CN106565698A - Substituted thiazole derivative, and preparation method and application thereof - Google Patents

Substituted thiazole derivative, and preparation method and application thereof Download PDF

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Publication number
CN106565698A
CN106565698A CN201610927946.1A CN201610927946A CN106565698A CN 106565698 A CN106565698 A CN 106565698A CN 201610927946 A CN201610927946 A CN 201610927946A CN 106565698 A CN106565698 A CN 106565698A
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compound
pharmaceutical composition
logical formula
thiazole
amido
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CN106565698B (en
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王文喜
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Nanjing Pallon Mstar Technology Ltd
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Nanjing Pallon Mstar Technology Ltd
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    • 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

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a novel substituted thiazole derivative with a structure shown in a general formula (I), and a pharmaceutically acceptable salt of the derivative. All groups are defined as shown in the specification. The invention furthermore relates to a preparation method for a compound, a drug composition containing the compound, and an application of the compound as a bio-active substance to the preparation of drugs for preventing and/or treating thromboembolic diseases.

Description

Substituted thiazole analog derivative and its production and use
Technical field
The present invention relates to anticoagulant field, specifically the present invention relates to new substituted thiazole analog derivative, its preparation method With it in the purposes for preparation prevention and/or treatment thrombotic disease medicine or pharmaceutical composition.
Background technology
In the cardiovascular of people, there is some visible components precipitations, coagulation in solidification or blood and form solid mass in blood Process, referred to as thrombosiss, the solid mass for being formed is thrombosis.Blood coagulation was a kind of protection machine of organism originally System, however, in the case of blood flow anomalies, blood vessel change in wall or thrombin exception, triggering abnormal coagulation process, blood Liquid just can form thrombosis or thromboembolism, so as to cause the thromboembolism such as myocardial infarction, apoplexy, DVT or pulmonary infarction Property disease.Thrombotic disease is the disease that most serious are endangered in cardiovascular disease, is the first killer of human health.
The medicine of existing antithrombotic embolism class diseases is divided into antiplatelet drug, anticoagulation medicine and fibrinolysiss Thing.Wherein, anticoagulation medicine mainly has thrombin inhibitor, vitamin K antagon and Xa factor inhibitor.With heparin and low point Sub- heparin is the shortcomings of thrombin inhibitor of representative has oral invalid, non-selective suppression and High risk of bleeding.With magnificent method Although the vitamin K antagon that Lin Wei is represented can be oral, therapeutic index is narrow and food drug interaction is big, individual Dose difference is also than larger.
Research shows that Xa factor is the best target of development of new anticoagulant, at present razaxaban, Eliquis With edoxaban listing.The direct suppression of Xa factor should produce efficient blood coagulation resisting function, and without thrombin inhibitor Side effect.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of brand-new substituted thiazole analog derivative, and the compound has anti- Solidifying effect, can be used in preventing and/or treating thrombotic disease.
To solve above-mentioned technical problem, the invention provides a kind of compound, with the structure as shown in formula (I)：
Or its pharmaceutically acceptable salt, wherein：
R1Selected from fluorine, chlorine, bromine；
R2It is selected from
Preferably, compound of the invention is selected from following compounds：
I-1：N- (4- chlorphenyls) -2- ((4- (3- oxomorpholins) phenyl) amido) thiazole -4-carboxamide；
I-2：N- (4- bromophenyls) -2- ((4- (3- oxomorpholins) phenyl) amido) thiazole -4-carboxamide；
I-3：N- (4- chlorphenyls) -2- ((4- (2- oxo-piperidine -1- bases) phenyl) amido) thiazole -4-carboxamide；
I-4：N- (4- fluorophenyls) -2- ((4- (2- oxo-piperidine -1- bases) phenyl) amido) thiazole -4-carboxamide；
Or its pharmaceutically acceptable salt.
The compound pharmaceutically acceptable salt of logical formula (I) of the present invention, both officinal salt, was logical formula (I) structure Compound and various mineral acids (including but not limited to, such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid) or organic acid (including But it is not limited to, such as formic acid, acetic acid, propanoic acid, trifluoroacetic acid, malic acid, citric acid, oxalic acid, fumaric acid, maleic acid, aminoacid, first Sulfonic acid, ethyl sulfonic acid, benzenesulfonic acid etc.) generate salt.
The compound pharmaceutically acceptable salt of logical formula (I) of the present invention, both officinal salt, can also be logical formula (I) The compound of structure and various alkaline matters (hydroxide, carbonate or bicarbonate such as alkali metal or alkaline-earth metal, including But it is not limited to：Sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate etc.) salt that generates, such as corresponding sodium salt, potassium salt or calcium salt Deng.Nontoxic organic base such as methylamine, triethylamine or meglumine etc. may also be employed and generates salt.
The compound of the present invention is synthesized by following steps：
Wherein：R1Selected from fluorine, chlorine, bromine；
R2It is selected from
The compound of logical formula VI reacts in a solvent the compound for generating logical formula IV with the compound of formula (V)；It is logical The compound Jing hydrolysis of formula IV prepares the compound of logical formula III；The compound of logical formula III exists with the compound of logical formula II Reaction in solvent generates the compound of logical formula I.
Wherein, leading to formula II and the compound of (V) can be obtained by commercial sources, such as lark prestige, Ah Fa Aishadeng companies, Can prepare by known method.
Wherein, solvent used in preparation method refers to inert organic solvent at reaction conditions, including but not limited to, Ether, such as tetrahydrofuran, ether, glycol dimethyl ether；Halogenated hydrocarbons, such as 1,2- dichloroethanes, dichloromethane, chloroform, four Chlorination carbon etc.；Alcohol, such as methanol, ethanol, isopropanol, the tert-butyl alcohol；Hydrocarbon, such as benzene,toluene,xylene, hexane, hexamethylene；Its It, such as dimethyl sulfoxide, dimethylformamide, acetonitrile, pyridine, water, hexamethyl phosphoric triamide.Solvent can also be above-mentioned molten The mixture of agent.
Wherein, in preparation method, alkali can also be added, suitable alkali can be conventional inorganic base or organic in reaction Alkali, including but not limited to, alkali-metal hydroxide, such as potassium hydroxide or sodium hydroxide；Alkali-metal carbonate, such as carbonic acid Potassium or sodium carbonate etc.；Alkoxide, such as Feldalat NM, Feldalat KM, Sodium ethylate, potassium ethoxide or potassium tert-butoxide；Amine, such as methylamine, hydrazine hydrate, Triethylamine, diisopropylethylamine, pyridine etc..The consumption of alkali is 1～5 mole, preferably 1～2 mole based on 1 molar reactive substrate.
Reaction can be carried out at various pressures, such as decompression, normal pressure or pressurization, be carried out under preferred normal pressure.
Reaction is typically carried out at a temperature of -78 DEG C to reflux temperature, and preferably 0 DEG C to reflux temperature of scope is carried out.
The compound or pharmaceutically acceptable salt thereof of the logical formula (I) structure of the present invention can play anticoagulation by suppressing Xa, Therefore can be used to prepare the medicine or pharmaceutical composition of prevention and/or treatment thrombotic disease.Wherein, thromboembolia type disease The concept of disease is known to those skilled in the art.
Additionally, the compound or pharmaceutically acceptable salt thereof of the logical formula (I) structure of the present invention can also be used to prevent external solidification, for example For preventing the solidification containing Xa factor biological sample.
The compound or pharmaceutically acceptable salt thereof of the logical formula (I) structure of the present invention, can be pharmaceutically acceptable with one or more Carrier, excipient or diluent make pharmaceutical composition jointly.The pharmaceutical composition can make solid orally ingestible, liquid The dosage form such as oral formulations or injection.
The solid orally ingestible includes：Tablet, dispersible tablet, enteric coatel tablets, chewable tablet, oral cavity disintegration tablet, capsule, granule.Adopt With Lactose or starch as the solid orally ingestible diluent；Using gelatin, methylcellulose, hypromellose, poly- Vinylpyrrolidone, starch slurry etc. are used as binding agent；Using starch, sodium carboxymethyl cellulose, carboxymethylstach sodium, low-substituted hydroxypropyl Methylcellulose, polyvinylpolypyrrolidone, Microcrystalline Cellulose are used as disintegrating agent；Using Pulvis Talci, micro- part of silica gel, tristerin, hard Fat acid calcium or magnesium etc. are used as antiadhesives and lubricant.
The preparation method of the solid orally ingestible is comprised the following steps：By active component and carrier and disintegrate additive Composition mixture, then makes the aqueous solution of the mixture and binding agent, and alcohol or aqueous alcohol solution are in suitable equipment Wet method or dry granulation are carried out, dry particle is subsequently added other disintegrating agents, lubricant and antiplastering aid and makes appropriate system Agent.
The liquid oral medicine includes syrup and oral solution.
The series compound of the present invention can also be administered by non-bowel form.Optimizing injection is administered, including injection Liquid drugs injection, injection powder pin and primary infusion.
The series compound of the present invention is effective in comparatively wide measures range, and the dosage for example taken daily is 1 In the range of～1000mg/ people, can divide and once or for several times be administered.The dosage for actually taking the compounds of this invention should be by doctor's root Determine according to relevant situation, the condition of these situations including patient, it is the route of administration of patient, the age, body weight, right The individual reaction of medicine and the order of severity of symptom etc..
Specific embodiment
With reference to embodiment, the present invention is described further, and embodiment is only explanatory, is in no way intended to it The scope of the present invention is limited by any way.
Embodiment 1：
Compound I-1：N- (4- chlorphenyls) -2- ((4- (3- oxomorpholins) phenyl) amido) thiazole -4-carboxamide；
8g compounds VI -1,6g compounds V, 1g Hydro-Giene (Water Science) .s, 0.5g8- hydroxyquinoline, 1.4g carbon are added in reaction bulb Sour potassium, 25mlDMF (dimethylformamide), nitrogen protection, stirring is warming up to backflow, and insulated and stirred, point plate control reaction is complete. Solvent to the greatest extent is steamed in decompression, adds 30ml water, ethyl acetate extraction (100ml × 3) to merge organic faciess, and saturated sodium-chloride water solution is washed (15ml × 1), anhydrous sodium sulfate drying, silica gel column chromatography obtains 6.0g pale solids, is compounds Ⅳ -1.
Add 5g compounds Ⅳ -1,20ml dehydrated alcohol in reaction bulb, 20m mass concentrations be 15% Lithium hydrate it is water-soluble Liquid, is stirred at room temperature, and point plate control reaction is complete.Ethanol to the greatest extent, 0-10 DEG C of Deca 20% (mass concentration) acetic acid aqueous solution are steamed in decompression PH is adjusted to 6-7, solid occurs, filtered, washed (25ml × 3), be dried, obtain 3.2g pale solids, be compound III -1.
Addition 1g compound III -1 in reaction bulb, 0.6g compound ii -1,0.5gTBTU (O- BTA-N, N, N', N'- tetramethylurea Tetrafluoroboric acids), 0.5g triethylamines, 10mlDMF, nitrogen protection is stirred at room temperature, and point plate control reaction is complete.Instead Answer liquid add 100ml water, ethyl acetate extraction (100ml × 3), merge organic faciess, saturated sodium-chloride water solution wash (15ml × 1), anhydrous sodium sulfate drying, silica gel column chromatography obtains 0.2g off-white powders, is compounds I -1.
1H-NMR(DMSO-d6),δ(ppm)：3.540(m,4H),4.280(s,2H),6.512(d,2H),6.578(d, 2H),6.682(s,1H),7.423(d,2H),7.556(d,2H),8.389(s,1H),10.448(s,1H)。
Embodiment 2：
Compound I-2：N- (4- bromophenyls) -2- ((4- (3- oxomorpholins) phenyl) amido) thiazole -4-carboxamide；
The present embodiment adopts synthetic method same as Example 1, and difference is compound II-2 different, specifically such as Under,
1H-NMR(DMSO-d6),δ(ppm):3.542(m,4H),4.300(s,2H),6.514(d,2H),6.580(d, 2H),6.684(s,1H),7.442(d,2H),7.556(d,2H),8.366(s,1H),10.452(s,1H)。
Embodiment 3：
Compound I-3：N- (4- chlorphenyls) -2- ((4- (2- oxo-piperidine -1- bases) phenyl) amido) thiazole -4- formyls Amine；
The present embodiment adopts synthetic method same as Example 1, and difference is compound VI-3 different, specifically such as Under,
1H-NMR(DMSO-d6),δ(ppm)：1.780(m,2H),2.180-2.240(m,4H),4.340(m,2H),6.338 (d,2H),6.580(d,2H),6.682(s,1H),7.448(d,2H),7.568(d,2H),8.480(s,1H),10.446(s, 1H)。
Embodiment 4：
Compound I-4：N- (4- fluorophenyls) -2- ((4- (2- oxo-piperidine -1- bases) phenyl) amido) thiazole -4- formyls Amine；
The present embodiment adopts synthetic method same as Example 1, and difference is that compound VI-4 is different with II-4, It is specific as follows,
1H-NMR(DMSO-d6),δ(ppm)：1.780(m,2H),2.180-2.240(m,4H),4.340(m,2H),6.328 (d,2H),6.480(d,2H),6.682(s,1H),7.248(d,2H),7.468(d,2H),8.480(s,1H),10.446(s, 1H)。
Embodiment 5
The compound or pharmaceutically acceptable salt thereof of the logical formula (I) structure of the present invention to the inhibitory action of factor Xa in the following manner Determine：
Testing compound is dissolved in DMSO by variable concentrations, and it is (public purchased from HYPHEN BioMed with the Xa factor of the mankind Department) and Tris buffer 37 DEG C temperature bath 2 minutes.It is subsequently adding chromogenic substrate (purchased from HYPHEN BioMed companies), 37 DEG C of temperature Bath excites measure with microplate reader after 50 minutes in 405nm.Compared with pure DMSO (dimethyl sulfoxide).Test substances will be contained Test mixing thing excite and control mixture without test substances comparison, and be calculated IC by these data50Value, The results are shown in Table 1.
The compound of table 1 suppresses the IC of FXa activity50
Embodiment 1 2 3 4
Compound I-1 I-2 I-3 I-4
IC50/nM 27 22 31 40
In order to more fully explain the enforcement of the present invention, there is provided following example of formulations.These embodiments only explain, Rather than restriction the scope of the present invention.Preparation can adopt any one compound in the present invention as active component.
Embodiment 6
The preparation of tablet：
Prescription 1000 consumptions
Compound I-1 obtained in embodiment 1 80g
Microcrystalline Cellulose 30g
Pregelatinized Starch 40g
Lactose 120g
Hypromellose 8g
Carboxymethyl starch sodium 12g
Magnesium stearate qs
Silicon dioxide qs
Technique：Active component adjuvant is crossed respectively 100 mesh sieves, principal agent and adjuvant (the half carboxymethyl shallow lake of recipe quantity is weighed Powder sodium) it is sufficiently mixed, hypromellose aqueous solution soft material processed in right amount is added, 24 mesh sieves are crossed, wet granular is obtained in 50-60 DEG C of baking About 2-3 hours are dried in case, remaining carboxymethyl starch sodium, magnesium stearate and silicon dioxide are mixed homogeneously with granule, granulate is surveyed Determine intermediates content, use special-shaped stamping.
Embodiment 7
The preparation of capsule：
Prescription 1000 capsule consumptions
Compound I-3 obtained in embodiment 3 100g
Microcrystalline Cellulose 20g
Lactose 120g
Low-substituted hydroxypropyl cellulose 6g
10% starch slurry qs
Magnesium stearate qs
Technique：Active component adjuvant is crossed respectively 100 mesh sieves, the principal agent and adjuvant for weighing recipe quantity is sufficiently mixed, adds Polyvidone aqueous solution soft material processed in right amount, crosses 20 mesh sieves, wet granular is obtained about 2-3 hours are dried in 50-60 DEG C of baking oven, by Hard Fat Sour magnesium is mixed homogeneously with granule, granulate, intermediates content is determined, with No. 2 capsule fills.

Claims (10)

1. a kind of compound, with the structure as shown in formula (I)：
Or its pharmaceutically acceptable salt, wherein：
R1Selected from fluorine, chlorine, bromine；
R2It is selected from
2. compound as claimed in claim 1, selected from following compounds：
I-1：N- (4- chlorphenyls) -2- ((4- (3- oxomorpholins) phenyl) amido) thiazole -4-carboxamide；
I-2：N- (4- bromophenyls) -2- ((4- (3- oxomorpholins) phenyl) amido) thiazole -4-carboxamide；
I-3：N- (4- chlorphenyls) -2- ((4- (2- oxo-piperidine -1- bases) phenyl) amido) thiazole -4-carboxamide；
I-4：N- (4- fluorophenyls) -2- ((4- (2- oxo-piperidine -1- bases) phenyl) amido) thiazole -4-carboxamide；
Or its pharmaceutically acceptable salt.
3. the compound as any one of claim 1 or 2, wherein, the pharmaceutically acceptable salt includes logical formula (I) The salt that the compound of structure is generated with mineral acid or organic acid.
4. the preparation method of the compound any one of claim 1 or 2, comprises the following steps：
Wherein：R1Selected from fluorine, chlorine, bromine；
R2It is selected from
The compound of logical formula VI reacts in a solvent the compound for generating logical formula IV with the compound of formula (V)；Formula (IV) compound Jing hydrolysis prepares the compound of logical formula III；The compound of the compound of logical formula III and logical formula II is molten Reaction in agent generates the compound of logical formula I.
5. the compound any one of claim 1 or 2 is preventing and/or is treating thrombotic disease medicine for preparing The purposes of thing or pharmaceutical composition.
6. a kind of pharmaceutical composition, wherein containing the compound described in any one of at least one claim 1 or 2 as effectively into Point, and containing one or more pharmaceutical acceptable carrier, diluent or excipient.
7. pharmaceutical composition as claimed in claim 6, wherein, described pharmaceutical composition is solid orally ingestible, liquid port Formulation or injection.
8. pharmaceutical composition as claimed in claim 7, wherein, the solid orally ingestible be tablet, dispersible tablet, enteric coatel tablets, Chewable tablet, oral cavity disintegration tablet, capsule or granule.
9. pharmaceutical composition as claimed in claim 7, wherein, the liquid oral medicine is syrup or oral solution.
10. pharmaceutical composition as claimed in claim 7, wherein, the injection is injection liquid drugs injection, injection powder pin or little Transfusion.
CN201610927946.1A 2016-08-15 2016-10-31 Substituted thiazole analog derivative and its preparation method and application Active CN106565698B (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101967145A (en) * 2010-09-09 2011-02-09 华东理工大学 Method for preparing antithrombotic medicament apixaban
CN102702186A (en) * 2012-06-20 2012-10-03 安润医药科技（苏州）有限公司 Synthesis method of rivaroxaban
CN103342704A (en) * 2013-07-25 2013-10-09 甘肃皓天化学科技有限公司 Preparation method of Apixaban as anti-thrombotic drug
CN103562183A (en) * 2011-03-29 2014-02-05 赛诺菲 Benzoic acid salt of otamixaban

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101967145A (en) * 2010-09-09 2011-02-09 华东理工大学 Method for preparing antithrombotic medicament apixaban
CN103562183A (en) * 2011-03-29 2014-02-05 赛诺菲 Benzoic acid salt of otamixaban
CN102702186A (en) * 2012-06-20 2012-10-03 安润医药科技（苏州）有限公司 Synthesis method of rivaroxaban
CN103342704A (en) * 2013-07-25 2013-10-09 甘肃皓天化学科技有限公司 Preparation method of Apixaban as anti-thrombotic drug

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