (WO2013082324A1, EP2606889A1), 5 (US20120225880A1, WO2010083246A1).
In the anti-tumor small molecular with thiazole parent nucleus, have and inhale the rarer report of electric substituent thiazolium compounds, particularly inhale the report less (Cancer Lett.340 (1): 63-71) of electric base for 2.Inhaling electric base for 2 makes thiazole ring reactive behavior greatly reduce, and chemical stability is poor.The thiazolium compounds of 2 ethanoyl or amide group replacement with anti-tumor activity also has no report.In addition, the report of the thiazolium compounds that the nitro with anti-tumor activity replaces is also few, and the people such as Cohen report the anti-tumor activity (Molecules18 (1): 97-113) of the thiazolium compounds that a class 5 nitros replace.And the thiazolium compounds that 4 nitros with anti-tumor activity replace has no any report.
Summary of the invention
The invention discloses the compound as shown in general formula I and II or its oxynitride, pharmacy acceptable salt or solvate:
Wherein:
X is H, NO 2, halogen, CN ,-SCF 3or-SO 2cF 3;
Y is S, NH, NHCH 2, O, SO or SO 2;
R 1represent one or more Z 1the aryl replaced or heteroaryl, wherein, Z 1be selected from halogen, itrile group, nitro, trifluoromethyl or-OR 3;
R 2for-COR 4,-CONR 5r 6or the Z of 1 ~ 6 carbon 2the alkyl replaced;
R 3and R 4it is the alkyl of 1 ~ 6 carbon;
R 5, R 6independently selected from alkyl or substituted alkyl, non-substituted or one or more Z of hydrogen atom, 1 ~ 10 carbon 3the aryl replaced or heteroaryl, or R 5, R 6with form 4 ~ 8 yuan of cyclic groups together with atom N that is non-substituted or that replace;
Z 2for-OH ,-OCOR 7or-NR 5r 6;
Z 3for halogen or-OR 8;
R 7be alkyl or the substituted alkyl of 1 ~ 6 carbon;
R 8it is the alkyl that the alkyl of 1 ~ 6 carbon or one or more Z4 of 1 ~ 6 carbon replace;
Z 4for-NR 9r 10or-OR 11;
R 9, R 10independently selected from the alkyl of hydrogen atom, 1 ~ 6 carbon or substituted alkyl or R 9, R 10form 3 ~ 8 yuan of cycloalkyl or R together 9, R 104 ~ 8 yuan of Heterocyclylalkyls are formed together with atom N that is non-substituted or that replace;
R 11for the alkyl of hydrogen atom or 1 ~ 6 carbon.
In formula I and II compound,
X preferred H, NO 2or CN;
Y preferred S, O, NH or NHCH 2;
R 1preferred one or more Z 1the phenyl replaced or pyridyl, wherein, Z 1preferred halogen, itrile group or nitro;
R 2preferably-COR 4or-CONR 5r 6, wherein, R 4it is the alkyl of 1 ~ 6 carbon; R 5, R 6independently selected from hydrogen atom or one or more Z 3the phenyl replaced or pyridyl, wherein, Z 3define as above-mentioned.
In formula I and II compound, preferred compound is as follows:
1-[5-(2,3-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone (Ia-1);
1-[5-(3,4-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone (Ia-2);
1-[5-(2,6-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone (Ia-3);
1-[5-(2,3-dichlorophenyl sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-1);
1-[5-(3,4-dichlorophenyl sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-2);
1-[5-(2,6-dichlorophenyl sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-3);
1-[5-(2,4 dichloro benzene base sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-4);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-5);
1-[5-(3-methoxyphenylthio)-4-nitrothiazole-2-base] ethyl ketone (Ib-6);
1-[5-(3,4-dimethoxyphenylthio)-4-nitrothiazole-2-base] ethyl ketone (Ib-7);
1-[5-(4-nitrophenyl sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-8);
1-[5-(3,4-dichlorobenzyl is amino)-4-nitrothiazole-2-base] ethyl ketone (Ib-9);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethanol (Ic);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl acetate (Id-1);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl chloroacetate (Id-2);
1-[5-(3,5-dichloropyridine base 4-sulfo-)-4-nitrothiazole-2-base] ethyl propionate (Id-3);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl butyrate (Id-4);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl benzoate (Id-5);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base]-N-methyl ethyl-amine (Ie-1);
N-benzyl-1-I5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethamine (Ie-2);
1-[2-(2,3-dichlorophenyl sulfo-)-thiazole-5-base] ethyl ketone (II-1);
1-[2-(3,4-dichlorophenyl sulfo-)-thiazole-5-base] ethyl ketone (II-2);
1-[2-(2,6-dichlorophenyl sulfo-)-thiazole-5-base] ethyl ketone (II-3);
1-[2-(2,4 dichloro benzene base sulfo-)-thiazole-5-base] ethyl ketone (II-4);
1-[2-(3-methoxyphenylthio)-thiazole-5-base] ethyl ketone (II-5);
1-[2-(3,4-dimethoxyphenylthio)-thiazole-5-base] ethyl ketone (II-6);
1-[2-(4-nitrophenyl sulfo-)-thiazole-5-base] ethyl ketone (II-7);
1-[2-(3,5-dichloropyridine base-4-sulfo-)-thiazole-5-base] ethyl ketone (II-8);
The bromo-5-of 2-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole (VIc-1);
5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VId-1);
N-methyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-1);
N, N-diethyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-2);
N-(1-methyl piperidine-4-base)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-3);
N-phenyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-4);
N-benzyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-5);
N-styroyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-6);
N-(4-p-methoxy-phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-7);
N-(3,4-Dimethoxyphenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI -8);
N-(3-chloro-4-methoxy phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-9);
N-(3-p-methoxy-phenyl 0-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-10);
N-(2-p-methoxy-phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-11);
N-(6-methoxypyridine-3-base)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-12);
N-[4-(3-dimethylin propoxy-) phenyl]-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-13).
Another order of the present invention 'sthere is provided the preparation method of formula I and formula II compound, shown in following reaction formula:
R 1, R 4, R 5, R 6, R 7defined with in the above-mentioned formula I of Y and formula II compound.
Specifically comprise the following steps:
(1) by compound III and R 1there is nucleophilic substitution reaction in the basic conditions and obtain Compound I a in YH; The feature of preparation Compound I a is, the alkaline reagents of employing is selected from salt of wormwood, sodium carbonate, sodium methylate, sodium ethylate, particular methanol sodium; The solvent adopted is methyl alcohol, ethanol, acetonitrile, preferably firstalcohol; The reaction times adopted is 1-24 hour; Temperature is adopted to be subzero 20 DEG C to 100 DEG C, preferably 50 DEG C to 70 DEG C.
(2) take compound III as starting raw material, carry out nitration reaction and obtain formula IV compound; The feature of preparation formula IV compound is, the nitrating agent of employing is selected from nitrosonitric acid, concentrated nitric acid, concentrated nitric acid/vitriol oil, preferred nitrosonitric acid; The solvent adopted is selected from acetic anhydride, trifluoro-acetic anhydride, preferred trifluoro-acetic anhydride; The reaction times adopted is 1-24 hour; The temperature adopted is subzero 50 DEG C to 25 DEG C, preferably subzero 25 DEG C to 0 DEG C.
(3) by compound IV and R 1there is nucleophilic substitution reaction and obtain compounds ib in YH.
(4) compounds ib generation reduction reaction obtains Ic; The feature of preparation Compound I c is, the original reagent of going back of employing is selected from sodium borohydride, POTASSIUM BOROHYDRIDE, Lithium Aluminium Hydride, preferred sodium borohydride; The solvent selected from methanol, ethanol, the tetrahydrofuran (THF) that adopt, particular methanol; The reaction times adopted is 1-10 hour; Temperature is adopted to be subzero 20 DEG C to 100 DEG C, preferred DEG C to 50 DEG C.
(5) Compound I c generation esterification obtains Id; The feature of preparation Compound I d is, the acylating reagent of employing is selected from acid anhydrides, acyl chlorides, carboxylic acid, preferred anhydrides and acyl chlorides; The alkali adopted is selected from triethylamine, DMAP, salt of wormwood, preferred DMAP; The solvent adopted is selected from methylene dichloride, chloroform, acetonitrile, preferred methylene dichloride; The reaction times adopted is 1-24 hour; Temperature is adopted to be subzero 20 DEG C to 100 DEG C, preferably 25 DEG C to 100 DEG C.
(6) compounds ib generation reductive amination process obtains Ie: the feature of preparation Ie is, the original reagent of going back of employing is sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, preferred itrile group sodium borohydride; The solvent adopted is methylene dichloride, ethyl acetate, tetrahydrofuran (THF), preferred methylene dichloride; The reaction times adopted is 1-24 hour; Temperature is adopted to be subzero 20 DEG C to 100 DEG C, preferably 25 DEG C to 50 DEG C.
(7) by compound V and R 1there is nucleophilic substitution reaction and obtain Compound II per in YH; The feature preparing Compound II per is, the alkaline reagents of employing is selected from salt of wormwood, sodium carbonate, sodium methylate, sodium ethylate, particular methanol sodium; The solvent adopted is methyl alcohol, ethanol, acetonitrile, DMF, particular methanol, DMF; The reaction times adopted is 1-24 hour; Temperature is adopted to be subzero 20 DEG C to 100 DEG C, preferably 25 DEG C to 70 DEG C.
(8) with compound VI a for starting raw material, carry out nitration reaction and obtain formula VIb compound; The feature of preparation formula VIb compound is, the nitrating agent of employing is selected from nitrosonitric acid, concentrated nitric acid, concentrated nitric acid/vitriol oil, preferred nitrosonitric acid; The solvent adopted is selected from acetic anhydride, trifluoro-acetic anhydride, preferred trifluoro-acetic anhydride; The reaction times adopted is 1-24 hour; The temperature adopted is subzero 50 DEG C to 25 DEG C, preferably subzero 25 DEG C to 0 DEG C;
(9) by compound VI b and R 1there is nucleophilic substitution reaction and obtain compound VI c in YH.
(10) with compound VI c for starting raw material, by reacting with CuCN, and continue hydrolysis and obtain compound VI d; The feature of preparation compound VI d is, adopts solvent to be N, N-diformamide, methyl-sulphoxide, pyridine, acetone, preferred N, N-diformamide when reacting with CuCN; The employing reaction times is 1-12 hour; Temperature is adopted to be 50 DEG C to 150 DEG C, preferably 120 DEG C to 140 DEG C.
(11) in acid solvent, be there is diazonium salt hydrolysis reaction in compound VI d and nitrous acid hydrochlorate and obtain compound VI e; The feature of preparation compound VI e is, nitrite adopts Sodium Nitrite, potassium nitrite, calcium nitrite, preferred Sodium Nitrite; The solvent adopted is strong acid aqueous solution, preferably 80% aqueous sulfuric acid; The employing reaction times is 0.5-6 hour, preferably 0.5 hour; Temperature is adopted to be subzero 20 DEG C to 25 DEG C, preferably 25 DEG C.
(12) compound VI e and R 5r 6nH reacts and generates VI; The feature of preparation compound VI is, acylating reagent employing Acetyl Chloride 98Min., Benzoyl chloride, grassacyl chlorides, chloroacetyl chloride, trichoroacetic chloride, phosphorus oxychloride, preferred phosphorus oxychloride; Selected solvent is acetonitrile, acetone, methylene dichloride, chloroform, tetrahydrofuran (THF), ether, preferred acetonitrile; The alkali adopted is triethylamine, diisopropylethylamine, pyridine, preferred diisopropylethylamine; Reaction times is 1-48 hour, preferred 5-12 hour; Temperature is adopted to be subzero 20 DEG C to 50 DEG C, preferably 25 DEG C.
The preparation method of concrete formula I and formula II compound is with reference to embodiment.
Another object of the present invention there is provided formula I and H compound or its oxynitride, pharmacy acceptable salt or the solvate purposes in the medicine preparing prevention and therapy tumour.Pharmacodynamic experiment result shows, general formula I of the present invention and II compound have significant anti-tumour cell proliferative effect.
Here is part pharmacological evaluation and the result of compound of the present invention.
1. experiment purpose: adopt each compound of CCK-8 Determination Staining on the impact of people's multiple myeloma cells RPMI-8226 in-vitro multiplication activity, and calculate respective half-inhibition concentration IC 50.
2. experiment material: the compounds of this invention DMSO dissolves and is mixed with mother liquor, adopts perfect medium to be diluted to proper concn before using; Reagent: CCK-8 test kit is purchased from Nanjing grace brilliantbio tech ltd; Substratum: RMPI-1640 substratum is purchased from Gibco company; Foetal calf serum: purchased from Gibco company; 96 porocyte culture plates are purchased from Costar company.
3. experimental technique: get the cell that live cell fraction reaches more than 90% and test.Cell inhibitory effect test adopts EnoGeneCell tMcounting Kit-8 (CCK-8) cell viability detection kit.Cell dissociation, to count, make concentration be 1 × 10 5the cell suspension of individual/m l, in 96 orifice plates, every hole adds 100ul cell suspension (every hole 1 × 10 4individual cell); 96 orifice plates are placed in 37 DEG C, 5%CO 2cultivate 24 hours in incubator; With perfect medium dilution medicine to desired concn, every hole adds the substratum of the corresponding drug containing of 100 μ L, sets up negative control group simultaneously, Vehicle controls group, often organizes 5 multiple holes; 96 orifice plates are placed in 37 DEG C, 5%CO 2cultivate 72 hours in incubator; Every hole adds 10 μ L CCK-8 solution, culture plate is hatched 4 hours in incubator, is determined at the OD value at 450nm place by microplate reader, calculates inhibiting rate and calculates IC 50value.
4. experimental result: part of compounds of the present invention is to the inhibit activities (IC of people multiple myeloma RPMI-8226 cell strain in-vitro multiplication 50) see the following form.
Compound IC 50(μM) Compound IC 50(μM) Compound IC 50(μM) Compound IC 50(μM)
Ia-1 87.60 Ib -5 20.97 Id-2 15.47 II -2 82.55
Ia-2 123.29 Ib-6 43.38 Id-3 28.35 II-3 91.36
Ia-3 114.36 Ib-7 5.86 Id-4 14.39 II-4 47.27
Ib-1 5.03 Ib-8 2.45 Id-5 17.30 II-5 79.20
Ib-2 4.69 Ib-9 44.27 Ie-1 14.57 II-6 129.55
Ib-3 6.86 Ic 23.39 Ie-2 14.00 II-7 25.33
Ib-4 2.64 Id-1 20.55 II-1 87.20 II-8 22.57
VIc-1 - VId-1 + VI-1 + VI-2 -
VI-3 ++ VI-4 + VI-5 + VI-6 +
VI-7 +++ VI-8 ++ VI-9 ++ VI-10 ++
VI-I1 ++ VI-12 +++ VI-13 +++
The numerical range that in form, symbol refers to is as follows:
-refer to IC 50be greater than 100 μMs ,+refer to IC 50be 100 μMs to 10 μMs, ++ refer to IC 50be 10 μMs to 1 μM, +++ refer to IC 50it is 1 μM to 0.1 μM.
Above-mentioned test result display, the growth of the compounds of this invention to multiple myeloma cells has restraining effect in various degree.Prompting the compounds of this invention may be used for preparing antitumor drug.
Present invention also offers a kind of pharmaceutical composition of prevention and therapy tumour, wherein contain the formula I treating significant quantity and II compound or its oxynitride, pharmacy acceptable salt or solvate as active ingredient and pharmaceutically acceptable carrier.Described pharmaceutical composition can be dosage form conventional on the technology of pharmaceutics such as conventional tablet or capsule, slow releasing tablet or capsule, controlled release tablet or capsule, granule, powder, syrup, oral liquid, injection.
Pharmaceutical composition Chinese style I of the present invention and II compound orthe dosage of its oxynitride, pharmacy acceptable salt or solvate is different with the difference such as symptom and age.For adult, when oral administration, the lower limit of single administration amount is 0.1mg (preferred 1mg), and the upper limit is 1000mg (preferred 500mg); When intravenously administrable, the lower limit of single administration amount is 0.01mg (preferred 0.1mg), and the upper limit is 500mg (preferred 250mg).Also this dosage range can be departed from according to the difference of the difference of disease degree and formulation.
Embodiment
Content of the present invention is illustrated below by embodiment.In the present invention, the embodiment of the following stated is to better set forth the present invention, is not for limiting the scope of the invention.
Embodiment 1
The preparation of 1-[5-(2,3-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone (1a-1)
2,3-thiophenol dichlorobenzene (120mg, 0.68mmol), sodium methylate (37mg, 0.68mmol) are added in dry methyl alcohol (6mL), stirred at ambient temperature 20 minutes.In reaction solution, add 2-ethanoyl-5-diuril azoles (100mg, 0.48mmol), be heated to 50 DEG C, reaction solution continues to stir until react completely.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.After evaporate to dryness, silica gel column chromatography obtains yellow solid (59mg, yield 31%).mp99-100℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：2.71(s，3H)，6.90-6.93(d，1H，J＝9Hz)，7.08-7.13(t，1H)，7.34-7.36(d，1H，J＝6Hz)，8.02(s，1H)；ESI MSm/z325.9[M+Na] +；HRMS forC 11H 7NOS 2Cl 2+Na cacld325.9244found325.0246.
Embodiment 2
The preparation of 1-[5-(3,4-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone (Ia-2)
Reactions steps, with reference to embodiment 1, obtains yellow solid (yield 26%).mp113-114℃； 1HNMR(CDCl 3，500MHz)δ[ppm)：2.68(s，3H)，7.16-7.18(m，1H)，7.38-7.42(m，2H)，7.95(s，1H)；ESI MSm/z325.9[M+Na] +；H RMS forC 11H 7NOS 2Cl 2+Na cacld325.9244found325.9246.
Embodiment 3
The preparation of 1-[5-(2,6-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone (Ia-3)
Reactions steps, with reference to embodiment 1, obtains yellow solid (43%).mp107℃； 1HNMR(CDCl 3，500MHz)δ(ppm)：2.63(s，3H)，7.27-7.32(m，1H)7.42-7.45(m，2H)，7.90(s，1H)ppm.ESIMSm/z303.9[M+H] +；HRMS forC 11H 7NOS 2Cl 2+H cacld303.9424found303.9428.
Embodiment 4
The preparation of 1-(the chloro-4-nitrothiazole of 5--2-base) ethyl ketone (IV)
The mixing solutions of trifluoroacetic anhydride (6.3mL), nitrosonitric acid (2.1mL) is cooled to subzero 20 DEG C; stir 1 hour; slowly add trifluoroacetic anhydride (2mL) solution of 2-ethanoyl-5-diuril azoles (1.10g, 6.8mmol) wherein.Reaction solution continues to stir 2 hours at subzero 20 DEG C.Reaction solution is concentrated, pours in frozen water, by extracted with diethyl ether, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.After evaporate to dryness, silica gel column chromatography obtains yellow solid (0.98g, yield 73%). 1HNMR(CDCl 3，300MHz)：δ(ppm)：2.72(s，3H)；ESI MSm/z204.9[M-H] +；HRMS for C 5H 3N 2O 3SCl-H cacld204.9475found204.9477.
Embodiment 5
The preparation of 1-[5-(2,3-dichlorophenyl sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-1)
2,3-thiophenol dichlorobenzene (94mg, 0.53mmmol), sodium methylate (29mg, 0.53mmol) are added dry methyl alcohol (5mL), stirred at ambient temperature 20 minutes.Then in reaction solution, add 1-(the chloro-4-nitrothiazole of 5--2-base) ethyl ketone (100mg, 0.48mmol), continue stirring under room temperature 4 hours.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Be spin-dried for rear silica gel column chromatography and obtain yellow solid (129mg, yield 76%).m x173℃； 1HNMR(CDCl 3，500MHz)δ(ppm)：2.67(s，3H)，7.37-7.40(m，1H)，7.72-7.73(m，2H)；ESI MS m/z371.0[M+Na] +；HRMS forC 11H 6N 2O 3S 2Cl 2+Na cacld370.9095found370.9097.
Embodiment 6
The preparation of 1-[5-(3,4-dichlorophenyl sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-2)
Reactions steps, with reference to embodiment 5, obtains yellow solid (yield 76%).mp133℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：2.66(s，3H)，7.52-7.56(dd，1H，J＝3，6Hz)，7.64-7.66(d，1H，J＝6Hz)，7.80-7.81(d，1H，J＝3Hz)；ESI MS m/z371.0[M+Na] +；HRMS forC 11H 6N 2O 38 2Cl 2+Na cacld370.9095found370.9096.
Embodiment 7
The preparation of 1-[5-(2,6-dichlorophenyl sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-3)
Reactions steps, with reference to embodiment 5, obtains light yellow solid (yield 88%).mp147-150℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：267(s，3H)，7.46-7.59(m，3H)；ESI MS m/z371.0[M+Na] +；HRMS for C ■H 6N 2O 3S 2Cl 2+Na cacld370.9095found370.9096.
Embodiment 8
The preparation of 1-[5-(2,4 dichloro benzene base sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-4)
Reactions steps, with reference to embodiment 5, obtains light yellow solid (76%).mp147-150℃. 1HNMR(CDCl 3，300MHz)δ(ppm)：2.65(s，3H)，7.41-7.44(m，1H)，7.66-7.67(d，1H，J＝3Hz)，7.70-7.73(d，1H，J＝9Hz)；ESI MSm/z370.9[M+Na] +；HRMS for C 11H 6N 2O 3S 2Cl 2+Na cacld370.9095found370.9098.
Embodiment 9
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-5)
Reactions steps, with reference to embodiment 5, obtains light yellow solid (yield 50%).mp154-155℃； 1HNMR(CD 3OD，300MHz)δ(ppm)：2.62(s，3H)，8.84(s，2H)；ESI MS m/z371.9[M+Na] +；HRMS for C 10H 5N 3O 3S 2Cl 2+Na cacld371.9047found371.9049.
Embodiment 10
The preparation of 1-[5-(3-methoxyphenylthio)-4-nitrothiazole-2-base] ethyl ketone (Ib-6)
Reactions steps, with reference to embodiment 5, obtains yellow solid (yield 88%).mp109-113℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：2.65(s，3H)，3.85(s，3H)，7.10-7.27(m，3H)，7.43-7.49(m，1H)；ESI MS m/z333.0[M+Na] +；HRMS for C 12H 10N 2O 4S 2+Na cacld332.9980found332.9983.
Embodiment 11
The preparation of 1-[5-(3,4-dimethoxyphenylthio)-4-nitrothiazole-2-base] ethyl ketone (Ib-7)
Reactions steps, with reference to embodiment 5, obtains yellow solid (yield 32%).mp181℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：2.65(s，3H)，3.88(s，3H)，3.95(s，3H)，6.97(d，1H，J＝6Hz)，7.10(s，1H)，7.26(d，1H，J＝6Hz)；ESI MS m/z341.0[M+H] +；HRMS forC 13H 12N 2O 5S 2+H cacld341.0266found341.0269.
Embodiment 12
The preparation of 1-[5-(4-nitrophenyl sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-8)
Reactions steps, with reference to embodiment 5, obtains yellow solid (90%).mp191℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：2.67(s，3H)，7.92(d，2H，J＝9Hz)，8.41(d，2H，J＝9Hz)；ESI MSm/z326.0[M+H] +；HRMS for C 11H 7N 3O 5S 2+H cacld.325.9905found325.9907.
Embodiment 13
The preparation of 1-[5-(3,4-dichlorobenzyl is amino)-4-nitrothiazole-2-base] ethyl ketone (Ib-9)
3,4-dichloro-benzylamine (128mg, 0.73mmo l), 1-(the chloro-4-nitrothiazole of 5--2-base) ethyl ketone (100mg, 0.48mmol) are dissolved in Virahol (2mL), reflux.After reaction terminates, by solvent evaporate to dryness, silica gel column chromatography obtains yellow solid (77mg, yield 46%).mp155-156℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：2.61(s，3H)，4.58(d，2H，J＝6Hz)，7.21(d，1H，J＝9Hz)，7.45-7.48(m，2H)，8.76(brs，1H)；ESI MS m/z346.0[M+H] +；HRMS for C 12H 9Cl 2N 3O 3+H cacld.345.9820found345.9823.
Embodiment 14
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethanol (Ic)
By sodium borohydride (11mg, 0.29mmol), 1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl ketone (100mg, 0.29mmol) adds in methyl alcohol (2mL), stirred at ambient temperature 1 hour.Add water cancellation by solvent concentration, being extracted with ethyl acetate, and merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Be spin-dried for rear silica gel column chromatography and obtain white solid (78mg, yield 8%).mp151℃； 1HNMR(CDCl 3，500MHz)δ(ppm)：1.61(d，3H，J＝5Hz)，3.08(s，1H)，5.07(q，1H，J＝5Hz)，8.71(s，2H)；ESI MS m/z351.9[M+H] +；HRMS for C ■H 7Cl 2N 3O 3S 2+H calcd.351.9384found351.9387.
Embodiment 15
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl acetate (Id-1)
By 1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethanol (100mg, 0.28mmol), acetic anhydride (58mg, 0.57mmol), DMAP (3mg, 0.03mmol) is dissolved in methylene dichloride (3mL).Stirring at room temperature 1 hour, adds water, dichloromethane extraction, merges organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Be spin-dried for rear silica gel column chromatography and obtain white solid (104mg, 93%).mp148-151℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：1.64(d，3H，J＝6Hz)，2.07(s，3H)，5.94(q，1H，J＝6Hz)，8.71(s，2H)；ESI MS m/z393.9[M+H] +；HRMS forC 12H 9Cl 2N 3O 4S 2+H calcd.393.9490found393.9495.
Embodiment 16
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl chloroacetate (Id-2)
Reactions steps, with reference to embodiment 15, obtains brown oil (yield 57%). 1HNMR(CDCl 3，300MHz)δ(ppm)：1.72(d，3H，J＝7Hz)，4.10(s，2H)，6.05(q，1H，J＝7Hz)，8.74(s，2H)；ESI MS m/z427.9[M+H] +；HRMS for C 12H 8Cl 3N 3O 4S 2+H calcd.427.9100found427.9104.
Embodiment 17
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl propionate (Id-3)
Reactions steps, with reference to embodiment 15, obtains yellow solid (yield 92%).mp72℃. 1HNMR(CDCl 3，300MHz)δ(ppm)：1.11(t，3H，J＝5Hz)，1.67(d，3H，J＝5Hz)，2.36(q，2H，J＝5Hz)，5.98(q，1H，J＝5Hz).
Embodiment 18
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl butyrate (Id-4)
Reactions steps, with reference to embodiment 15, obtains water white oil (yield 85%). 1HNMR(CDCl 3，500Hz)δ(ppm)：0.91(t，3H，J＝7Hz)，1.59-1.67(m，5H)，2.32(t，2H，J＝7Hz)，5.98(q，1H，J＝6Hz)，8.72(s，2H)；ESI MSm/z422.0[M+H] +；HRMS for C 14H 13Cl 2N 3O 4S 2+Hcalcd.421.9803found421.9807.
Embodiment 19
The preparation of 1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl benzoate (Id-5)
Reactions steps, with reference to embodiment 15, obtains light yellow solid (yield 78%).mp143-144℃. 1HNMR(CDCl 3，300MHz)δ(ppm)：1.79(d，3H，J＝7Hz)，6.20(q，1H，J＝7Hz)，7.41-7.46(m，2H)，7.57-7.62(m，1H)，7.96-7.98(m，2H)，8.68(s，2H)；ESI MS m/z456.0[M+H] +；HRMS for C 17H ¨Cl 2N 3O 4S 2+H calcd，455.9646found455.9649.
Embodiment 20
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitro thiophene azoles-2-base] preparation of-N-methyl ethyl-amine (Ie-1)
By 1-[5-(3,4-dichlorobenzyl is amino)-4-nitrothiazole-2-base] ethyl ketone (80mg, 0.23mmol) be dissolved in methylene dichloride (1mL), add dimethylamine (the THF solution of 2M, 0.9mL, 1.82mmol), add acetic acid and adjust pH to 5 ~ 6.Reaction solution stirring at room temperature, until raw material disappears, adds sodium cyanoborohydride (29mg, 0.45mmol), stirring at room temperature 1 hour.Add shrend to go out, with dichloromethane extraction, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.Be spin-dried for rear silica gel column chromatography and obtain yellow solid (27mg, yield 32%).mp111℃； 1HNMR(CDCl 3，500MHz)δ(ppm)：1.44(d，3H，J＝7Hz)，2.41(s，3H)，3.89(q，1H，J＝7Hz)，8.70(s，2H)；ESI MS m/z365.1[M+H] +；HRMS forC 11H 10Cl 2N 4O 2S 2+H calcd.364.9700found364.9703.
Embodiment 21
The preparation of N-benzyl-1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethamine (Ie-2)
Reactions steps, with reference to embodiment 20, obtains yellow solid (yield 61%).mp106℃； 1HNMR(CDCl 3，500MHz)δ(ppm)：1.47(d，3H，J＝6Hz)，1.82(brs，1H)，3.76(s，2H)，4.06(q，1H，J＝6Hz)，7.18-7.20(m，2H)，7.27-730(m，3H)，8.72(s，2H)；ESI MS m/z441.0[M+H] +；HRMS for C 17H 14Cl 2N 4O 2S 2+H calcd.441.0013found441.0016.
Embodiment 22
The preparation of 1-[2-(2,3-dichlorophenyl sulfo-)-thiazole-5-base] ethyl ketone (II-1)
2,3-thiophenol dichlorobenzene (120mg, 0.68mmol), sodium methylate (37mg, 0.68mmol) are added dry methyl alcohol (6mL), stirred at ambient temperature 20 minutes.Then in reaction solution, add the chloro-5-acetylthiazole (100mg, 0.48mmol) of 2-, stirring at room temperature is until react completely.By solvent evaporate to dryness, be extracted with ethyl acetate, merge organic layer, saturated common salt water washing, anhydrous sodium sulfate drying.After evaporate to dryness, silica gel column chromatography obtains white solid (129mg, yield 69%).mp108-109℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：2.51(s，3H)，7.27-7.33(m，1H)，7.60-7.68(m，2H)，8.14(s，1H)；ESI MS m/z303.9[M+H] +；HRMS forC 11H 7Cl 2NOS 2+H calcd，303.9424found303，9427.
Embodiment 23
The preparation of 1-[2-(3,4-dichlorophenyl sulfo-)-thiazole-5-base] ethyl ketone (II-2)
Reactions steps, with reference to embodiment 22, obtains white solid (yield 70%).mp122-123℃； 1HNMR(CDCl 3，500MHz)δ(ppm)：2.50(s，3H)，7.50(dd，1H，J＝2，8Hz)，7.55(d，1H，J＝8Hz)，7.77(d，1H，J＝2Hz)，8.12(s，1H)；ESI MS m/z303.9[M+H] +；HRMS forC 11H 7Cl 2NOS 2+H calcd.303.9424found303.9427.
Embodiment 24
The preparation of 1-[2-(2,6-dichlorophenyl sulfo-)-thiazole-5-base] ethyl ketone (II-3)
Reactions steps, with reference to embodiment 22, obtains white solid (yield 58%).mp104℃； 1HNMR(CDCl 3，500MHz)δ(ppm)：2.49(s，3H)，7.39-7.42(m，1H)，7.52-7.53(m，2H)，8.10(s，1H).ESI MSm/z303.9[M+H] +；HRMSfor C ■H 7Cl 2NOS 2+Hcalcd.303.9424found303.9427.
Embodiment 25
The preparation of 1-[2-(2,4 dichloro benzene base sulfo-)-thiazole-5-base] ethyl ketone (II-4)
Reactions steps, with reference to embodiment 22, obtains white solid (yield 69%).mp106℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：2.50(s，3H)，7.36(dd，1H，J＝2，8Hz)，7.60(d，1H，J＝2Hz)，7.68(d，1H，J＝8Hz)，8.12(s，1H)；ESIMS m/z303.9[M+H] +；HRMS forC 11H 7Cl 2NOS 2+Hcalcd.303.9424found303.9427.
Embodiment 26
The preparation of 1-[2-(3-methoxyphenylthio)-thiazole-5-base] ethyl ketone (II-5)
Reactions steps, with reference to embodiment 22, obtains white solid (yield 71%).mp114-115℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：2.48(s，3H)，3.83(s，3H)，7.04-7.07(m，1H)，7.20-7.27(m，2H)，7.37-7.42(m，1H)，8.11(s，1H)；ESI MSm/z266.0[M+H] +；HRMS forC 12H ■NO 2S 2+H calcd.266.0309found266.0311.
Embodiment 27
The preparation of 1-[2-(3,4-dimethoxyphenylthio)-thiazole-5-base] ethyl ketone (II-6)
Reactions steps, with reference to embodiment 22, obtains white solid (yield 69%).mp122℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：2.46(s，3H)，3.88(s，3H)，3.93(s，3H)，6.95(d，1H，J＝8Hz)，7.13(d，1H，J＝2Hz)，7.26-7.29(m，1H)，8.09(s，1H)；ESI MS m/z296.0[M+H] +；HRMS for C 13H 13NO 3S 2+H calcd.296.0415found296.0417.
Embodiment 28
The preparation of 1-[2-(4-nitrophenyl sulfo-)-thiazole-5-base] ethyl ketone (II-7)
Reactions steps, with reference to embodiment 22, obtains yellow solid (yield 87%).mp95-96℃； 1HNMR(CDCl 3，500MHz)δ(ppm)：2.53(s，3H)，7.78(m，2H)，8.18(s，1H)，8.27(m，2H)；ESI MSm/z281.0[M+H] +；HRMS for C 11H 8N 2O 3S 2+H calcd.281.0055found281.0057.
Embodiment 29
The preparation of 1-[2-(3,5-dichloropyridine base-4-sulfo-)-thiazole-5-base] ethyl ketone (II-8)
Reactions steps, with reference to embodiment 22, obtains yellow solid (yield 43%).mp96℃； 1HNMR(CDCl 3，300MHz)δ(ppm)：2.53(s，3H)，8.10(s，1H)，8.67(s，2H)；ESI MS m/z304.9[M+H] +；HRMS forC 10H 6N 2OS 2+H calcd.304.9377found304.9381.
Embodiment 30
The preparation of the bromo-4-nitrothiazole (VI-b) of 2,5-bis-
Add in trifluoroacetic anhydride (40mL) by under-20oC by nitrosonitric acid (13ML) ,-20oC stirs 2h.At same temperature, slowly 2,5-bis-bromo thiazole (14g) is instilled reaction solution ,-20oC stirs and spends the night.Solvent evaporated, slowly adds water (100mL), and EA extracts, and anhydrous Na 2SO4 is dry, solvent evaporated, and PE pulls an oar, and filters to obtain crude pale yellow solid 3.34g (yield 20%)).ESI MS m/z289.0[M+H] +
Embodiment 31
The preparation of the bromo-5-of 2-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole (VIc-1)
Chloro-for 3,5-bis-4-mercaptopyridine (2.3g, 1.1eq) is dissolved in 50mL commercial anhydrous methyl alcohol, add sodium methylate (690mg, 1.1eq), 40 DEG C are stirred 2h, add 2, the bromo-4-nitrothiazole (3.34g) of 5-bis-, 40 DEG C are stirred 2.5h, and solvent evaporated, adds 50mL water, EA extracts, anhydrous Na 2sO 4drying, solvent evaporated, PE pulls an oar, and filters to obtain crude yellow solid 2.57g (crude yield 83%). 1HNMR(CDCl 3，300MHz)δ(ppm)：8.73(s，2H)；ESI MS m/z385.6[M+H] +
Embodiment 32
The preparation of 5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VId-1)
By bromo-for 2-5-(3,5-dichloropyridine base) sulfydryl-4-nitrothiazole (100mg) is dissolved in DMF (1mL, analytical pure) in, add cuprous cyanide (41.6mg, 1.8eq), 120 DEG C of stirring (the prior preheating of oil bath) 1.5h, are cooled to room temperature, add EA (20mL) fully to stir, cross filtering goprecipitation, EA phase washes twice, anhydrous Na 2sO 4drying, solvent evaporated, adds methyl alcohol concussion, filters to obtain crude pale yellow solid 30mg.(crude yield 33%). 1HNMR(DMSO，300MHz)δ(ppm)：8.95(s，2H)，8.52(s，1H)，8.17(s，1H)；ESI MS m/z349.1[M-H] -
Embodiment 33
The preparation of N-methyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-1)
By 5-(3, the chloro-4-pyridyl of 5-bis-) sulfydryl-4-nitrothiazole-2-carboxylic acid (100mg) is suspended in MeCN (5mL), room temperature instillation phosphorus oxychloride (0.037mL, 1.5eq), stirring at room temperature 30min, methylamine hydrochloride (22mg is added under ice bath, 1.1eq), instillation DIEA (0.237mL, 5eq), stirring at room temperature 1.5h after completing, steam in solvent, with frozen water (15mL), filter gained precipitation ether and wash twice, obtain white powder 22mg (yield 21%). 1HNMR(DMSO，300MHz)δ(ppm)：9.09(d，J＝5.2Hz，1H)，8.96(s，2H)，2.73(d，J＝4.8Hz，3H)；ESI MS m/z362.6[M-H] -
Embodiment 34
N, N-diethyl-5-[(3, 5-dichloropyridine-4-base) sulfydryl] preparation of-4-nitrothiazole-2-methane amide (VI-2) is by 5-(3, the chloro-4-pyridyl of 5-bis-) sulfydryl-4-nitrothiazole-2-carboxylic acid (100mg) is suspended in MeCN (5mL), room temperature instillation phosphorus oxychloride (0.037mL, 1.5eq), stirring at room temperature 30min, diethylamine hydrochloride (35mg is added under ice bath, 1.1eq), instillation DIEA (0.237mL, 5eq), after completing, stirring at room temperature crosses liquid, solvent evaporated, with frozen water (15mL), be placed in 0 DEG C of crystallization, filter gained precipitation and obtain white powder 18mg (yield 16%) by preparative column chromatography purification. 1HNMR(DMSO，300MHz)δ(ppm)：8.95(s，2H)，3.56-3.54(m，4H)，1.32-1.15(m，6H)；ESI MSm/z405，1[M] +
Embodiment 35
N-(1-methyl piperidine-4-base)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-3)
Preparation
5-(the chloro-4-pyridyl of 3,5-bis-) sulfydryl-4-nitrothiazole-2-carboxylic acid (50mg) is suspended in 3mL MeCN, room temperature instillation phosphorus oxychloride (0.02mL, 1.5eq), stirring at room temperature 30min, adds N-methyl-4-amino piperidine (17.8mg, 1.1eq) under ice bath, instillation DIEA (0.117mL, 5eq), stirring at room temperature 1.5h after completing, solvent evaporated, with frozen water (15mL), use saturated NaHCO 3adjust pH to 7, EA extraction, washing, anhydrous Na 2sO 4drying, solvent evaporated, adds ether and smashs to pieces, filters gained solid ether and washes, and obtains yellow powder 30mg (yield 47%). 1HNMR(DMSO，300MHz)δ(ppm)：9.22(s，1H)，8.95(s，2H)，3.95(s，1H)，3.10(m，4H)，2.72(s，3H)，1.96(m，4H)；ESI MS m/z446.1[M-H] -
Embodiment 36
The preparation of N-phenyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-4)
Reactions steps, with reference to embodiment 33, obtains pressed powder (yield 8%). 1HNMR(DMSO，300MHz)δ(ppm)：11.08(s，1H)，9.00(s，2H)，7.77(d，J＝7.9Hz，2H)，7.36(t，J＝7.6Hz，2H)，7.16(t，J＝7.2Hz，1H)；ESI MSm/z425.0[M-H] -
Embodiment 37
The preparation of N-benzyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-5)
5-(the chloro-4-pyridyl of 3,5-bis-) sulfydryl-4-nitrothiazole-2-carboxylic acid (80mg) is suspended in MeCN (3mL), room temperature instillation phosphorus oxychloride (0.03mL, 1.5eq), benzylamine (26.8mg, 1.1eq) is added under ice bath, instillation DIEA (0.19mL, 5eq), after completing, stirring at room temperature crosses liquid, solvent evaporated, add 15mL frozen water, EA extracts, and 1NHCl washes 5 times, anhydrous Na 2sO 4drying, solvent evaporated, adds triturated under ether and obtains pale yellow powder 25mg (yield 25%). 1HNMR(DMSO，300MHz)δ(ppm)：9.76(t，J＝5.9Hz，1H)，8.97(s，2H)，7.34-7.20(m，5H)，4.40(d，J＝6.1Hz，2H)；ESI MS m/z438.8[M-H] -
Embodiment 38
The preparation of N-styroyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-6)
Reactions steps, with reference to embodiment 37, obtains pale yellow powder (yield 22%). 1HNMR(DMSO，300MHz)δ(ppm)：9.28(s，1H)，8.96(s，2H)，7.19(s，3H)，2.94(s，1H)，2.73(s，1H)；ESIMS m/z455.3[M+H] +
Embodiment 39
The preparation of N-(4-p-methoxy-phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-7)
Reactions steps, with reference to embodiment 37, obtains dark red powder (yield 8/). 1HNMR(DMSO，300MHz)δ(ppm)：10.96(s，1H)，8.98(s，2H)，7.66(d，J＝9.0Hz，2H)，6.91(d，J＝9.1Hz，2H)，3.72(s，3H)；ESI MS m/z455.0[M-H]-
Embodiment 40
The preparation of N-(3,4-Dimethoxyphenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-8)
Reactions steps, with reference to embodiment 37, obtains green powder (yield 8%). 1HNMR(DMSO，300MHz)δ(ppm)：10.93(s，1H)，7.40(m，2H)，6.90(m，1H)，3.60(m，6H)；ESI MS m/z484.9[M-H] -
Embodiment 41
The preparation of N-(3-chloro-4-methoxy phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-9)
Reactions steps, with reference to embodiment 37, obtains green powder (yield 29%). 1HNMR(DMSO，300MHz)δ(ppm)：11.15(s，1H)，9.00(s，2H)，7.90(s，1H)，7.70(m，1H)，7.15(m，1H)，3.91(s，3H)；ESI MS m/z488.8[M-H] -
Embodiment 42
The preparation of N-(3-p-methoxy-phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-10)
Reactions steps, with reference to embodiment 37, obtains green powder (yield 29%). 1HNMR(DMSO，300MHz)δ(ppm)：11.03(s，1H)，8.97(s，2H)，7.40(m，2H)，7.23(m，1H)，6，71(m，1H)，3.98(s，3H)；ESIMS m/z479.4[M+Na] +
Embodiment 43
The preparation of N-(2-p-methoxy-phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-11)
Reactions steps, with reference to embodiment 37, obtains brown ceramic powder (yield 13%). 1HNMR(DMSO，300MHz)δ(ppm)：9.80(s，1H)，9.00(s，2H)，7.85(m，1H)，7.10(m，3H)，3.88(s，3H)；ESI MSm/z454.7[M-H] -
Embodiment 44
The preparation of N-(6-methoxypyridine-3-base)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-12)
Reactions steps, with reference to embodiment 37, obtains dark red powder (yield 13%). 1HNMR(DMSO，300MHz)δ(ppm)：11.15(s，1H)，9.00(s，2H)，8.49(m，1H)，8.05(s，1H)，6.86(s，1H)，3.88(s，3H)；ESI MS m/z455.9[M-H] -
Embodiment 45
The preparation of N-[4-(3-dimethylin propoxy-) phenyl]-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-13)
Reactions steps, with reference to embodiment 37, obtains pale yellow powder (yield 22%). 1HNMR(DMSO，300MHz)δ(ppm)：10.97(s，1H)，8.99(s，2H)，7.66(d，J＝8.6Hz，2H)，6.92(d，J＝8.6Hz，2H)，3.98(t，J＝6.1Hz，1H)，2.46(d，J＝6.9Hz，1H)，2.24(s，6H)，1.87(dd，J＝13.1，6.4Hz，1H)；ESI MS m/z526.1[M-H] -
Embodiment 46
Tablet
By compounds ib-4 (50g) obtained in embodiment 8, HPMC E (150g), starch (200g), PVP K30, appropriate and Magnesium Stearate (1g) mixing, granulates, compressing tablet.

Claims (9)

1. general formula I or the compound shown in II or its oxynitride, pharmacy acceptable salt or solvate:
Wherein:
X is H, NO 2, halogen, CN ,-SCF 3or-SO 2cF 3;
Y is S, NH, NHCH 2, O, SO or SO 2;
R 1represent one or more Z 1the aryl replaced or heteroaryl, wherein, Z 1be selected from halogen, itrile group, nitro, trifluoromethyl or-OR 3;
R 2for-COR 4,-CONR 5r 6or the Z of 1 ~ 6 carbon 2the alkyl replaced;
R 3and R 4it is the alkyl of 1 ~ 6 carbon;
R 5, R 6independently selected from alkyl or substituted alkyl, non-substituted or one or more Z of hydrogen atom, 1 ~ 10 carbon 3the aryl replaced or heteroaryl, or R 5, R 64 ~ 8 yuan of heterocyclic radicals are formed together with atom N that is non-substituted or that replace;
Z 2for-OH ,-OCOR 7or-NR 5r 6;
Z 3for halogen or-OR 8;
R 7be alkyl or the substituted alkyl of 1 ~ 6 carbon;
R 8be the alkyl of 1 ~ 6 carbon or one or more Z of 1 ~ 6 carbon 4the alkyl replaced;
Z 4for-NR 9r 10or-OR 11;
R 9, R 10independently selected from the alkyl of hydrogen atom, 1 ~ 6 carbon or substituted alkyl or R 9, R 10form 3 ~ 8 yuan of cycloalkyl or R together 9, R 104 ~ 8 yuan of Heterocyclylalkyls are formed together with atom N that is non-substituted or that replace;
R 11for the alkyl of hydrogen atom or 1 ~ 6 carbon.
2. compound as claimed in claim 1, is characterized in that, in described formula 1 and formula II compound:
X is H, NO 2or CN;
Y is S, O, NH or NHCH 2;
R 1for one or more Z 1the phenyl replaced or pyridyl, wherein, Z 1for halogen, itrile group or nitro;
R 2for-COR 4or-CONR 5r 6, wherein, R 4it is the alkyl of 1 ~ 6 carbon; R 5, R 6independently selected from hydrogen atom or one or more Z 3the phenyl replaced or pyridyl, wherein, Z 3as defined in claim 1.
3. compound as claimed in claim 1, is characterized in that described formula I and formula II compound comprise following compound:
1-[5-(2,3-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone (Ia-1);
1-[5-(3,4-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone (Ia-2);
1-[5-(2,6-dichlorophenyl sulfo-) thiazol-2-yl] ethyl ketone (Ia-3);
1-[5-(2,3-dichlorophenyl sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-1);
1-[5-(3,4-dichlorophenyl sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-2);
1-[5-(2,6-dichlorophenyl sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-3);
1-[5-(2,4 dichloro benzene base sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-4);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-5);
1-[5-(3-methoxyphenylthio)-4-nitrothiazole-2-base] ethyl ketone (Ib-6);
1-[5-(3,4-dimethoxyphenylthio)-4-nitrothiazole-2-base] ethyl ketone (Ib-7);
1-[5-(4-nitrophenyl sulfo-)-4-nitrothiazole-2-base] ethyl ketone (Ib-8);
1-[5-(3,4-dichlorobenzyl is amino)-4-nitrothiazole-2-base] ethyl ketone (Ib-9);
1-[5-(3,5 -dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethanol (Ic);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl acetate (Id-1);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl chloroacetate (Id-2);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl propionate (Id-3);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl butyrate (Id-4);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethyl benzoate (Id-5);
1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base]-N-methyl ethyl-amine (Ie-1);
N-benzyl-1-[5-(3,5-dichloropyridine base-4-sulfo-)-4-nitrothiazole-2-base] ethamine (Ie-2);
1-[2-(2,3-dichlorophenyl sulfo-)-thiazole-5-base] ethyl ketone (II-1);
1-[2-(3,4-dichlorophenyl sulfo-)-thiazole-5-base] ethyl ketone (II-2);
1-[2-(2,6-dichlorophenyl sulfo-)-thiazole-5-base] ethyl ketone (II-3);
1-[2-(2,4 dichloro benzene base sulfo-)-thiazole-5-base] ethyl ketone (II-4);
1-[2-(3-methoxyphenylthio)-thiazole-5-base] ethyl ketone (II-5);
1-[2-(3,4-dimethoxyphenylthio)-thiazole-5-base] ethyl ketone (II-6);
1-[2-(4-nitrophenyl sulfo-)-thiazole-5-base] ethyl ketone (II-7);
1-[2-(3,5-dichloropyridine base-4-sulfo-)-thiazole-5-base] ethyl ketone (II-8);
The bromo-5-of 2-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole (VIc-1);
5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VId-1);
N-methyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-1);
N, N-diethyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-2);
N-(1-methyl piperidine-4-base)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-3);
N -phenyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-4);
N-benzyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-5);
N-styroyl-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-6);
N-(4-p-methoxy-phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-7);
N-(3,4-Dimethoxyphenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-8);
N-(3-chloro-4-methoxy phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl [-4-nitrothiazole-2-methane amide (VI-9);
N-(3-p-methoxy-phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-10);
N-(2-p-methoxy-phenyl)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-11);
N-(6-methoxypyridine-3-base)-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-12);
N-[4-(3-dimethylin propoxy-) phenyl]-5-[(3,5-dichloropyridine-4-base) sulfydryl]-4-nitrothiazole-2-methane amide (VI-13).
4. the preparation method of compound described in claim 1, shown in following reaction formula:
Specifically comprise the following steps:
(1) take compound III as starting raw material, carry out nitration reaction and obtain formula IV compound;
(2) by compound IV and R 1there is nucleophilic substitution reaction and obtain compounds ib in YH:
In above-mentioned reaction formula, R 1, R 4with Y as defined in claim 1.
5. the preparation method of compound described in claim 1, shown in following reaction formula:
Specifically comprise the following steps:
(1) with compound VI a for starting raw material, carry out nitration reaction and obtain formula VIb compound;
(2) by compound VI b and R 1there is nucleophilic substitution reaction and obtain compound VI c in YH;
(3) with compound VI c for starting raw material, by reacting with CuCN, and continue hydrolysis and obtain compound VI d;
(4) in acid solvent, be there is diazonium salt hydrolysis reaction in compound VI d and nitrous acid hydrochlorate and obtain compound VI e;
(5) compound VI e and R 5r 6nH reaction generates VI;
In above-mentioned reaction formula, R 1, R 5, R 6with Y as defined in claim 1.
6. the formula 1 of claim 1 or formula II compound or the application in preparation prevention or treatment tumor disease medicine of its oxynitride, pharmacy acceptable salt or solvate.
7. purposes according to claim 6, it is characterized in that the medicine for the preparation of prevention or treatment multiple myeloma disease.
8. the pharmaceutical composition of a prevention or treatment multiple myeloma disease, it is characterized in that, contain the formula I treating significant quantity or II compound or its oxynitride, pharmacy acceptable salt or solvate in described pharmaceutical composition as active ingredient and pharmaceutically acceptable carrier.
9. pharmaceutical composition according to claim 8, it is characterized in that, described pharmaceutical composition can be dosage form conventional on the technology of pharmaceutics such as conventional tablet or capsule, slow releasing tablet or capsule, controlled release tablet or capsule, granule, powder, syrup, oral liquid, injection.
CN201410062371.2A 2014-02-25 2014-02-25 Thiazole compounds, and preparation method and application thereof in pharmacy Pending CN104860900A (en)

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