CN102643269B - Phosphatidase A2 inhibitor containing pyrromonazole structure and application thereof - Google Patents
Phosphatidase A2 inhibitor containing pyrromonazole structure and application thereof Download PDFInfo
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- SNFLLQFAECNDBT-UHFFFAOYSA-N CCN(CC)CC[n](c(COCCN(C1=C2CCC1)C(SCc(cc1)ccc1F)=NC2=O)c1)nc1-c1ccc(C)cc1 Chemical compound CCN(CC)CC[n](c(COCCN(C1=C2CCC1)C(SCc(cc1)ccc1F)=NC2=O)c1)nc1-c1ccc(C)cc1 SNFLLQFAECNDBT-UHFFFAOYSA-N 0.000 description 1
- LDOQKBXKUPWUNI-UHFFFAOYSA-N Cc(cc1)ccc1-c1n[n](CCN)c(COCCOS(C)(=O)=O)c1 Chemical compound Cc(cc1)ccc1-c1n[n](CCN)c(COCCOS(C)(=O)=O)c1 LDOQKBXKUPWUNI-UHFFFAOYSA-N 0.000 description 1
- KGKHGMLLRQLUFP-UHFFFAOYSA-N O=C(C(CCC1)=C1N1)N=C1SCc(cc1)ccc1F Chemical compound O=C(C(CCC1)=C1N1)N=C1SCc(cc1)ccc1F KGKHGMLLRQLUFP-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention relates to the field of medicaments for cardiovascular and cerebrovascular diseases and specifically relates to a novel compound containing a pyrromonazole and pyrimidine structure as shown in general formula I, derivatives and pharmaceutically acceptable salts thereof, a preparation method and an application of the compound with the structure as shown in the general formula I or the pharmaceutically acceptable salts thereof in the aspect of preparation of medicaments for treating Lp-phosphatidase A2-related diseases (such as atherosclerosis), wherein the definition of groups is as described in specification.
Description
Technical field
The present invention relates to cardiovascular and cerebrovascular disease pharmaceutical field, derivative, preparation method and the pharmaceutical composition that contains them and purposes in particular to a class containing the Pyrimdinone of pyrazoles.
Background technology
The phospholipase A that lipoprotein is relevant
2, claim again platelet-activating factor acetylhydrolase, be the key enzyme that regulates low-density lipoprotein.It is secreted by platelet cell, and main and low-density lipoprotein binds together, and accounts for 80%.Remaining 20% and high-density lipoprotein (HDL) bind together.Low-density lipoprotein (LDL) is by Lp-PLA
2be transported to the position of easy damaged on arterial blood tube wall, in LDL oxidising process subsequently, Lp-PLA
2catalytic hydrolysis sn-2 position, opens fat key, generates the phosphatide shortening.In this process, generate two kinds of biochemical active grease intermediates of tool, the free fatty acids (NEFA) of lyso-phosphatidylcholine (lysoPC) and oxidation, these two kinds of materials can cause leukocyte recruitment, cause inflammation, cause vascular damaged, thereby cause the sclerosis of arteries atherosclerotic.In addition, in many Patients with geriatric cardiovascular and cerebrovascular diseases and animal model test, the position display of focus a large amount of Lp-PLA
2expression.Therefore, seek narrow spectrum Lp-PLA effectively
2inhibitor becomes the focus of scientist's research in the last few years.Current main Lp-PLA
2inhibitor structure classification is WO2008/140449 and the disclosed structure of US2004097525:
Wherein, X is O, S, R
5, R
6for aromatic nucleus.
Other pertinent literature comprises Helen F.Boyd et al Bioorganic & Medicinal Chemistry Letters, 2002,12,51-55; Josie A.Blackie et al Bioorganic & Medicinal Chemistry Letters, 2002,12,2603-2606; Helen F.Boyd, et al Bioorganic & Medicinal Chemistry Letters, 2001,11,701-704; Emile R.Mohler et al Journal of the American College of Cardiology, 2008,51,1632-1641 etc.
The invention provides the novel Pyrimdinone derivatives containing pyrazoles structure of a class as novel Lp-PLA
2inhibitor, lays the first stone for further developing the cardiovascular medicaments such as arteriosclerosis.
Summary of the invention
An object of the present invention is to provide compound and pharmacy acceptable salt and the preparation method with general formula I structure.
Another object of the present invention is to provide the compound that contains general formula I structure and pharmacy acceptable salt thereof as effective constituent, the medicinal compositions forming with one or more pharmaceutically acceptable pharmaceutical excipients.
A further object of the present invention has been to provide compound of Formula I and pharmacy acceptable salt thereof, or the application of its medicinal compositions aspect the cardiovascular medicaments such as preparation prevention and treatment arteriosclerosis.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
Wherein:
R1 is: hydrogen ,-C
1-6alkyl, hydroxyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, iodine, haloalkyl, R1 can replace for contraposition, ortho position or a position, can be monosubstituted or two replacements;
R2, R3 are: methyl, ethyl, propyl group, sec.-propyl;
R4 is: fluorine, chlorine, bromine;
N1, n2, n3 are: 1,2,3;
X＝O、S。
The present invention has the compound of general formula I, preferably:
I-1:1-(2-((1-(2-(diethylamino) ethyl)-3-(4-p-methoxy-phenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
I-2:1-(2-((1-(2-(diethylamino) ethyl)-3-(4-aminomethyl phenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
I-3:1-(2-((1-(2-(diethylamino) ethyl)-3-phenyl-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
I-4:1-(2-((1-(2-(diethylamino) ethyl)-3-(4-fluorophenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
I-5:1-(2-((1-(2-(diethylamino) ethyl)-3-(4-chloro-phenyl-)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
I-6:1-(2-((1-(2-(diethylamino) ethyl)-3-(4-bromophenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
I-7:1-(2-((1-(2-(diethylamino) ethyl)-3-(4-trifluoromethyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
I-8:1-(2-((1-(2-(diethylamino) ethyl)-3-(3-chloro-phenyl-)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one
I-9:1-(2-((1-(2-(diethylamino) ethyl)-3-(2-chloro-phenyl-)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one
Compound of Formula I of the present invention is synthesized by following steps:
Compound I I reacts in alkaline alcoholic solution with oxalic acid diethyl ester, after without separation directly with after acid neutralization with hydrazine hydrate effect generation compound III, acid be organic acid as formic acid, acetic acid or mineral acid example hydrochloric acid, sulfuric acid etc., highly basic can be sodium alkoxide, sodium hydride etc.Compound III under alkaline condition with two bromoalkanes reacting generating compound IV in organic solvent, alkaline condition is as salt of wormwood, potassium hydroxide etc., two bromoalkanes comprise methylene bromide, glycol dibromide, 1,3-dibromopropanes etc., organic solvent is as acetonitrile, tetrahydrofuran (THF) etc.Compound IV and amine are made catalyzer with potassiumiodide and are generated compound V in the organic solvent under alkaline condition, and alkaline condition is as salt of wormwood, potassium hydroxide etc., organic solvent is as acetonitrile, tetrahydrofuran (THF) etc., and amine is dimethylamine, diethylamine etc., catalyzer is potassiumiodide, the salt such as sodium iodide.Compound V is hydrogenated the reductive agent reduction such as aluminium lithium and generates compound VI in organic solvent, and organic solvent is tetrahydrofuran (THF), ether etc.Compound VI first in organic solvent with the effect such as potassium tert.-butoxide, sodium tert-butoxide, sodium hydride, then generate compound VI I with the effect of halogenated acetic acids ethyl ester, organic solvent is the trimethyl carbinol, tetrahydrofuran (THF) etc.Compound VI I is hydrogenated the reductive agent reduction such as aluminium lithium and generates compound VI II in organic solvent, and organic solvent is tetrahydrofuran (THF), ether etc.Compound VI II and Methanesulfonyl chloride or Tosyl chloride act on and generate Compound I X in dry methylene dichloride.Compounds X and urea or thiocarbamide as refluxed and generate XI under the effect of sodium alkoxide under alkaline condition in alcoholic solution, and alcohol can be methyl alcohol or ethanol.The benzyl chlorine of compounds X I and para-orientation reacting generating compound XII in alkaline organic solvent, alkali can be salt of wormwood, potassium hydroxide, organic solvent is acetone, acetonitrile etc.Compound I X and compounds X II generate Compound I under alkaline effect in organic solvent, and alkali is salt of wormwood, sodium carbonate etc., and organic solvent is DMF, acetonitrile etc.
The pharmacy acceptable salt of formula I compound of the present invention, according to different derivatives, can contain amino, and amino can react with acidic substance, they include, but are not limited to: hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid etc. form pharmaceutically acceptable salt, also can adopt nontoxic organic acid, as tartrate, methylsulfonic acid, acetic acid, amino acid etc. generate salt.
Formula I compound of the present invention or its pharmacy acceptable salt, can make pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made the formulations such as solid oral agent, oral liquid, injection.
Described solid and oral liquid comprise: tablet, dispersion agent, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, syrup, granule, oral solution, injection.
Can adopt lactose or starch as the carrier of described solid orally ingestible; Use is named as, methylcellulose gum, hypromellose, polyvinylpyrrolidone, and starch slurries etc. are as tackiness agent; Use starch, sodium cellulose glycolate, sodium carboxymethylstarch, low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, Microcrystalline Cellulose as disintegrating agent; Use talcum powder, micropowder silica gel, stearin, calcium stearate or magnesium etc. are as antiadhesives and lubricant.
The preparation method of described oral liquid formulations comprise the steps: by activeconstituents and carrier and optionally with a disintegration additive composition mixture, then make the aqueous solution of this mixture and tackiness agent, alcohol or aqueous alcohol solution carry out wet method or dry granulation in suitable equipment, dried particles, adds other disintegrating agents, lubricant and resistance to bond agent to make suitable preparation subsequently.
Series compound of the present invention can also pass through non-enteron aisle form administration.Preferred parenterai administration form is injection administration.
Biological activity reference literature Bioorganic & Medicinal Chemistry Letters 10 (2000) the 2557-2561 measuring methods of compound of the present invention improve, take PAF as substrate, measure one of product (enzyme decomposes the acid discharging), calculate enzyme activity.Test result: test result shows that this series has good restraining effect containing the derivative of general formula I structure to Lp-PLA2, can be used for treating arteriosclerosis and relevant cardiovascular and cerebrovascular diseases.The dosage of the actual compound of taking of series compound of the present invention should be decided according to relevant situation by doctor, these situations comprise the person's of being treated physical state, and the person's of choosing route of administration, age, body weight, patient are to severity of individual reaction patient's symptom of medicine etc.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment is only for explanation, and not for limiting the present invention.The various variations that those skilled in the art's training centre according to the present invention is made all should be within the desired protection domain of the application's claim.
embodiment 1the preparation of 3-(4-chloro-phenyl-)-pyrazole-5-ethyl formate
Get 500mL there-necked flask, 3.6g sodium is dissolved in 120mL dehydrated alcohol to mechanical stirring, with dropping funnel, add oxalic acid diethyl ester 21mL after completion of the reaction, stir 10min, with separating funnel, slowly drip parachloroacetophenone 20g, 1.5h drips off, stirring at room 4h, and TLC detects without raw material.
With separating funnel, drip 9.3g Glacial acetic acid, 15min adds, and stirs 10min.With dropping funnel, drip 9.8ml 80% hydrazine hydrate, 0.5h adds.Stirring at room 3h.
Process: revolve steaming and remove most of ethanol, add methylene dichloride 200mL, respectively with saturated NaCl salts solution and washing three times, anhydrous sodium sulfate drying.Revolve to steam and obtain product.White solid.Recrystallization, fusing point: 136-138 ℃;
1h NMR (300MHz, CDCl
3) δ: 11.82 (br, 1H), 7.72 (d, J=8.4Hz, 2H), 7.39 (d, J=8.4Hz, 2H), 7.07 (s, 1H), 4.38 (q, J=7.2Hz, 2H), 1.39 (t, J=7.2Hz, 3H).
embodiment 2-9
With reference to the operation of embodiment 1, difference is to carry out the parachloroacetophenone in alternate embodiment 1 with the Compound I I of different structure, obtains the product compound of following formula III.
embodiment 10the preparation of 1-(2-bromotrifluoromethane)-3-(4-chloro-phenyl-)-pyrazole-5-ethyl formate
The product of 1eq embodiment 1 [3-(4-chloro-phenyl-)-pyrazole-5-ethyl formate] is dissolved in appropriate acetonitrile, adds the glycol dibromide of 2eq, 3eq Anhydrous potassium carbonate, the potassiumiodide solid of catalytic amount, stirring at room 10min, heated and stirred refluxes afterwards, reacts 3 hours.
Be chilled to room temperature, suction filtration is gone out solid, revolves and steams the acetonitrile of sloughing large portion, adds 200mL water, and with dichloromethane extraction, anhydrous sodium sulfate drying, revolves steaming.Column chromatography is separated.
Fusing point: 90-91 ℃, HNMR: δ: 7.69 (d, J=8.1Hz, 2H), 7.22 (d, J=8.1Hz, 2H), 4.97 (t, J=7.1Hz, 2H), 4.37 (q, J=7.2Hz, 2H), 3.75 (t, J=7.1Hz, 2H), 2.37 (s, 3H), 1.41 (t, J=7.2Hz, 3H);
13c NMR (75MHz, CDCl3) δ: 160.18,151.26,138.60.134.20,129.98,129.92,126.03,108.62,61.80,52.84,30.01,21.79,14.75.
Embodiment 11-18
With reference to the operation of embodiment 10, difference is to carry out 3-(4-chloro-phenyl-)-pyrazole-5-ethyl formate and the dibromo alkane reaction in alternate embodiment 10 by the compound III of different structure, obtains the compound of following formula IV.
embodiment 19the preparation of 1-(2-(diethylamino) ethyl)-3-(4-aminomethyl phenyl)-pyrazole-5-ethyl formate
The synthetic product of the embodiment of 1 equivalent 12 is dissolved in 150mL acetonitrile, adds 3 equivalent salt of wormwood, the potassiumiodide of 0.1 equivalent, 2 equivalent diethylamine, stirring at room 10min, then reflux 10h.
Reaction system suction filtration, with a small amount of acetonitrile, wash, merging filtrate and washing lotion, then revolve to steam and slough most of acetonitrile, add 200mL methylene dichloride, water and saturated common salt washing three times, organic phase anhydrous sodium sulfate drying, revolve to steam and slough large portion solvent, column chromatography is separated, and petrol ether/ethyl acetate=15/1 washes away the impurity of top.With the eluent wash-out of petrol ether/ethyl acetate=5/1, obtain product again, product is pale yellow oily liquid body.
1HNMR(300MHz，CDCl
3)δ：7.69(d，J＝8.1Hz，2H)，7.20(d，J＝8.1Hz，2H)，7.06(s，1H)，4.68(t，J＝7.1Hz，2H)，4.35(q，J＝7.2Hz，2H)，2.90(t，J＝7.1Hz，2H)，2.59(q，J＝7.2Hz，4H)，2.36(s，3H)，1.39(t，J＝7.2Hz，3H)，1.00(t，J＝7.2Hz，6H)；13CNMR(75MHz，CDCl
3)δ：160.32，150.54，138.18，134.18，130.44，129.83，125.96，108.11，61.44，53.50，50.12，47.87，21.76，14.79，12.59。
Embodiment 20-27
With reference to the operation of embodiment 19, difference is to come 1-(2-bromotrifluoromethane)-3-(4-the aminomethyl phenyl)-pyrazole-5-ethyl formate in alternate embodiment 19 to react with ammoniac compounds by the compound IV of different structure, obtains the compound of following formula V.
embodiment 28the preparation of 1-(2-(diethylamino) ethyl)-3-(4-aminomethyl phenyl)-pyrazoles-5-methyl alcohol
The synthetic product of the embodiment of the upper step of 1 equivalent 19 is dissolved in the THF solution that 150mL is dry, and ice bath slowly adds the LiAlH of 1.2 equivalents under stirring
4, stirring at room 1h then.TLC detects without raw material.
Suction filtration, washes 3 times with THF, and merging filtrate and washing lotion, revolve and evaporate most of THF, adds 100mL water, uses dichloromethane extraction 3 times, merges organic phase, with anhydrous sodium sulfate drying, and evaporate to dryness.Obtain pale yellow oily liquid body.
1H NMR(300MHz，CDCl
3)δ：7.67(d，J＝8.1Hz，2H)，7.19(d，J＝8.1Hz，2H)，6.46(s，1H)，4.55(s，2H)，4.22-4.24(m，2H)，2.83-2.86(m，2H)，2.45(q，J＝7.2Hz，4H)，2.36(s，3H)，0.91(t，J＝7.2Hz，6H)。
Embodiment 29-36
Operation with reference to embodiment 28, difference is to carry out 1-(2-(diethylamino) ethyl)-3-(4-the aminomethyl phenyl)-pyrazole-5-ethyl formate generation reduction reaction in alternate embodiment 28 with the compound V of different structure, obtains the compound of following formula VI.
embodiment 372-(the preparation of (1-(2-(diethylamino) ethyl)-3-(4-p-methoxy-phenyl)-5-pyrazolyl) methoxyacetic acid tert-butyl ester
The metal K of 3 equivalents is dissolved in the trimethyl carbinol that 100mL heavily steams, the product of the embodiment of upper step 32 is dissolved in a small amount of trimethyl carbinol, join in reaction system, drip the ethyl chloroacetate of 4 equivalents.Reflux 3h, it is muddy that solution becomes, and becomes orange red.Suction filtration, revolves to steam and removes most of trimethyl carbinol, adds 100mL water, dichloromethane extraction, and anhydrous sodium sulfate drying, concentrated, petrol ether/ethyl acetate/triethylamine=3/1/0.02 column chromatography is separated.
1H NMR(400MHz，CDCl
3)δ：7.70(d，J＝7.2Hz，2H)，6.92(d，J＝7.2Hz，2H)，6.42(s，1H)，4.70(s，2H)，4.27(t，J＝6.8Hz，2H)，3.97(s，2H)，3.83(s，3H)，2.91(t，J＝6.8Hz，2H)，2.55(q，J＝7.2Hz，4H)，1.48(s，9H)，0.99(t，J＝7.2Hz，6H)。
Embodiment 38-45
Operation with reference to embodiment 37, difference is to carry out 1-(2-(diethylamino) ethyl)-3-(the 4-p-methoxy-phenyl)-pyrazoles-5-methyl alcohol generation reduction reaction in alternate embodiment 37 by the compound VI of different structure, obtains the compound of following formula VII.
embodiment 462-((1-(2-(diethylamino) ethyl)-3-(4-aminomethyl phenyl)-5-pyrazolyl) methyl cellosolve
The product of previous step embodiment 38 is dissolved in dry THF, under condition of ice bath, slowly adds the LiAlH4 of 1.2 equivalents.Stirring at room 1h, suction filtration, by a small amount of THF washing, merging filtrate and washing lotion, revolves to steam and sloughs most of THF, adds 200mL methylene dichloride, with a small amount of water and saturated nacl aqueous solution, wash three times, organic phase anhydrous sodium sulfate drying, evaporate to dryness obtains pale yellow oily liquid body.
1H NMR(400MHz，CDCl
3)δ：7.64(d，J＝8.1Hz，2H)，7.17(d，J＝8.1Hz，2H)，6.43(s，1H)，4.61(s，2H)，4.28(t，J＝6.8Hz，2H)，3.70-3.73(m，2H)，3.66-3.68(m，2H)，2.89(t，J＝6.8Hz，2H)，2.46(q，J＝7.2Hz，4H)，2.37(s，3H)，1.00(t，J＝7.2Hz，6H)。
Embodiment 47-54
Operation with reference to embodiment 46, difference is to carry out 2-in alternate embodiment 46 by the compound VI I with different structure, and ((1-(2-(diethylamino) ethyl)-3-(4-aminomethyl phenyl)-5-pyrazolyl) methoxyacetic acid tert-butyl ester generation reduction reaction obtains the compound of following formula VIII.
embodiment 55methylsulphonic acid (2-((1-(2-(diethylamino) ethyl)-3-(4-aminomethyl phenyl)-5-pyrazolyl) methoxyl group) ethyl ester
The product of embodiment 46 is dissolved in dry dichloromethane solution, adds the triethylamine of 3 equivalents, stir 10min, under ice bath, add the Tosyl chloride of 2 equivalents, nitrogen protection, stirring at room 30min.
Add a small amount of washing three times, methylene dichloride anhydrous sodium sulfate drying, revolves steaming, with petrol ether/ethyl acetate/triethylamine=1/1/0.02, crosses post.Product is pale yellow oily liquid body.
1H NMR(300MHz，CDCl
3)δ：7.76(d，J＝8.1Hz，2H)，7.66(d，J＝8.1Hz，2H)，7.28(d，J＝7.8Hz，2H)，7.19(d，J＝7.8Hz，2H)，6.39(s，1H)，4.56(s，2H)，4.15-4.18(m，2H)，4.14(t，J＝6.9Hz，2H)，3.62-3.65(m，2H)，2.85(t，J＝6.9Hz，2H)，2.51(q，J＝7.2Hz，4H)，2.39(s，3H)，2.35(s，3H)，0.96(t，J＝7.2Hz，6H)。
Embodiment 56-63
Operation with reference to embodiment 55, difference is to carry out 2-in alternate embodiment 55 by the compound VI II with different structure, and ((1-(2-(diethylamino) ethyl)-3-(4-aminomethyl phenyl)-5-pyrazolyl) methyl cellosolve reacts, and obtains the compound of following formula IX.
embodiment 642-sulfydryl-5,6-pentamethylene pyrimidin-4-one
The sodium of 1.5 equivalents is joined in 100mL dehydrated alcohol, be stirred to completely and dissolve, be chilled to room temperature, add the thiocarbamide of 1.2 equivalents, stir 0.5h, add 2-ketone ring penta carboxylic acid, ethyl ester of 1 equivalent, solution solidifies rapidly, nitrogen protection, reflux 16h.
Revolve to steam and slough most of ethanol, with a small amount of water dissolution, adjust pH to 5, be chilled to 0～5 ℃, suction filtration, a small amount of water washing of solid, dries.Fusing point: 340-341 ℃.
embodiment 652-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one
The product of upper step (embodiment 64) is dissolved in acetone, add successively 1.1 equivalents to fluorobenzyl chloride, the salt of wormwood of 3 equivalents, the potassiumiodide of 0.1 equivalent, stirs 10min, then reflux 1h.
Stop refluxing, with the water of 50mL, the solid in bottle is transferred at twice in the beaker of 200mL, with dilute hydrochloric acid, adjust pH to a large amount of white solids of neutral appearance, suction filtration, with the solvent wash of petrol ether/ethyl acetate=3/1, the dry white solid that obtains.Faint yellow solid, fusing point: 209-210 ℃,
1h NMR (300MHz, DMSO-d
6) δ: 12.49 (br, s, 1H), 7.46 (dd, J=8.4Hz, J=1.5Hz, 2H), 7.14 (t, J=8.4Hz, J=8.4Hz, 2H), 4.380 (s, 2H), 2.69 (t, J=7.5Hz, 2H), 2.59 (t, J=7.2Hz, 2H), 1.91-2.01 (m, J=7.2Hz, J=7.5Hz, 2H).
embodiment 661-(2-((1-(2-(diethylamino) ethyl)-3-(4-aminomethyl phenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one
The product of embodiment 55 and 65 was dissolved in DMF according to 1: 1, the salt of wormwood that adds 3 equivalents, 80 ℃ of oil bath 3h, add 500mL methylene dichloride, wash with water five times, methylene dichloride anhydrous sodium sulfate drying, revolves to steam afterwards and crosses silicagel column with the eluent of petrol ether/ethyl acetate/triethylamine=3/1/0.05.(code name is product: be I-1) pale yellow oily liquid body.
Embodiment 67-74
With reference to the operation of embodiment 55, difference is to come corresponding IX and XII in alternate embodiment 55 to react with Compound I X and the XII of different structure, obtains the compound of following formula I.
The nuclear magnetic data of above compound is as follows:
Compound I-1:1-(2-((1-(2-(diethylamino) ethyl)-3-(4-aminomethyl phenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1h NMR (300MHz, CDCl
3) δ: 7.65 (d, J=7.8Hz, 2H), 7.34-7.38 (m, 2H), 7.18 (d, J=7.8Hz, 2H), 6.92-6.98 (m, 2H), 6.43 (s, 1H), 4.64 (s, 2H), 4.50 (t, J=4.8Hz, 2H), 4.33 (s, 2H), 4.23 (t, J=7.2Hz, 2H), 3.76 (t, J=4.8Hz, 2H), 2.84-2.92 (m, 4H), 2.77 (t, J=7.2Hz, 2H), 2.53 (q, J=7.2Hz, 4H), 2.355 (s, 3H), 2.02-2.12 (m, 2H), 0.99 (t, J=7.6Hz, 6H).
13c NMR (75MHz, CDCl
3) δ: 176.20,169.10,165.57,164.01,160.76,150.78,140.15,137.66, (134.28,134.23), (130.89,130.78), 129.72,125.90, (116.09,115.84), 115.56,104.26,68.41,65.78,63.98,53.83,49.03,48.15,35.06,34.58,26.81,22.34,21.71,12.49; HR-MS (ESI-Q-TOF): m/z Calcd for C
33h
40fN
5o
2s ([M+H]
+) 590.2965 Found 590.2964.
Compound I-2:1-(2-((1-(2-(diethylamino) ethyl)-3-(4-p-methoxy-phenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1h NMR (400MHz, CDCl
3) δ: 7.69 (d, J=6.8Hz, 2H), 7.34-7.39 (m, 2H), 6.93-6.98 (m, 2H), 6.92 (d, J=6.8Hz, 2H), 6.39 (s, 1H), 4.64 (s, 2H), 4.48-4.51 (t, J=4.8Hz, 2H), 4.34 (s, 2H), 4.20 (t, J=7.2Hz, 2H), 3.83 (s, 3H), 3.76 (t, J=4.8Hz, 2H), 2.85-2.90 (m, 4H), 2.78 (t, J=7.2Hz, 2H), 2.53 (q, J=7.2Hz, 4H), 2.05-2.09 (m, 2H), 0.96 (t, J=7.2Hz, 6H).
13c NMR (100MHz, CDCl
3) δ: 175.22,168.18,164.66,162.65,160.21,158.79,149.54,139.34, (133.48,133.45), (130.01,129.93), 126.28,115.14, (114.86,114.64), 113.53,102.99,67.55,64.91,63.04,54.77,52.90,48.05,47.23,34.10,33.66,25.89,21.38,11.63.
Compound I-3:1-(2-((1-(2-(diethylamino) ethyl)-3-phenyl-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1h NMR (400MHz, CDCl
3) δ: 7.75-7.77 (m, 2H), 7.35-7.40 (m, 4H), 7.28-7.30 (m, 1H), 6.94-6.98 (m, 2H), 6.47 (s, 1H), 4.65 (s, 2H), 4.50 (t, J=4.8Hz, 2H), 4.34 (s, 2H), 4.22 (t, J=7.2Hz, 2H), 3.77 (t, J=4.8Hz, 2H), 2.85-2.91 (m, 4H), 2.78 (t, J=7.2Hz, 2H), 2.53 (q, J=7.6Hz, 4H), 2.05-2.11 (m, 2H), 0.99 (t, J=7.6Hz, 6H).
13c NMR (100MHz, CDCl
3) δ: 175.69,168.54,165.03,163.06,160.62,150.17,139.72, (133.71,133.50), (130.36,130.28), 128.53,127.46,125.46,115.57, (115.30,115.09), 103.95,67.88,65.26,63.43,53.30,48.55,47.61,34.53,34.06,26.29,21.82,11.98.
Compound I-4:1-(2-((1-(2-(diethylamino) ethyl)-3-(4-fluorophenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1h NMR (400MHz, CDCl
3) δ: 7.69 (d, J=6.8Hz, 2H), 7.44-7.49 (m, 2H), 7.03-7.08 (m, 2H), 6.92 (d, J=6.8Hz, 2H), 6.53 (s, 1H), 4.64 (s, 2H), 4.48-4.51 (t, J=4.8Hz, 2H), 4.34 (s, 2H), 4.20 (t, J=7.2Hz, 2H), 3.83 (s, 3H), 3.76 (t, J=4.8Hz, 2H), 2.85-2.90 (m, 4H), 2.78 (t, J=7.2Hz, 2H), 2.53 (q, J=7.2Hz, 4H), 2.05-2.09 (m, 2H), 0.96 (t, J=7.2Hz, 6H).
13c NMR (100MHz, CDCl
3).
Compound I-5:1-(2-((1-(2-(diethylamino) ethyl)-3-(4-chloro-phenyl-)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1h NMR (400MHz, CDCl
3) δ: 7.69 (d, J=6.8Hz, 2H), 7.34-7.39 (m, 2H), 7.33 (d, J=6.8Hz, 2H), 6.93-6.98 (m, 2H), 6.44 (s, 1H), 4.64 (s, 2H), 4.49 (t, J=4.8Hz, 2H), 4.34 (s, 2H), 4.21 (t, J=7.2Hz, 2H), 3.76 (t, J=4.8Hz, 2H), 2.85-2.90 (m, 4H), 2.78 (t, J=7.2Hz, 2H), 2.52 (q, J=7.2Hz, 4H), 2.05-2.09 (m, 2H), 0.96 (t, J=7.2Hz, 6H);
13cNMR (100MHz, CDCl
3) δ: 175.59,168.51,164.94,162.99,160.55,148.93,139.96, (133.68,133.65), 132.03, (130.27,130.20), 128.56,126.62,115.45, (115.19,115.98), 103.73,67.93,65.14,63.33,53.21,48.60,47.55,34.44,33.98,26.20,21.72,11.92.
Compound I-6:1-(2-((1-(2-(diethylamino) ethyl)-3-(4-bromophenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1h NMR (400MHz, CDCl
3) δ: 7.63 (d, J=6.8Hz, 2H), 7.49 (d, J=6.8Hz, 2H), 7.34-7.39 (m, 2H), 6.93-6.98 (m, 2H), 6.44 (s, 1H), 4.64 (s, 2H), 4.49 (t, J=4.8Hz, 2H), 4.34 (s, 2H), 4.21 (t, J=7.2Hz, 2H), 3.76 (t, J=4.8Hz, 2H), 2.85-2.90 (m, 4H), 2.78 (t, J=7.2Hz, 2H), 2.52 (q, J=7.2Hz, 4H), 2.04-2.09 (m, 2H), 0.96 (t, J=7.2Hz, 6H);
13cNMR (100MHz, CDCl
3) δ: 175.67,168.57,165.02,163.06,160.62,149.08,140.08, (133.70,133.49), (130.34,130.26), 128.49,127.45,125.45,115.52, (115.26,115.05), 103.93,68.04,65.23,63.41,53.13,48.48,47.57,34.52,34.04,26.27,21.79,11.80; HR-MS (ESI-Q-TOF): m/z Calcd for C
32h
37brFN
5o
2s ([M+H]
+) 654.1914 Found654.1918.
Compound I-7:1-(2-((1-(2-(diethylamino) ethyl)-3-(4-trifluoromethyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1hNMR (400MHz, CDCl
3) δ: 7.69 (d, J=6.8Hz, 2H), 7.51-7.54 (m, 2H), 7.41-7.43 (m, 2H), 6.92 (d, J=6.8Hz, 2H), 6.45 (s, 1H), 4.64 (s, 2H), 4.48-4.51 (t, J=4.8Hz, 2H), 4.34 (s, 2H), 4.20 (t, J=7.2Hz, 2H), 3.83 (s, 3H), 3.76 (t, J=4.8Hz, 2H), 2.85-2.90 (m, 4H), 2.78 (t, J=7.2Hz, 2H), 2.53 (q, J=7.2Hz, 4H), 2.05-2.09 (m, 2H), 0.96 (t, J=7.2Hz, 6H).
Compound I-8:1-(2-((1-(2-(diethylamino) ethyl)-3-(3-chloro-phenyl-)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5, 6-pentamethylene pyrimidin-4-one, 1H NMR (400MHz, CDCl3) δ: 7.69 (d, J=6.8Hz, 2H), 7.48-7.50 (m, 1H), 7.35-7.37 (m, 1H), 7.33 (d, J=6.8Hz, 2H), 7.21-7.26 (m, 2H), 6.53 (s, 1H), 4.64 (s, 2H), 4.49 (t, J=4.8Hz, 2H), 4.34 (s, 2H), 4.21 (t, J=7.2Hz, 2H), 3.76 (t, J=4.8Hz, 2H), 2.85-2.90 (m, 4H), 2.78 (t, J=7.2Hz, 2H), 2.52 (q, J=7.2Hz, 4H), 2.05-2.09 (m, 2H), 0.96 (t, J=7.2Hz, 6H).
Compound I-9:1-(2-((1-(2-(diethylamino) ethyl)-3-(2-chloro-phenyl-)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5, 6-pentamethylene pyrimidin-4-one, 1H NMR (400MHz, CDCl3) δ: 7.69 (d, J=6.8Hz, 2H), 7.35-7.42 (m, 2H), 7.33 (d, J=6.8Hz, 2H), 7.16-7.20 (m, 2H), 6.54 (s, 1H), 4.64 (s, 2H), 4.49 (t, J=4.8Hz, 2H), 4.34 (s, 2H), 4.21 (t, J=7.2Hz, 2H), 3.76 (t, J=4.8Hz, 2H), 2.85-2.90 (m, 4H), 2.78 (t, J=7.2Hz, 2H), 2.52 (q, J=7.2Hz, 4H), 2.05-2.09 (m, 2H), 0.96 (t, J=7.2Hz, 6H).
embodiment 75compound salify:
Compound I-1 is dissolved in methyl alcohol, adds the tartrate of 1 equivalent, stir, methyl alcohol is sloughed in decompression, with the solid that is white in color after ether washing.Fusing point: 70-71 ℃
embodiment 76method for preparing tablet thereof is as follows:
Prescription consumption/sheet
I-1 100mg
Microcrystalline Cellulose 20mg
Starch 40mg
Lactose 100mg
Polyvidone 8mg
Sodium Hydroxymethyl Stalcs 10mg
Magnesium Stearate qs
Micropowder silica gel qs
Amount to about 280mg
Technique: activeconstituents auxiliary material is crossed respectively to 100 mesh sieves; the main ingredient and the auxiliary material (half Sodium Hydroxymethyl Stalcs) that take recipe quantity fully mix; add polyvinylpyrrolidone aqueous solution softwood processed in right amount; cross 24 mesh sieves, the wet granular of system is dry about 2-3 hour in 40-50 degree Celsius of baking oven, will remain Sodium Hydroxymethyl Stalcs; Magnesium Stearate and micropowder silica gel mix with particle; whole grain, measures intermediate content, with the shallow stamping of 9mm.
embodiment 77capsule preparation method thereof is as follows:
Prescription consumption/capsule
I-2 100mg
Microcrystalline Cellulose 20mg
Lactose 60mg
Sodium Hydroxymethyl Stalcs 6mg
Hypromellose 5mg
Micropowder silica gel 5mg
Magnesium Stearate qs
Talcum powder qs
Amount to about 200mg
Technique: activeconstituents auxiliary material is crossed respectively to 100 mesh sieves; the main ingredient and the auxiliary material that take recipe quantity fully mix; add hypromellose solution softwood processed in right amount; cross 24 mesh sieves; be worth wet granular dry about 2-3 hour in 40-50 degree Celsius of baking oven, Magnesium Stearate and talcum powder mixed to whole grain with particle; measure intermediate content, filling with No. 2 capsules.
embodiment 78take solution preparation (every bottle of amount)
Prescription consumption/capsule
I-3 200mg
N.F,USP MANNITOL 100mg
Citric acid 20mg
Orange taste essence 10mg
Aspartame 10mg
Tegosept E qs
Distilled water 100mL
Technique: get distilled water 10mL, the citric acid, N.F,USP MANNITOL, orange taste essence, aspartame, the sample that take recipe quantity are stirred to dissolve, and add after sanitas, filling in bottle.
embodiment 79every bag of granule contains:
Prescription consumption/capsule
I-4 100mg
Lactose 730mg
N.F,USP MANNITOL 150mg
Soluble saccharin 5mg
Essence 5mg
2% hypromellose (water) qs
Technique: main ingredient and auxiliary material are crossed respectively to 100 mesh sieves, fully mix, then take recipe quantity auxiliary material and main ingredient and fully mix.Add tackiness agent softwood processed, 14 mesh sieves are granulated again, and 45 degrees Celsius dry, and the whole grain of 16 mesh sieves is measured heavily packing of bag.
embodiment 80the preparation of injection liquid
Prescription consumption/capsule
I-5 50mg
SODIUM PHOSPHATE, MONOBASIC 10mg
Citric acid 20mg
Sodium-chlor 90mg
Water for injection 50mL
Technique: get water for injection 50mL, take the citric acid of recipe quantity, SODIUM PHOSPHATE, MONOBASIC, sodium-chlor are stirred to dissolve, and add sample stirring and dissolving, is 4.0-7.0 with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L, adds 0.1% charcoal absorption 20 minutes.First with 045 μ m filter membrane, filter, then filter by 022 μ m essence.By every peace cut open 2 milliliters filling, injection liquid is remembered in 105 celsius temperature sterilizings 30 minutes.
Embodiment 81
Document Bioorganic & Medicinal Chemistry Letters 10 (2000) 2557-2561 measuring methods improve, and take PAF as substrate, measure one of product (enzyme decomposes the acid discharging), calculate enzyme activity.Result is as follows:
| Compound | Concentration | Enzyme inhibition rate (%) |
| I-1 | 5uM | 90 |
| I-2 | 5uM | 96 |
| I-3 | 5uM | 93 |
| I-4 | 5uM | 91 |
| I-5 | 5uM | 88 |
| I-6 | 5uM | 93 |
| I-7 | 5uM | 80 |
Claims (8)
1. there is the compound of general formula I structure and acceptable salt pharmaceutically thereof,
Wherein:
R1 is: hydrogen, C
1-6alkyl, hydroxyl, methoxyl group, oxyethyl group, fluorine, chlorine, bromine, iodine, R1 is that contraposition, ortho position or a position replace, and is monosubstituted or two replacements;
R2, R3 are: methyl, ethyl, propyl group, sec.-propyl;
R4 is: fluorine, chlorine, bromine;
N1, n2, n3 are: 1,2,3;
X=O、S。
2. a compound, is selected from:
1-(2-((1-(2-(diethylamino) ethyl)-3-(4-p-methoxy-phenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1-(2-((1-(2-(diethylamino) ethyl)-3-(4-aminomethyl phenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1-(2-((1-(2-(diethylamino) ethyl)-3-phenyl-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1-(2-((1-(2-(diethylamino) ethyl)-3-(4-fluorophenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1-(2-((1-(2-(diethylamino) ethyl)-3-(4-chloro-phenyl-)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1-(2-((1-(2-(diethylamino) ethyl)-3-(4-bromophenyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1-(2-((1-(2-(diethylamino) ethyl)-3-(4-trifluoromethyl)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1-(2-((1-(2-(diethylamino) ethyl)-3-(3-chloro-phenyl-)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one,
1-(2-((1-(2-(diethylamino) ethyl)-3-(2-chloro-phenyl-)-5-pyrazolyl) methoxyl group) ethyl)-2-(4-fluorophenyl methylthio group)-5,6-pentamethylene pyrimidin-4-one.
3. the defined compound of Formula I of claim 1, by the following method preparation:
Compound I I reacts in alkaline alcoholic solution with oxalic acid diethyl ester, after without separation directly with after acid neutralization with hydrazine hydrate effect generation compound III, acid is formic acid, acetic acid, hydrochloric acid, sulfuric acid, highly basic is sodium alkoxide, sodium hydride; Compound III under alkaline condition with two bromoalkanes reacting generating compound IV in organic solvent, alkaline condition is salt of wormwood, potassium hydroxide, two bromoalkanes are methylene bromide, glycol dibromide, 1,3-dibromopropane, organic solvent is acetonitrile, tetrahydrofuran (THF); Compound IV and amine are made catalyzer with potassiumiodide and are generated compound V in the organic solvent under alkaline condition, and alkaline condition is salt of wormwood, potassium hydroxide, and organic solvent is acetonitrile, tetrahydrofuran (THF); Compound V is hydrogenated the reduction of aluminium lithium reductive agent and generates compound VI in organic solvent, and organic solvent is tetrahydrofuran (THF), ether; Compound VI first in organic solvent with potassium tert.-butoxide, sodium tert-butoxide, sodium hydride effect, then generate compound VI I with the effect of halogenated acetic acids ethyl ester, organic solvent is the trimethyl carbinol, tetrahydrofuran (THF); Compound VI I is hydrogenated the reduction of aluminium lithium reductive agent and generates compound VI II in organic solvent, and organic solvent is tetrahydrofuran (THF), ether; Compound VI II and Methanesulfonyl chloride act on and generate Compound I X in dry methylene dichloride; Compounds X and urea or thiocarbamide reflux and generate XI under the effect of sodium alkoxide in alcoholic solution, and alcohol is methyl alcohol or ethanol; The benzyl chlorine of compounds X I and para-orientation reacting generating compound XII in alkaline organic solvent, alkali is salt of wormwood, potassium hydroxide, organic solvent is acetone, acetonitrile; Compound I X and compounds X II generate Compound I under alkaline effect in organic solvent, and alkali is salt of wormwood, sodium carbonate, and organic solvent is DMF, acetonitrile; Synthetic route is as follows:
Wherein, R1-R4, n1, n3, X define as claimed in claim 1; N2 is 1.
The defined compound of Formula I of claim 1 and pharmaceutically acceptable salt at preparation treatment Lp-phospholipase A
2the application of the medicine aspect of relative disease.
The defined compound of claim 2 and pharmaceutically acceptable salt at preparation treatment Lp-phospholipase A
2the application of the medicine aspect of relative disease.
6. a pharmaceutical composition, contains generalformulaⅰcompound claimed in claim 1, and suitable carrier or vehicle.
7. a pharmaceutical composition, contains compound claimed in claim 2, and suitable carrier or vehicle.
8. the pharmaceutical composition described in claim 6 or 7, wherein, described composition is solid orally ingestible, liquid oral medicine or injection.
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