CN1064965C - Novel sulfonamides compound and its use as medicine - Google Patents

Novel sulfonamides compound and its use as medicine Download PDF

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CN1064965C
CN1064965C CN951202502A CN95120250A CN1064965C CN 1064965 C CN1064965 C CN 1064965C CN 951202502 A CN951202502 A CN 951202502A CN 95120250 A CN95120250 A CN 95120250A CN 1064965 C CN1064965 C CN 1064965C
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pyridine
base
pyrimidine
methoxyl group
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CN1132751A (en
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V·布略
K·布里
J-M·卡萨尔
M·科劳泽尔
G·赫思
B-M·略福勒
M·姆勒
W·奈哈特
H·拉姆兹
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F Hoffmann La Roche AG
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Abstract

A compound of the formula I is an endothelin receptor inhibitor, wherein substituent groups are disclosed in the specification. The endothelin receptor inhibitor can be used for treating diseases relative to the endothelin activity, particularly for treating circulation diseases, such as hypertension, ischemia, angiospasm and angina pectoris.

Description

New sulfamide compound and as the purposes of medicine
The present invention relates to new sulfamide compound and as the purposes of medicine.Particularly, the present invention relates to the new compound of following formula
R wherein 1Be meant heterocyclic radical; R 2Be meant hydrogen, low alkyl group, lower alkoxy, lower alkylthio, lower alkoxy low alkyl group, low alkyl group alkylsulfonyl lower alkoxy, phenyl, low alkyl group phenyl, lower alkoxyphenyl, low-grade alkylidene dioxy base phenyl, phenyl lower alkyl, low alkyl group phenyl lower alkyl, lower alkoxyphenyl low alkyl group, low-grade alkylidene dioxy base phenyl lower alkyl, heterocyclic radical or heterocyclic radical low alkyl group; R 3Be meant low alkyl group, lower alkoxy, formyl radical, junior alkyl halides, hydroxyl low-grade alkyl, amino low alkyl group or-CH 2The O-A-low alkyl group ,-(CH 2) m-O-(CR nR b) nOH ,-(CH 2) m-O-(CR nR b) nOR 9,-(CH 2) m-O-(CR nR b) nNH 2Or-(CH 2) m-O-(CR aR b) n-B-R 9R 4-R 8Be meant hydrogen, lower alkoxy or halogen; R 9Be meant heterocyclic radical; Phenyl or the phenyl that is replaced by low alkyl group, lower alkoxy and/or halogen, or low alkyl group; R nAnd R bBe meant hydrogen or low alkyl group; A is meant ketone acetalization 1,2-dihydroxyl-ethylidene; B is meant-OC (O) O-, OC (O) NH-,-NHC (O) NH-or-NHC (O) O-; N is meant 2,3 or 4; Be meant 0 or 1 with m.
Term used herein " rudimentary " is meant the group that contains 1-7 carbon atom, preferred 1-4 carbon atom.Alkyl, alkoxyl group, alkylthio and the alkyl of forming as alkanoyl can be straight or brancheds.Methyl, ethyl, propyl group, sec.-propyl, butyl, sec-butyl and the tertiary butyl are the examples of this alkyl.Halogen is meant chlorine, bromine and iodine, preferred chlorine.Low-grade alkylidene dioxy phenyl is an ethylidene dioxy phenyl for example.Ketone acetalization 1,2-dihydroxyl ethylidene are for example 2,2-dimethyl-1,3-dioxolane-4,5-two bases.The example of heterocyclic radical particularly replaces or dibasic or unsubstituted monocycle or the dicyclo that contains oxygen, nitrogen or sulfur heteroatom by low alkyl group for example, lower alkane acyl group, halogen or by another heterocyclic radical one.For example 2-and 3-furyl, pyrimidyl, 2-, 3-and 4-pyridyl, 1,2-and 1,4-diazines base, morpholino, 2-and 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrryl, benzofuryl, benzothienyl, indyl, purine radicals, quinolyl, isoquinolyl and quinazolyl.Heterocyclic radical R 1Example particularly replace or unsubstituted pyridine base, pyrimidyl, thienyl and isoxazolyl.Heterocyclic radical R 2(sic) particularly pyrimidyl and morpholino of example.Heterocyclic radical R 9Example particularly pyridyl, pyrimidyl and furyl.
Preferred formula I compound is following compound, wherein R 1Be monocycle S-, N-and/or O-heterocyclic radical, particularly unsubstituted or by pyridyl, pyrimidyl, isoxazolyl, furyl and the thienyl of low alkyl group, halogen, amino, single low-grade alkyl amino or two elementary alkyl amido or lower alkane acyl substituted.In addition, preferred R wherein 2Be the formula I compound of hydrogen, pyrimidyl, pyridyl, morpholino, thiomorpholine generation, piperidino-(1-position only), pyrrolidino, benzo dioxolyl (benzodioxolyl), lower alkoxyphenyl or lower alkylthio, and [wherein] R 3Be-O-(CR aR b) nOH ,-O-(CR aR b) nNH 2Or-O (CH 2) 2-B-R 9, and R 9It is the formula I compound of monocycle N-and/or O-heterocyclic radical (particularly pyridyl, pyrazinyl or furyl).
Making us interested especially is R wherein 1The pyridyl, the R that are replaced by low alkyl group 2Be morpholino, R 3Be-O (CH 2) 2OC (O) NHR 9, R 4Be lower alkoxy and R 5-R 8It is the formula I compound of hydrogen.Preferred R 9Group is a heterocyclic radical, particularly pyridyl such as 2-pyridyl.
Above-mentioned formula I compound is an Endothelin Receptor inhibitor.Therefore they can be used for the treatment of and endothelin active diseases associated, particularly circulatory diseases, as hypertension, local asphyxia, vasospasm and stenocardia.
Formula I compound can prepare by following method: a) with formula II compound
Figure 9512025000151
R wherein 1, R 2And R 4-R 8Implication is the same, and Hal is halogen, reacts with following formula: compound
HO(CR aR b) nXH
Wherein n, R aAnd R bImplication is the same, and X is meant O or NH, perhaps b) with formula III compound
Figure 9512025000161
R wherein 2-R 8Implication is the same, reacts with following formula: compound
R 1SO 2Z
R wherein 1Implication is the same, and therefore Y represents that halogen and Z represent amino, and perhaps Y represents that amino and Z represent halogen, perhaps c) with formula IV compound
Figure 9512025000162
R wherein 1, R 2, R 4-R 8, R a, R b, X, m and n implication be the same, c1) with formula R 9The isocyanic ester of NCO or formula R 9The carbamyl chlorine compound reaction of NCOCl, wherein R 9Implication is the same, perhaps c2) and phosgene reaction, then with formula R 9The alcohol reaction of OH; Perhaps with formula R 9The chloro-formic ester reaction of OC (O) Cl; Perhaps d) R wherein 3The formula I compound of expression junior alkyl halides and following formula: compound reaction
HO (CH) 2-A-low alkyl group
Wherein A represents ketone acetalization 1,2-dihydroxyl-ethylidene, and, if desired, can change the substituting group that exists on the gained formula I compound and/or gained formula I compound is converted into salt.
At formula II compound and formula HO (CR aR b) nIn the reaction of XH compound, can use formula HO (CR with the alkali metal alcohol salt form easily aR b) nThe XH compound.Therefore preferably with corresponding dibasic alcohol or ammonia alcohol for example ethylene glycol or monoethanolamine (when the n=2) as solvent.The preferred sodium alkoxide of alkali metal alcoholates.This reaction can for example be heated under the 40-120 ℃ of condition and carry out easily in heating.In preferred embodiments, use formula HO (CR aR b) nThe XH compound as a sodium salt of ethylene glycol, propylene glycol or butyleneglycol or monoethanolamine, a sodium salt of aminopropanol or amino butanol.
Formula III compound and formula R 1SO 2The reaction of Z compound can be carried out according to the currently known methods of preparation sulfamide compound, for example in inert organic solvents such as dimethyl sulfoxide (DMSO), for example carry out under the argon atmospher under heating condition and at protective atmosphere easily.
Method c1) reaction can be carried out according to the currently known methods for preparing carbamate and urea by alkohol and amine respectively.Therefore, can suitable anhydrous organic solvent for example in hydrocarbon such as the toluene, under heating condition, use formula R 9The isocyanic ester of NCO is converted into formula IV compound wherein, and B is-the formula I compound of OC (O) NH-.Isocyanic ester can be by thermolysis by formula R 9CON 3Trinitride produce on the spot.Equally, using B wherein is that the formula IV compound of NH can obtain wherein that B is-the formula I compound of NHC (O) NH-.
According to method c2), can be the formula IV compound and the phosgene reaction of oxygen with B wherein, then with formula R 9The reaction of the alcohol of OH obtains wherein that A is-the formula I compound of OC (O) O-group.Can use phosgene salt such as trichloromethylchloroformate (Cl-COOCCl 3) or triphosgene (CO (OCCl 3) 2Replace phosgene.Be that the formula IV compound of NH begins by B wherein similarly, can obtain wherein that B is-the formula I compound of NHC (O) O-.Can use phosgene with the solution form in inert water-free organic solvent (for example hydrocarbon such as toluene) easily.Can carry out in room temperature with the reaction of phosgene.The acyl chlorides that obtains with intermediate forms, easily under heating condition directly with pure R 9The OH reaction.
Method d) reaction can a) be carried out under the required reaction conditions in method, to obtain wherein R 3Be-CH 2The formula I compound of O-A-low alkyl group.
The substituting group that exists in the formula I compound that so obtains can be changed.Therefore can be by oxygenizement with methyl R 3Be converted into formyl radical.Oxidizing reaction can for example be carried out with tin anhydride according to known method itself.Formyl radical in the compound that so obtains can be reduced into methylol.Reduction reaction can for example be used reductive agent such as NaBH according to known method itself 4Carry out.By with halogenating agent such as POCl 3/ PCl 5Reaction can be converted into monochloromethyl with methylol.Moreover N-heterocyclic radical such as pyridyl can be oxidized to the N-oxide compound.All these reactions can be carried out according to known method itself.Formula I compound can be converted into salt according to known method itself, for example alkali salt such as sodium salt and sylvite or alkaline earth salt such as calcium salt or magnesium salts.
If as the compound of raw material is not known or its preparation method is described below, so these compounds can according to the similar method of currently known methods or according to hereinafter in greater detail method be prepared.
Formula I compound can adopt following experimental technique to be confirmed to the inhibition activity of endothelin receptor: I: the restraining effect of endothelin and reorganization ETA receptors bind
The cDNA of coding people placenta ETA acceptor is cloned (M.Adachi, Y.-Y.Yang, Y.Furuichi and C.Miyamoto, BBRC180 1265-1272), and expresses in the baculovirus insect cell system.After infection, centrifugal (3000 * g, 15 minutes, 4 ℃) 60 hours separate baculovirus insect cell from 23 liters of fermented products, and resuspending is in Tris damping fluid (5mM, pH7.4,1mM MgCl 2) in, and recentrifuge.Will through suspend once more and centrifugal after cell suspension in the same damping fluid of 800ml, and-120 ℃ of freeze-drying.When the suspension fusion in the hypotonic buffer mixture, cell disruption.After repeating freeze-drying/fusion circulation, suspension is stirred and centrifugal (25000 * g, 15 minutes, 4 ℃).Be suspended in Tris damping fluid (75mM, pH7.4,25mM MgCl 2, 250mM sucrose) in after, respectively be the sample aliquot of 1ml (protein content is about 3.5mg/ml)-85 ℃ of storages.
In order to carry out binding analysis, with freeze dried film preparation fusion, and 20 ℃ with 25000g centrifugal 10 minutes, (50mM Tris damping fluid, pH7.4 contains 25mM MnCl to resuspending in analysis buffer afterwards 2, 1mM EDTA and 0.5% bovine serum albumin) in.At analysis buffer (25000cpm, final concentration is 20mM) and contain in the 100 μ l analysis buffer of different concns experimental compound, will contain proteic this film suspension of 100 μ l of 70 μ g and cultivate with 50 μ l 1251-endothelin (specific activity 2200Ci/mMol).This cultivation was carried out 2 hours or was carried out 24 hours at 4 ℃ at 20 ℃.By using glass fibre filter filtering separation free and membrane-bound radioligand.
The inhibition activity of the formula I compound of proof is represented with IC50 in table is in this experiment, promptly represents with the required concentration of the particular combination that suppresses 50% 1251-endothelin [nM].
The Compound I C50[nM of table 1 embodiment] 34 0.351 0.4 II. the restraining effect of the contraction that endothelin in the isolating rat aorta ring is caused
Downcut the ring of long 5mm from the thoracic aorta of ripe Wistar-Kyoto rat.Internal surface rub gently to remove endothelium-denuded.In isolating bath, in 37 ℃, each ring is immersed in the 10ml Krebs-Henseleit solution, feed 95% oxygen and 5% carbonic acid gas simultaneously.Measure the isometric elongation (isometric stretching) of each ring.To encircle to elongate makes F strain (pre-tension) reach 3 grams.After cultivating 10 minutes with experimental compound or vehicle, add the endothelin-1 of integral dose.By observing in the presence of the different concns antagonist, the activity of experimental compound is determined in the migration to the right of the dosage-activity curve of endothelin-1.This moves to the right (perhaps " dosage than ", DR) with exist and do not exist under the situation of antagonist, the quotient of the EC50 value of endothelin-1 is corresponding, the EC50 value is meant the concentration of endothelin that the half maximum collapse is required.
According to the following equation of " dosage than " DR of each single dosage-activity curve, the program of using a computer is calculated corresponding PA2 value, and this value is the active observed value of experimental compound.
PA2=log (DR-1)-log (antagonist-concentration)
Experimental compound not in the presence of, the EC50 value of endothelin is 0.3nM.
Provided the PA2 value that obtains with formula I compound in the table 2.
The compound dosage of table 2 embodiment is than (turning right) 34 9.751 9.2
Because formula I compound can suppress the endothelin combination, so it can increase the medicine of diseases related as treatment and vasoconstriction frequency.The example of this disease is hypertension, coronary disease, cardiac insufficiency, kidney and myocardial ischaemia, renal insufficiency, dialysis, cerebral ischaemia, cerebral infarction, migraine, subarachnoid hemorrhage, Raynaud syndrome and pulmonary hypertension.They can also be used for atherosclerosis, prevention is with the restenosis behind the air bag expansion blood vessel, inflammation, gastric duodenal ulcer, ulcus cruris, gram negative sepsis, shock, glomerulonephritis, renal colic, glaucoma, asthma, treatment and prevent diabetes complication and use S-Neoral complication therefore, and other and endothelin activity diseases associated.
Formula I compound can oral administration, rectum, non-enteron aisle (as in vein, intramuscular, subcutaneous, the sheath or transdermal) administration; Perhaps through the hypogloeeis or with the form of ophthalmic preparation or with the aerosol form administration.Oral capsule, tablet, suspension or solution, suppository, injection liquid, eye drops, ointment or spray solution are the examples of form of medication.
Preferably use vein, intramuscular or oral administration form.The effective dose of the formula I compound of being used depends on character, patient's age and needs and the administering mode of concrete activeconstituents.In general, dosage can be the about 0.1-100mg of per kilogram of body weight every day.The preparation that contains formula I compound can contain inert or drug activity additive.Tablet or granule can contain for example a series of binding agents, weighting agent, carrier or thinner.Liquid preparation can exist with the solution form that sterilized water can dissolve each other.Except activeconstituents, capsule can contain weighting agent or thickening material.Moreover, odor control additive and also can exist as the material of sanitas, stablizer, wetting Agent for Printing Inks and emulsifying agent and the salt, damping fluid and other additive that improve osmotic pressure.
Described carrier and thinner can comprise organic or inorganic substance, for example water, gelatin, lactose, starch, Magnesium Stearate, talcum, gum arabic and polyglycol etc.The most important condition is that all assistant agents that are used to prepare preparation are nontoxic.
The following example illustrates in greater detail the present invention.
Embodiment 1
At 50 ℃, 1.29g sodium is dissolved in the 50ml ethylene glycol.Then, under same temperature, add the 3.0g 5-tertiary butyl-thiophene-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides in batches, this mixture was heated 4.5 hours at 100 ℃.Clear soln is poured in ice/dilute hydrochloric acid solution, with this mixture of each ethyl acetate extraction of 0.21 3 times.Organic phase washes with water 3 times, uses dried over sodium sulfate, evaporation (sic) on rotatory evaporator at last.Obtain the 5-tertiary butyl-thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2, the 2 ＇-Lian pyrimidine-4-base acid amides of weak yellow foam shape thus.MS：493(M-SO 2)。Preparation initial compounds: a) in room temperature, the 2.0g 5-tertiary butyl-thiophene-2-SULPHURYL CHLORIDE is dissolved in the 30ml methyl alcohol, with 50ml 25% ammonia treatment, reflux 4.5 hours.Enriched mixture on rotatory evaporator, the resistates water treatment with ethyl acetate (150ml) extraction, is used dried over mgso, and is concentrated once more on rotatory evaporator.Obtain the 5-tertiary butyl-2-thiophene-2-sulphonamide thus, be white crystals.MS：219(M)。The potassium tert.-butoxide that is used in the methyl alcohol obtains sylvite.B) with 3.49g 4,6-two chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine is dissolved in the 125ml dimethyl sulfoxide (DMSO).Add 3.855g (the 5-tertiary butyl-thiophene-2-sulphonamide) potassium in room temperature, then this solution of stirring at room 20 hours.Use 1.285g (the 5-tertiary butyl-thiophene-2-sulphonamide) potassium to handle again, and it was reacted 2 hours in room temperature again.In vigorous stirring, in reaction mixture, add 200ml water, [and] add the 200ml ether then, form tiny, white crystalline precipitate thus, suction strainer goes out this precipitation.Crystallization is suspended in the diluted hydrochloric acid aqueous solution, and stirring at room 0.5 hour, suction strainer was also dry under high vacuum.Obtain the 5-tertiary butyl-thiophene-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides thus, be white crystalline solid.MS：523．4(M+H)。
Embodiment 2
The 3.23g 5-tertiary butyl-thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides, 1.71g 2-pyridine agent formic acid trinitride and 70mg were heated 2 hours at 80 ℃ toluene (50ml) solution of Dimethylamino pyridine.Remove toluene on rotatory evaporator, resistates distributes between methylene dichloride (0.51) and 1N hydrochloric acid soln (0.351).The organic phase dried over mgso is removed on rotatory evaporator at last and is desolvated.Crude product on silica gel, make eluent with methylene chloride (5/1), through chromatogram purification.Obtain pyridine-2-aminocarbamic acid 2-[6-(the 5-tertiary butyl-thiophene-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base oxygen thus]-ethyl ester, be faint yellow solid, with its recrystallization from methylene chloride.MS：678．3(M+H)。
Embodiment 3
At 50 ℃, 26mg sodium is dissolved in the 2ml thanomin, under same temperature, use 150mg embodiment 1b in batches) compound treatment of section, with this solution 100 ℃ of heating 4 hours.Then, mixture is poured in ice/water, regulated pH to 6 with 3N HCl, thereby isolate faint yellow crystalline solid, suction strainer goes out this solid, wash with water, and dry under high vacuum.Obtain the yellow crystalline 5-tertiary butyl-thiophene-2-sulfonic acid 6-(2-amino-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides thus.MS：557．4(M+H)。
Embodiment 4
With the 100mg 5-tertiary butyl-thiophene-2-sulfonic acid 6-(2-amino-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides is dissolved in the 10ml toluene, handle with 53mg 2-pyridyl formic acid trinitride, and heated these solution 4 hours at 120 ℃.Remove toluene on rotatory evaporator, resistates distributes between ethyl acetate and water.The organic phase dried over mgso concentrates on rotatory evaporator at last.Resistates on silica gel, make eluent with methylene chloride (30/1), through chromatogram purification.Obtain the 5-tertiary butyl-thiophene-2-sulfonic acid 5-(2-methoxyl group-phenoxy group)-6-[2-(3-pyridine-2-base-urea groups)-oxyethyl group thus]-2,2 ＇-Lian pyrimidine-4-base acid amides, be crystalline solid.MS：677．4(M+H)。
Embodiment 5
In room temperature, to 162.5mg 4-amino-6-methoxyl group-5-(2-methoxyl group-phenoxy group)-2, add 92mgNaH (65%) in the 2 ＇-solution of Lian pyrimidine in the 10ml tetrahydrofuran (THF), this solution of stirring at room 1.5 hours, under same temperature, add the 162.5mg 5-tertiary butyl-thiophene-2-SULPHURYL CHLORIDE then.In this mixture of room temperature restir 2 hours, pour in ice/water, use ethyl acetate extraction, with aqueous phase as acidified and use dichloromethane extraction.The organic phase dried over mgso that merges concentrates on rotatory evaporator.Resistates on silica gel, make eluent with methylene chloride (20/1), through chromatogram purification.Obtain the 5-tertiary butyl-N-[6-methoxyl group-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-yl thus]-thiophene-2-sulphonamide, be yellow powder.MS：463(M-SO 2)。The preparation initial compounds: a) with 2.09g 4,6-two chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine (EP-A-0 526 708) is suspended in the 75ml methyl alcohol, adds (condensed) 150ml ammonia at 75 ℃ with feed-pipe.Make reaction mixture return to ambient temperature overnight, concentrate under the jet of water vacuum, resistates distributes between less water and methylene dichloride (500ml).The organic phase dried over sodium sulfate, and on rotatory evaporator, concentrate.Resistates is developed with ether, separating obtained solid, and dry under high vacuum.Obtain 4-amino-6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine thus, for almost being the thin powder of white.MS：329(M)。B) the 6.55g sodium methylate is added in 4-amino-6-chloro-5-(2-methoxyl group-phenoxy group)-2, the 2 ＇-solution of Lian pyrimidine in 200ml methyl alcohol in room temperature, then with this vlil 32 hours.On rotatory evaporator, remove methyl alcohol, resistates is dissolved in the methylene dichloride, with 1N salt acid elution.The organic phase dried over mgso is removed under the jet of water vacuum at last and is desolvated.Crude product on silica gel, make eluent with methylene chloride (10/1), through chromatogram purification.Obtain 4-amino-6-methoxyl group-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine thus, be the lemon yellow powder.MS：325(M)。
Embodiment 6
According to method similar to Example 1, by sodium glycolate and 5-amyl group-thiophene-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides obtains 5-amyl group-thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides are white solid.MS：570．3(M+H)。Preparation initial compounds: a) obtain (5-n-pentyl-thiophene-2-sulphonamide) potassium, and the potassium tert.-butoxide that is used in the methyl alcohol forms salt by 2-amyl group-5-(tertiary butyl sulfonamido) thiophene (EP-A-0 512 675) and ethanol/concentrated hydrochloric acid.B) according to embodiment 1b) the similar method of section, by (5-n-pentyl-thiophene-2-sulphonamide) potassium and 4,6-two chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine reaction, obtain 5-amyl group-thiophene-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides are white solid.MS：545(M)。
Embodiment 7
According to method similar to Example 2, by 2-pyridyl formic acid trinitride and 5-amyl group-thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides obtains pyridine-2-aminocarbamic acid 2-[5-(2-methoxyl group-phenoxy group)-6-(5-amyl group-thiophene-2-ylsulfonylamino)-2,2 ＇-Lian pyrimidine-4-base oxygen]-ethyl ester, be white solid.MS：692．4(M+H)。
Embodiment 8
According to method similar to Example 2; by sodium glycolate and 5-(2; 2-dimethyl-propionyl)-thiophene-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2; 2 ＇-Lian pyrimidine-4-base acid amides obtains 5-(2; 2-dimethyl-propionyl)-and thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2.2 ＇-Lian pyrimidine-4-base acid amides, be pink powder.MS：586．3(M+H)。
The preparation initial compounds: a) according to embodiment 1b) the similar method of section; by 5-(2; 2-dimethyl propylene acyl group) sylvite of thiophene-2-sulphonamide (preparation: J Org.Chem., Vol 56,4260) and 4; 6-two chloro-5-(2-methoxyl group-phenoxy group)-2; 2 ＇-Lian pyrimidine reaction obtain 5-(2,2-dimethyl-propionyl)-thiophene-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2; 2 ＇-Lian pyrimidine-4-base acid amides are crystalline solid.MS：560．1(M+H)。The potassium tert.-butoxide that is used in the methyl alcohol obtains sylvite.
Embodiment 9
According to method similar to Example 2; by 2-pyridyl formic acid trinitride and 5-(2; 2-dimethyl-propionyl)-thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2; 2 ＇-Lian pyrimidine-4-base acid amides obtains pyridine-2-aminocarbamic acid 2-[6-[5-(2; 2-dimethyl propylene acyl group)-thiophene-2-ylsulfonylamino]-5-(2-methoxyl group-phenoxy group)-2; 2 ＇-Lian pyrimidine-4-base oxygen]-ethyl ester, be cream-coloured powder.MS：704．3(M+H)。
Embodiment 10
At 50 ℃, 1.75g sodium is dissolved in the 70ml ethylene glycol.Then, under same temperature, add 4.9g 5-sec.-propyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides in batches, this mixture was heated 4 hours at 100 ℃.Clear soln is poured in the 200ml water, regulated pH to 1 with 3N hydrochloric acid, suction strainer goes out isolating yellow crystal (sic), washes with water, and is then with the ether washing, dry under high vacuum at last.Obtain yellow crystalline solid 5-sec.-propyl-pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides thus.MS：537．3(M-H)。The preparation initial compounds: a) in room temperature, 4.0g 5-isopropyl pyridine-2-sulphonamide is dissolved in (sic) 40ml methyl alcohol, adds the 2.308g potassium tert.-butoxide, and restir 20 minutes.On rotatory evaporator, thoroughly concentrate then, and the sylvite that will obtain thus is dry under high vacuum.B) with 3.49g 4,6-two chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine is dissolved in the 125ml dimethyl sulfoxide (DMSO), adds 4.7g (5-sec.-propyl-pyridine-2-sulfuryl amine) potassium in room temperature, then this solution of stirring at room 20 hours.Under vigorous stirring, be poured in 350ml water and the 90ml ether, by adding the pH regulator to 1 of 3N hydrochloric acid with solution.Suction strainer goes out white crystalline precipitate, water, washs with ether then.Crystallization is suspended in the diluted hydrochloric acid aqueous solution (100ml water and 50ml (sic) 1N hydrochloric acid), stirred 5 minutes, suction strainer washes with water and drying under high vacuum again.Obtain 5-sec.-propyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides thus, be white crystalline solid.MS：511．3(M+H)。
Embodiment 11
With 2.0g 5-sec.-propyl-pyridine-2-sulfonic acid 6-(2-amino-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides is dissolved in the 80ml toluene, handle with 1.1g 2-pyridyl formic acid trinitride, and heated these solution 4 hours at 90 ℃.It is concentrated on rotatory evaporator, and resistates distributes between 1N hydrochloric acid and ethyl acetate.The organic phase dried over mgso is removed under the jet of water vacuum at last and is desolvated, resistates on silica gel, make eluent with methylene chloride (30/1), through chromatogram purification.Obtain pyridine-2-aminocarbamic acid 2-[6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base oxygen thus]-ethyl ester, be yellow crystal.MS：657．3(M+H)。
In order to prepare dihydrochloride, this compound is dissolved in the methylene dichloride, in room temperature, be used in the 4.4N salt acid treatment of the respective amount in the ethanol.On rotatory evaporator, concentrate this solution, separate isolating crystalline solid, and at 60 ℃ of dry 4 hours (sic) under high vacuum.
Embodiment 12
According to method similar to Example 4, by 5-sec.-propyl-pyridine-2-sulfonic acid 6-(2-amino-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides and 2-pyridyl formic acid trinitride obtain required 5-sec.-propyl-pyridine-2-sulfonic acid 5-(2-methoxyl group-phenoxy group)-6-[2-(3-pyridine-2-base-urea groups)-oxyethyl group]-2,2 ＇-Lian pyrimidine-4-base acid amides are yellow crystal.MS：656．3(M+H)。
According to method similar to Example 3, by thanomin and embodiment 10b) section compound obtain initial compounds, be yellow foam.MS：538．3(M+H)。
Embodiment 13
According to method similar to Example 10, by pyridine-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides and ethylene glycol obtain pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides are white crystals.MS：615．4(M-H)。Preparation initial compounds: a) 1.7g 2-pyridyl SULPHURYL CHLORIDE (J Org.Chem., Vol.54,389) is dissolved in the 30ml ethanol,, then this mixture heating up was refluxed 4 hours with adding 30ml 25% ammonia solution in ice-cooled.Concentrated reaction solution on rotatory evaporator, resistates distributes between ethyl acetate and water, and the organic phase dried over mgso concentrates on rotatory evaporator at last, separates the 2-pyridyl sulfonamide that obtains cream-coloured crystalline solid.MS：469．2(M+H)。The potassium tert.-butoxide that is used in the methyl alcohol obtains sylvite.B) according to embodiment 10b) the similar method of section, by (2-pyridyl sulfonamide)-potassium and 4,6-two chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine reaction, obtain pyridine-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides, be white crystals.MS：495．3(M-H)。
Embodiment 14
According to method similar to Example 11, by pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides and 2-pyridyl formic acid trinitride obtain pyridine-2-aminocarbamic acid 2-[5-(2-methoxyl group-phenoxy group)-6-pyridine-2-ylsulfonylamino)-2,2 ＇-Lian pyrimidine-4-base oxygen]-ethyl ester, be white crystals.MS：615．4(M-H)。
Embodiment 15
According to method similar to Example 10, by pyridine-3-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides and ethylene glycol obtain pyridine-3-sulphonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 '-Lian pyrimidine-4-base acid amides, be white crystals.MS：496(M)。The preparation initial compounds: a) according to embodiment 13a) the similar method of section, obtain the 3-pyridyl sulfonamide of white crystalline solid by 3-pyridyl SULPHURYL CHLORIDE (J Org.Chem., Vol.54,389) and ammonia, the potassium tert.-butoxide that is used in the methyl alcohol obtains sylvite.B) according to embodiment 10b) the similar method of section, by (3-pyridyl sulfonamide)-potassium and 4,6-two chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine reaction, obtain pyridine-3-sulphonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides, be white crystals.MS：470(M)。
Embodiment 16
According to method similar to Example 11, by pyridine-3-sulphonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides and 2-pyridyl formic acid trinitride obtain pyridine-2-aminocarbamic acid 2-[5-(2-methoxyl group-phenoxy group)-6-pyridin-3-yl sulfonamido)-2,2 ＇-Lian pyrimidine-4-base oxygen]-ethyl ester, be white crystals.MS：615．4(M-H)，
Embodiment 17
With 213mg 6-[2-(tertiary butyl-dimethyl-silicon alkoxyl group (silanoxy))-oxyethyl group]-5-(2-chloro-5-methoxyl group-phenoxy group)-pyrimidine-4-base amine is dissolved in the 15ml tetrahydrofuran (THF), handle with 92mg sodium hydride (65%) in room temperature, stirring at room 2 hours, add the 155mg 5-tertiary butyl-thiophene-2-SULPHURYL CHLORIDE then in batches.This solution of stirring at room 2 hours, pour in the frozen water, with the ethyl acetate extraction of 200ml altogether 2 times.After organic phase is carried out conventional processing, the crude product of silyl protection on silica gel, make eluent with dichloromethane/ethyl acetate (8/1), through chromatogram purification.
The brown foam of gained (219mg) is dissolved in the 15ml acetonitrile, handles at room temperature formula 1.5mlHF solution (40%), and stirs 2 hours.Reaction mixture distributes between ethyl acetate and semi-saturation sodium chloride solution, and organic phase is carried out conventional processing.Crude product on silica gel, make eluent with dichloromethane/ethyl acetate (4/1), through chromatogram purification, recrystallization from ether/hexane.Obtain the 5-tertiary butyl-thiophene-2-sulfonic acid 5-(2-chloro-5-methoxyl group-phenoxy group)-6-(2-hydroxyl-oxyethyl group)-pyrimidine-4-base acid amides thus, be white crystals.MS：449(M-SO 2)。The preparation initial compounds: a) according to M.Julia and I.de Rosnay, Chimie Therapeutique 5 (1969), and 334 method is converted into 2-chloro-5-methoxyphenol with SULPHURYL CHLORIDE with the 3-methoxyphenol.B) 18.2g 2-chloro-5-methoxyphenol is dissolved in the 150ml dehydrated alcohol.Add the 9.3g sodium methylate, add 25g chlorine dimethyl malonate then.50 ℃ of stirred reaction mixtures 2 hours.After distilling solvent, in separating funnel, resistates is distributed between toluene and water, and neutral washing.Behind alcohol crystal, obtain (2-chloro-5-methoxyl group) phenoxy group-dimethyl malonic ester, be white crystals, fusing point 68-69 ℃.C) 1.43g sodium is dissolved in the 70ml methyl alcohol.Add 5.8g (2-chloro-5-methoxyl group) phenoxy group-dimethyl malonic ester and 2.29g carbonamidine then; Reaction mixture stirred 1.5 hours under refluxing.Distill solvent then, resistates is water-soluble, and the water ethyl acetate extraction discards organic phase, and water is acidified with acetic acid to pH4, separate to obtain 5-(2-chloro-5-methoxyl group) phenoxy group-4,6-(1H, 5H)-pyrimidine dione, be white powder.MS：m／e=268(M)。D) with 3.75g 5-(2-chloro-5-methoxyl group) phenoxy group-4, and 6-(1H, 5H)-pyrimidine dione, 5.4g N-ethyl diisopropyl amine, 12.5ml POCl 3Mixture in the 20ml dioxan stirred 18 hours under refluxing.After distilling volatile component, resistates distributes between ethyl acetate and water, neutral washing.After distilling solvent, this compound is on silica gel, carry out purifying with methylene dichloride as eluent.Obtain 4,6-two chloro-5-(2-chloro-5-methoxyl group-phenoxy group)-pyrimidine are white crystals, and the fusing point from ethanol behind the recrystallization is 88-89 ℃.E) at-78 ℃, with the NH of about 500ml 3Adding embodiment 1d) 9.9g 4 is in 6-two chloro-5-(2-chloro-5-methoxyl group-phenoxy group)-solution of pyrimidine in 400ml ethanol.At-78 ℃ reaction mixture stirred 15 hour thereafter.And stirring at room 50 hours, final evaporation.Resistates distributes between ethyl acetate and water, and organic phase is handled.Obtain 6-chloro-5-(2-chloro-5-methoxyl group-phenoxy group)-pyrimidine-4-base amine thus, be yellow crystal.MS：285(M)。F), the 8.53 above-mentioned compounds that obtain are added in the solution of 0.82g sodium in 100ml ethylene glycol at 50 ℃.This solution is heated to 100 ℃, kept 20 hours.Thereafter at semi-saturation NH 4Distribute between Cl solution and the methylene dichloride, and handle.Obtain 2-[6-amino-5-(2-chloro-5-methoxyl group-phenoxy group)-4-pyrimidine-4-base oxygen of 8.3g white solid thus]-1-ethanol, do not need purifying to be about to its silylanizing., above-mentioned substance (8.3g) is dissolved in the 300ml methylene dichloride for this reason, handles, handle with the 10.05g TERT-BUTYL DIMETHYL CHLORO SILANE in room temperature at last with the 8.15g Dimethylamino pyridine.Stirring at room reaction soln 5 hours.With its filtration, concentrate this solution then, vaporized residue is at half saturated NH 4Distribute between Cl solution and the ethyl acetate, organic phase is handled.Crystallization from dichloromethane/hexane then obtains 7g 6-[2-(tertiary butyl-dimethyl-silicon alkoxyl group)-oxyethyl group]-5-(2-chloro-5-methoxyl group-phenoxy group)-pyrimidine-4-base amine.MS：410(M-CH 3)。
Embodiment 18
According to method similar to Example 2, obtain pyridine-2-aminocarbamic acid 2-[6-(the 5-tertiary butyl-thiophene-2-ylsulfonylamino)-5-(2-chloro-5-methoxyl group-phenoxy group)-Lian pyrimidine-4-base oxygen by the 5-tertiary butyl-thiophene-2-sulfonic acid 5-(2-chloro-5-methoxyl group-phenoxy group)-6-(2-hydroxyl-oxyethyl group)-pyrimidine-4-base acid amides and 2-pyridyl formic acid trinitride]-ethyl ester, be white crystals.MS：634．3(M+H)。
Embodiment 19
According to method similar to Example 2, compound and 4-pyridyl formic acid trinitride by embodiment 17 obtain pyridin-4-yl carboxylamine 2-[6-(the 5-tertiary butyl-thiophene-2-ylsulfonylamino)-5-(2-chloro-5-methoxyl group-phenoxy group)-Lian pyrimidine-4-base oxygen]-ethyl ester, be white crystals.MS：634．3(M+H)。
Embodiment 20
According to method similar to Example 17, with 6-[2-(tertiary butyl-dimethyl-silicon alkoxyl group)-oxyethyl group]-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-base amine is as reacted constituent, obtain the 5-tertiary butyl-thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-base acid amides, be white solid.MS：479(M)。
Embodiment 21
In the sodium glycolate solution that obtains by 1.5ml ethylene glycol and 46mg sodium, add the 180mg compound that above-mentioned steps obtains.Adding 1ml DMSO dissolves it fully.At 90 ℃ with mixture reaction 3 hours.After being cooled to room temperature, reaction medium is acidified to pH4, uses the resulting compound of ethyl acetate extraction then with aqueous citric acid solution.After distilling ethyl acetate, crystallization obtains N-[5-(2-chloro-5-methoxyl group-phenoxy group)-6-(2-hydroxyl-oxyethyl group)-pyrimidine-4-yl from ethanol]-5-sec.-propyl-pyridine-2-sulfuryl amine.Obtain the 175mg white crystals, this crystallization is 180 ℃ of decomposition.The preparation initial compounds: with 306mg 4,6-two chloro-5-(2-chloro-5-methoxyl group-phenoxy group)-pyrimidine, 320mg 5-sec.-propyl-2-pyridine-sulphonamide and 180mg potassium tert.-butoxide are dissolved among the 2mlDMSO, at 90 ℃ it are reacted 3 hours.After being cooled to room temperature, with aqueous citric acid solution with the reaction medium acidifying; With this compound of ethyl acetate extraction, and after distilling solvent, crystallization from ethanol.Obtain 250mg N-[6-chloro-5-(2-chloro-5-methoxyl group-phenoxy group)-pyrimidine-4-yl]-5-sec.-propyl-pyridine-sulphonamide, be white crystals, fusing point 174-175 ℃.
Embodiment 22
With 100mg N-[5-(2-chloro-5-methoxyl group-phenoxy group)-6-(2-hydroxyl-oxyethyl group)-pyrimidine-4-yl]-5-sec.-propyl-pyridine-2-sulfuryl amine and 38.5mg 2-pyridyl-formic acid trinitride be dissolved in the anhydrous dioxan of 1ml.Stir this solution 2 hours at 95 ℃, thereby discharge nitrogen.After distilling solvent, crystalline compounds from ethanol.Obtain 115mg pyridine-2-base-carboxylamine 2-[5-(2-chloro-5-methoxyl group-phenoxy group)-6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-pyrimidine-4-base oxygen]-ethyl ester, be white crystals, fusing point 190-191 ℃.
Embodiment 23
According to embodiment 21 similar methods, obtain 5-sec.-propyl-N-[6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-(3-methoxyl group-phenyl)-pyrimidine-4-yl]-pyridine-2-sulfuryl amine, fusing point 139-140 ℃ (crystallization from ethanol).The preparation initial compounds:
According to the 2nd section similar method of embodiment 21, by 330mg 4,6-two chloro-2-(3-methoxyl group-phenyl)-5-(2-methoxyl group-phenoxy group)-pyrimidine and 420mg (5-sec.-propyl-pyridine-2-sulfuryl amine) potassium obtain 400mg N-[6-chloro-5-(2-methoxyl group-phenoxy group)-2-(3-methoxyl group-phenoxy group)-pyrimidine-4-yl]-5-sec.-propyl-pyridine-2-sulfuryl amine.
Embodiment 24
According to embodiment 22 similar methods, by 115mg 5-sec.-propyl-N-[6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-(3-methoxyl group-phenyl)-pyrimidine-4-yl]-pyridine-2-sulfuryl amine and 38.5mg 2-pyridyl-formic acid trinitride, obtain 120mg pyridine-2-base-carboxylamine 2-[6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2-(3-methoxyl group-phenyl)-pyrimidine-4-base oxygen]-ethyl ester, fusing point 158-160 ℃ (crystallization from ethanol).
Embodiment 25a) according to embodiment 21 similar methods, by 4,6-two chloro-2-methyl sulfane base (sulphanyl)-5-(2-methoxyl group-phenoxy group)-pyrimidines and (5-sec.-propyl-pyridine-2-sulfuryl amine) potassium, obtain N-[6-chloro-5-(2-methoxyl group-phenoxy group)-2-methyl sulfane base-pyrimidine-4-yl]-5-sec.-propyl-pyridine-2-sulfuryl amine, 192 ℃ of fusing points (crystallization from ethanol).B) with sodium glycolate this compound is converted into 5-sec.-propyl-N-[6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-methyl sulfane base-pyrimidine-4-yl]-pyridine-2-sulfuryl amine, fusing point 76-78 ℃ (crystallization from ethanol).
Embodiment 26
According to embodiment 22 similar methods, by 100mg 5-sec.-propyl-N-[6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-methyl sulfane base-pyrimidine-4-yl]-pyridine-2-sulfuryl amine and 2-pyridyl-formic acid trinitride, obtain 106mg pyridine-2-base-carboxylamine 2-[6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2-methyl sulfane base-pyrimidine-4-base oxygen]-ethyl ester.Fusing point 213-214 ℃ (crystallization from ethanol).
Embodiment 27a) by 4,6-two chloro-2-(1,3-benzo dioxole-5-yl)-5-(2-methoxyl group-phenoxy group)-pyrimidine and (5-sec.-propyl-pyridine-2-sulfuryl amine) potassium, obtain N-[6-chloro-2-(1,3-benzo dioxole-5-yl)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-yl]-5-sec.-propyl-pyridine-2-sulfuryl amine.B) with sodium glycolate this compound is converted into N-[2-(1,3-benzo dioxole-5-yl)-6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-yl]-5-sec.-propyl-pyridine-2-sulfuryl amine, 184 ℃ of fusing points (crystallization from ethanol).
Embodiment 28
According to embodiment 22 similar methods, by 116mg N-[2-(1,3-benzo dioxole-5-yl)-6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-yl]-5-sec.-propyl-pyridine-2-sulfuryl amine and 2-pyridyl-formic acid trinitride, obtain 110mg pyridine-2-base-carboxylamine 2-[2-(1,3-benzo dioxole-5-yl)-6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-base oxygen]-ethyl ester.184 ℃ of fusing points (crystallization from ethanol).
Embodiment 29a) by 4,6-two chloro-2-morpholine-4-base-pyrimidines and (5-sec.-propyl-pyridine-2-sulfuryl amine) potassium obtain N-[6-chloro-5-(2-chloro-5-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-yl]-5-sec.-propyl-pyridine-2-sulfuryl amine.B) this compound and sodium glycolate reaction obtains N-[5-(2-oxygen-5-methoxyl group-phenoxy group)-6-(2-hydroxyl-oxyethyl group)-2-morpholine-4-base-pyrimidine-4-yl]-5-sec.-propyl-pyridine-2-sulfuryl amine, fusing point 189-190 ℃ (crystallization from ethanol).
Embodiment 30
According to embodiment 22 similar methods, with 2-pyridyl-formic acid trinitride with 116mg N-[5-(2-chloro-5-methoxyl group-phenoxy group)-6-(2-hydroxyl-oxyethyl group)-2-morpholine-4-base-pyrimidine-4-yl]-5-sec.-propyl-pyridine-2-sulfuryl amine is converted into pyridine-2-base-carboxylamine 2-[5-(2-chloro-5-methoxyl group-phenoxy group)-6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-2-morpholine-4-base-pyrimidine-4-base oxygen]-ethyl ester.Crystallization from ethanol obtains the 106mg white crystals, and this crystallization is 240 ℃ of decomposition.
Embodiment 31
According to embodiment 21 similar methods, by 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-yl]-acid amides and sodium glycolate, obtain 5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides, 190 ℃ of fusing points (crystallization from ethanol).Prepare initial compounds: a),, and be converted into 2-bromo-5-picoline with 2-amino-5-picoline diazotization according to the method (JACS 68 (1946), 2547) of F.H.Case.B) at 150 ℃, will be in this compound of the 4.8g in the 40ml propylene glycol and the reaction of 7.4g sodium sulfhydrate.After being cooled to room temperature, Dropwise 5 ml acetate in reaction mixture separates obtaining 2-sulfydryl-5-picoline, is yellow powder.C) with 30 minutes, 1.2 moles of clorox of Dropwise 5 0ml in being cooled to-10 ℃ the two-phase mixture of 40ml methylene dichloride, 20ml 37% aqueous hydrochloric acid and 3g 2-sulfydryl-5-picoline.Then, the water extracted organic phase is 3 times.Obtain 5-picoline SULPHURYL CHLORIDE after distilling solvent, be weak yellow liquid.D) with SULPHURYL CHLORIDE and the reaction of 25% solution of ammonium hydroxide, obtain 5-picoline-2-sulphonamide.E) will be O.7g 4,6-two chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine, 520mg 5-picoline-2-sulphonamide and 320mg potassium tert.-butoxide are dissolved among the 2mlDMSO, at 80 ℃ it are stirred 3 hours.After reaction mixture carried out conventional processing, obtain 410mg 5-methyl-pyridine-2-sulfonic acid [6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-yl]-acid amides.
Embodiment 32
According to embodiment 22 similar methods, by 105mg 5-methyl-pyridine-2-sulfonic acid (6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-yl]-acid amides and 30mg 2-pyridyl-formic acid trinitride, obtain 100mg pyridine-2-base-carboxylamine 2-[5-(2-methoxyl group-phenoxy group)-6-(5-methyl-pyridine-2-ylsulfonylamino)-2,2 ＇-Lian pyrimidine-4-base oxygen]-ethyl ester, be cream-coloured crystallization.Fusing point: 198 ℃ of decomposition.
Embodiment 33a) according to embodiment 22 similar methods, by 712mg 4,6-two chloro-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine and (5-methyl-pyridine-2-sulfuryl amine) potassium obtain 580mg 5-methyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides.B), obtain 5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides with this compound and sodium glycolate reaction.Fusing point 195-196 ℃ (crystallization from ethanol).
Embodiment 34
According to embodiment 22 similar methods, by 105mg 5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base-acid amides and 2-pyridyl-formic acid trinitride, obtain 117mg pyridine-2-base-carboxylamine 2-[5-(2-methoxyl group-phenoxy group)-6-(5-methyl-pyridine-2-ylsulfonylamino)-2-morpholine-4-base-pyrimidine-4-base oxygen]-ethyl ester.
Embodiment 35
With 105mg 5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base-acid amides of the solution-treated of 3ml 1.9 moles of phosgene in toluene in the 2ml methylene dichloride.After 1 hour, be completed into chloro-formic ester in room temperature.Then, distill excessive reagent; Resistates is dissolved in the mixture of chloroform and pyridine; Add 0.5g 3-(methylol)-furans, and make this mixture reaction 3 hours at 60 ℃.After routine is handled, (volume ratio is that methylene dichloride-ether of 4: 1 is used as eluent) this compound of purifying on silica gel.Obtain 65mg formic acid furans-3-ylmethyl ester 2-[5-(2-methoxyl group-phenoxy group)-6-(5-methyl-pyridine-2-sulfuryl amino)-2-morpholine-4-base-pyrimidine-4-base oxygen]-ethyl ester, MS:640.5[M-H)-].
Embodiment 36
Under 120 ℃ and argon atmospher, will be at the 9.2g4-[4-chloro-5-in the 130ml anhydrous dimethyl sulphoxide (2-chloro-5-methoxyl group-phenoxy group)-6-methyl-pyrimidine-2-base]-morpholine and 17.8g 5-sec.-propyl-heating of pyridine-2-sulfuryl amine potassium 16 hours.Thereafter, distill dimethyl sulfoxide (DMSO), resistates distributes between ethyl acetate and 1N hydrochloric acid, and organic phase is carried out the neutrality washing.With the organic phase drying, solvent evaporated, resistates is recrystallization from ethanol.Obtain 10.3g 5-sec.-propyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxyl group-phenoxy group)-6-methyl-2-morpholine-4-base-pyrimidine-4-base acid amides, MS:M=534.
Embodiment 37
In autoclave, at 170 ℃, compound that will obtain at the 1g embodiment 36 in the 40ml dioxan and 2.1g tin anhydride stirred 7 hours.Reaction mixture is filtered and concentrated filtrate.Resistates distributes between ethyl acetate and water.Dry organic phase, evaporating solvent, and on silica gel, with ethyl acetate/hexane purifying resistates.Obtain 0.53g 5-sec.-propyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxyl group-phenoxy group)-6-formyl radical-2-morpholine-4-base-pyrimidine-4-base acid amides, 194 ℃ of fusing points.
Embodiment 38
Handle the compound that the 0.1g embodiment 37 in 3ml ethanol obtains with the 0.014g sodium borohydride.80 ℃ of stirred reaction mixtures 1 hour.Thereafter, distill ethanol, resistates distributes between chloroform and 1N hydrochloric acid.Organic phase washes with water, and dry, evaporating solvent, resistates on silica gel, make eluent with chloroform-methanol, through chromatogram purification.From dichloromethane-ethanol, behind the recrystallization, obtain 0.072g 5-sec.-propyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxyl group-phenoxy group)-6-methylol-2-morpholine-4-base-pyrimidine-4-base acid amides, 105 ℃ of fusing points.
Embodiment 39
At 20 ℃, will be at 3.5ml POCl 3In 0.2g embodiment 38 compound and the 0.083g PCl that obtain 5Stirred together 2 hours.Distill POCl thereafter, 3, resistates distributes between ethyl acetate and sodium bicarbonate aqueous solution (sic).Organic phase washes with water, dry and evaporating solvent.Resistates on silica gel, make eluent with chloroform-methanol, through chromatogram purification.Obtain 0.150g 5-sec.-propyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxyl group-phenoxy group)-6-methylol-2-morpholine-4-base-pyrimidine-4-base acid amides, 205 ℃ of fusing points.
Embodiment 40
Obtain sodium glycolate solution by 0.35g ethylene glycol and 0.021g sodium, to wherein adding the compound that 0.130g embodiment 39 obtains.Under 80 ℃ and argon atmospher, stirred this reaction mixture 2 hours.Thereafter, distill ethylene glycol, resistates distributes between ethyl acetate and iN hydrochloric acid.Organic phase washes with water, with dried over sodium sulfate and distill solvent.Resistates is recrystallization from ether-sherwood oil.Obtain 0.104g 5-(2-chloro-5-methoxyl group-phenoxy group)-6-(2-hydroxyl-ethoxyl methyl)-2-morpholine-4-base-pyrimidine-4-base acid amides, 166 ℃ of fusing points.
Embodiment 41
According to method similar to Example 2, compound pyridine-2-base-carboxylamine 2-[5-(2-chloro-5-methoxyl group-phenoxy group)-6-(5-sec.-propyl-pyridine-2-sulfuryl the amino)-2-morpholine-4-base-pyrimidine-4-ylmethoxy that obtains by embodiment 40]-ethyl ester, MS:(M-H)-=713.
Embodiment 42
According to method similar to Example 2, compound pyridine-2-base-carboxylamine 5-(2-chloro-5-methoxyl group-phenoxy group)-6-(5-sec.-propyl-pyridine-2-the ylsulfonylamino)-2-morpholine-4-base-pyrimidine-4-ylmethyl ester that obtains by embodiment 38, MS:(M-H)-=669.
Embodiment 43
According to embodiment 40 similar methods, the compound that obtains by embodiment 39 and (RS)-2,2-dimethyl-1,3-dioxolane-4-sodium methylate, obtain 5-sec.-propyl-pyridine-2-sulfonic acid (RS)-5-(2-chloro-5-methoxyl group-phenoxy group)-6-(2,2-dimethyl-1,3-dioxolane-3-ylmethoxy-methyl)-2-morpholine-4-base-pyrimidine-4-base acid amides, MS:(M-H)-=663.
Embodiment 44
With the solution of compound in the 2ml dioxan of 2ml 1N salt acid treatment 0.05g embodiment 43 preparations, and be heated to 80 ℃, kept 15 minutes.After the evaporation, resistates is made eluent with chloroform-methanol on silica gel, through chromatogram purification, obtain 5-sec.-propyl-pyridine-2-sulfonic acid (RS)-5-(2-chloro-5-methoxyl group-phenoxy group)-6-(2,3-dihydroxyl-propoxy-methyl)-2-morpholine-4-base-pyrimidine-4-base acid amides, 116 ℃ of fusing points, MS:(M-H)-=623.
Embodiment 45
At 80 ℃, 345mg sodium is dissolved in 50ml not to be had in the water glycol.Solution is placed into cold slightly, adds 1.56g 5-sec.-propyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides.Stirred gained solution 24 hours at 140 ℃, under high vacuum, remove and desolvate, and resistates is dissolved in the 40ml water.At 5 ℃ after 4 hours, with this mixture suction strainer, crystallization is suspended in the 40ml water, use acetic acid ethyl dissolution, and when stirring, drip the 1N aqueous hydrochloric acid and handle, reduce to 3.5 up to pH.Water is with ethyl acetate extraction 3 times, organic phase wash with water 2 times, with saturated nacl aqueous solution washing 1 time.The organic phase that merges is dry and be concentrated into and produce crystallization (about 5ml).Suction strainer goes out crystallization, with ether washing and dry.Obtain 1.144g (70%) 5-sec.-propyl-pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides, be white crystals, fusing point 157-160 ℃, MS:(M-H)-=544.4.The preparation initial compounds:
At 80 ℃, with 1.18g 4,6-two chloro-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine and 2.12g (8.88mmol) 5-sec.-propyl-pyridine-2-sulfuryl amine sylvite solution heating in the anhydrous DMSO of 25ml 3 hours is up to the dichloride completely dissolve.Under high vacuum, remove DMSO, resistates 60ml water dissolution, the aqueous solution washs 3 times with ether.With 1N hydrochloric acid solution is acidified to pH3.5 then, product ethyl acetate extraction 3 times.Organic phase washes with water 2 times, with saturated nacl aqueous solution washing 1 time, merges at last, with dried over sodium sulfate and evaporation.The crystalline resistates digests with anhydrous diethyl ether, to remove the 5-sec.-propyl-pyridine-2-sulfuryl amine of trace fully.Leach the remaining crystallization in back and dry.Obtain 1.66g (96%) 5-sec.-propyl-pyridine-2-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides, be white crystals, fusing point 168-176 ℃, MS:(M-H)-=518.3.
Embodiment 46
According to embodiment 45 similar methods, adding under the condition of DMSO as solubilizing agent (ethylene glycol: DMSO 5: 2), after 120 ℃ are carried out 10 hours by a definite date reaction, obtain 5-tertiary butyl thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides, be the white solid foam, productive rate 54%, MS:565.5 (M+H)+.
Embodiment 47
According to embodiment 45 similar methods, after 140 ℃ are carried out 3 hours by a definite date reaction, obtain 2,5-dichloro-thiophene-3-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides, be white crystals, productive rate 43%, MS:575.3 (M-H)-.
Embodiment 48
According to embodiment 45 similar methods, after 140 ℃ are carried out 3.5 hours by a definite date reaction, obtain 3,5-dimethyl isoxazole-4-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides, be white crystals, fusing point 144-147 ℃, MS:520.4 (M-H)-.
Embodiment 49
At 50 ℃, 110mg sodium is dissolved in the 2.5ml ethylene glycol.Solution is cooled to room temperature, adds 260mg 2,5-dichloro-thiophene-3-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides., under high vacuum, remove ethylene glycol, and solid residue is dissolved in the 20ml water after 2 hours 50 ℃ of heating.By adding 0.3ml acetate precipitated product.After the filtration, wash with water, and it is dry under high vacuum at 50 ℃, obtain 182mg (67%) 2,5-dichloro-thiophene-3-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides, be cream-coloured crystallization, fusing point 157-160 ℃, MS:M+ (569), 470 (M+-(SO 2+ Cl)).The preparation initial compounds:
With 0.349g 4,6-two chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine and 0.405g 2, the 5-dichloro-thiophene-solution of 3-sulphonamide sylvite in the anhydrous DM-SO of 5ml kept 16 hours in room temperature.Add the 0.112g potassium tert.-butoxide afterwards, so within 5 minutes, react completely.Reaction mixture is poured in the 40ml ice-water, and used the 40ml extracted with diethyl ether, to remove excessive reagent.Water is saltoutd with saturated nacl aqueous solution (20ml), washs after filtration and with ether, separates obtaining 2,5-dichloro-thiophene-3-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides (0.54g cream-coloured powder).
In order to obtain the free sulphonamide, sodium salt is suspended in water, suspension acetate acidifying, and use ethyl acetate extraction, wherein be added with a small amount of methylene dichloride.Organic phase is with saturated nacl aqueous solution washing 2 times, with dried over mgso and reduction vaporization.Resistates washs simply with ether and hexane, and is dry then.Obtain 0.30g (54%) cream-coloured powder thus, 140 ℃ of fusing points (decomposition).MS：444(M+-(SO 2+Cl))。
Similarly, with 3,5-dimethyl isoxazole base-4-sulphonamide obtains 3,5-dimethyl isoxazole-4-sulfonic acid 6-chloro-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides, and productive rate 71% is cream-coloured, reddish powder, fusing point 184-187 ℃.MS：M+=488，393(M-(SO 2+OCH 3))。
Embodiment 50
According to embodiment 49 similar methods, obtain 3,5-dimethyl isoxazole-4-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides is cream-coloured powder, fusing point 200-204 ℃.MS：514(M+)，450(M+-SO 2)，419(450-CH 3O)。
Embodiment 51
888mg pyridine-the solution of 2-carbonyl azide thing in the anhydrous dioxan of 15ml was heated 15 minutes at 80 ℃.Make solution cold slightly, add the compound of 1.09g embodiment 45 preparations, heated these solution 4 hours at 90 ℃.Afterwards, it is evaporated to dried, resistates is dissolved in the ethyl acetate, washes with water 2 times and with saturated nacl aqueous solution washing 1 time, merges organic phase, and is dry and concentrate, thus the separated product crystallization.In order to carry out final purifying, with it on silica gel, make eluent with ethyl acetate/dichloromethane (1: 1), through chromatogram purification, obtain 931mg (70%) pyridine-2-aminocarbamic acid 2-[6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base oxygen thus] ethyl ester, be white crystals, fusing point 200-202 ℃.MS：664．4(M-H)-。IR (KBr) 1730cm-1 (carbamate).
Embodiment 52
According to embodiment 51 similar methods, compound by embodiment 49 preparations, obtain pyridine-2-aminocarbamic acid 2-[6-(2,5-dichloro-thiophene-3-ylsulfonylamino)-and 5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base oxygen] ethyl ester, be white crystals, fusing point 194-197 ℃, MS:690.1 (M+H)+, IR (KBr) 1732cm-1 (carbamate), productive rate 61%.
Embodiment 53
According to embodiment 51 similar methods, compound by embodiment 50 preparations, obtain pyridine-2-aminocarbamic acid 2-[5-(2-methoxyl group-phenoxy group)-6-(3,5-dimethyl-isoxzzole-4-ylsulfonylamino)-and 2,2 ＇-Lian pyrimidine-4-base oxygen] ethyl ester, be faint yellow crystallization, fusing point 217-218 ℃, MS:635.3 (M+H)+, IR (KBr) 1736cm-1 (carbamate), productive rate 68%.
Embodiment 54
According to embodiment 51 similar methods, compound by embodiment 46 preparations, obtain pyridine-2-aminocarbamic acid 2-[6-(5-tertiary butyl thiophene-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base oxygen] ethyl ester, be white foam, MS:683.5 (M-H)-, productive rate 90%.
Embodiment 55
According to embodiment 51 similar methods, compound by embodiment 47 preparations, obtain pyridine-2-aminocarbamic acid 2-[6-(2,5-dichloro-thiophene-3-ylsulfonylamino)-and 5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base oxygen] ethyl ester, be white crystals, fusing point 194-196 ℃.MS:695.3 (M-H)-, productive rate 55%.
Embodiment 56
According to embodiment 51 similar methods, compound by embodiment 48 preparations, obtain pyridine-2-aminocarbamic acid 2-[6-(3,5-dimethyl-isoxzzole-4-ylsulfonylamino)-and 5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base oxygen] ethyl ester, be white crystals, fusing point 106-109 ℃.MS:640.4 (M-H)-, productive rate 70%.
Embodiment 57
5-sec.-propyl-pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides (54.5mg) is dissolved in N, in the N-N,N-DIMETHYLACETAMIDE (5ml), add 14.4mg60%NaH suspension in room temperature, and stirred this mixture 20 minutes.At last, add 2-chloropyrimide (11.7mg).Stirring at room reaction mixture 18 hours, and pour in the frozen water.Add saturated ammonium chloride solution, use the ethyl acetate extraction mixture.Organic phase washes with water, with dried over mgso and the evaporation, resistates on silica gel, with methylene chloride (100/1) as eluent, through chromatogram purification.Obtain 5-sec.-propyl-pyridine-2-sulfonic acid { 5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-6-[2-(pyrimidine-2-base oxygen)-oxyethyl group]-pyrimidine-4-yl }-acid amides thus, be white crystals.MD：624(M+H)
Embodiment 58a) according to embodiment 45 similar methods, by 5-sec.-propyl-pyridine-2-sulfonic acid [6-chloro-2-(3-methoxyl group-benzyl)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-yl]-acid amides and the sodium in ethylene glycol are reacted, obtain 5-sec.-propyl-pyridine-2-sulfonic acid [6-(2-hydroxyl-oxyethyl group)-2-(3-methoxyl group-benzyl)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-yl]-acid amides, be white foam.MS:579.3 (M-H) prepares raw material: b) in room temperature, 10.8g 3-p-methoxy-phenyl acetonitrile is dissolved in the ethanol (100ml), makes this solution saturated with hydrogenchloride.In this mixture of stirring at room 12 hours, solution is cooled to 0 ℃ then, draws out sedimentary crystallization.Recrystallization in the acetone of meditating.Obtain 2-(3-methoxyl group-phenyl)-ethylenemine acid ethyl ester hydrochloride salt thus, be white crystalline solid.MS:193 (M) c) 2-(3-methoxyl group-phenyl)-ethylenemine acid ethyl ester hydrochloride salt (12g) is dissolved in the ethanol (100ml), handles with the 14ml ammonia liquor at-75 ℃.Make this mixture return to room temperature with 5 minutes, on rotatory evaporator, evaporate then.Resistates is suspended in the acetone, draws out sedimentary crystallization, and is dry under high vacuum.Obtain 2-(3-methoxyl group-phenyl)-B amidine hydrochloric acid salt thus, be white solid.Complexion 64 (M) d) sodium (2.3g) is dissolved in the methyl alcohol (40ml), adds 2-(3-methoxyl group-phenyl)-B amidine hydrochloric acid salt (10g) and (2-methoxyl group phenoxy group)-dimethyl malonate (12.67g) continuously in room temperature.This mixture concentrates on rotatory evaporator stirring at room 5 hours, and crude product is poured in the water.Water washs with ethyl acetate, regulates pH to 1, draws out sedimentary crystallization, and dry under high vacuum.Obtain 2-(3-methoxyl group-benzyl)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4 thus, the 6-glycol is cream-coloured crystallization.MS:354 (M) e) with 2-(3-methoxyl group-benzyl)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4,6-glycol (14g) is dissolved in the acetonitrile (150ml).Add collidine (5.24ml) and phosphoryl chloride (21.7ml) in room temperature, and with this mixture stirring at room 9 hours.Mixture is poured in the frozen water, used ethyl acetate extraction.Organic phase is with the washing of semi-saturation potassium bicarbonate solution, with dried over mgso and evaporation.Resistates is dissolved in hexane/ether, filters, and evaporated filtrate on rotatory evaporator obtains 4 thus, and 6-two chloro-2-(3-methoxyl group-benzyl)-5-(2-methoxyl group-phenoxy group)-pyrimidine are the light brown crystallization.MS:390 (M) f) according to embodiment 45 similar methods, by with 4,6-two chloro-2-(3-methoxyl group-benzyl)-5-(2-methoxyl group-phenoxy group)-pyrimidine and 5-sec.-propyl-pyridine-2-sulfuryl amine nak response, obtain 5-sec.-propyl-pyridine-2-sulfonic acid [6-chloro-2-(3-methoxyl group-benzyl)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-yl]-acid amides, be yellow foam.MS：553．1(M-H)
Embodiment 59a) according to embodiment 45 similar methods, by with 5-sec.-propyl-pyridine-2-sulfonic acid [6-chloro-2-(3-methoxyl group-benzyl)-5-phenoxy group)-pyrimidine-4-yl]-acid amides and sodium reaction in ethylene glycol, obtain 5-sec.-propyl-pyridine-2-sulfonic acid [6-(2-hydroxyl-oxyethyl group)-2-(3-methoxyl group-benzyl)-5-phenoxy group)-pyrimidine-4-yl]-acid amides, be faint yellow crystallization.MS:549.2 (M-H) prepares raw material: b) according to the similar method of embodiment 58d, by 2-(3-methoxyl group-phenyl)-B amidine hydrochloric acid salt and the reaction of phenoxy propionic acid dimethyl ester, obtain 2-(3-methoxyl group-benzyl)-5-phenoxy group)-pyrimidine-4, the 6-glycol is yellow foam.MS:324 (M) c) according to embodiment 58e) similar method, by with phosphoryl chloride with 2-(3-methoxyl group-benzyl)-5-phenoxy pyrimidine-4, the chlorination of 6-glycol obtains 4,6-two chloro-2-(3-methoxyl group-benzyl)-5-phenoxy group-pyrimidine are yellow crystal.MS:360 (M) d) according to embodiment 45 similar methods, by with 4,6-two chloro-2-(3-methoxyl group-benzyl)-5-phenoxy group-pyrimidine and 5-sec.-propyl-pyridine-2-sulfuryl amine nak response, obtain 5-sec.-propyl-pyridine-2-sulfonic acid [6-chloro-2-(3-methoxyl group-benzyl)-5-phenoxy group)-pyrimidine-4-yl]-acid amides, be yellow foam.MS：523(M-H)
Embodiment 60
5-sec.-propyl-pyridine-2-sulfonic acid [6-(2-hydroxyl-oxyethyl group)-2-(3-methoxyl group-benzyl)-5-phenoxy group)-pyrimidine-4-yl]-acid amides (55mg) is dissolved in the anhydrous methylene chloride (3ml).At 0 ℃ of boron tribromide (50mg) that is added in the methylene dichloride (2ml), and reacted again 4 hours, on rotatory evaporator, evaporate in room temperature, resistates on silica gel, make eluent with dichloromethane/ethyl acetate, through chromatogram purification.Obtain 5-sec.-propyl-pyridine-2-sulfonic acid [2-(3-hydroxyl-benzyl)-6-(2-hydroxyl-oxyethyl group)-5-phenoxy group-pyrimidine-4-yl]-acid amides thus, be white crystals.MS：525．1(M-H)
Embodiment A
The tablet that contains following ingredients according to the ordinary method preparation: the every chip I of composition compound 10.0-100.0mg lactose 125.0mg W-Gum 75.0mg talcum 4.0mg Magnesium Stearate 1.0mg
Embodiment B
The capsule that contains following ingredients according to the ordinary method preparation: the every chip I of composition compound 25.0mg lactose 150.0mg W-Gum 20.0mg talcum 5.0mg
Embodiment C
Injection liquid with following composition: formula I compound 3.0mg gelatin 150.0mg phenol 4.7mg water for injection adds to 1.oml
Embodiment D
500mg formula I compound is suspended in 3.5ml Myglyol 812 and the 0.08g benzylalcohol.This suspension packed into be equipped with in the container of dosage valve.Under pressure, charge into 5.0g Freon12 by valve.Jolting is dissolved in the mixture of Myglyol-benzylalcohol Freon.This automiser spray contains 100 the single dosage of having an appointment, and these can use separately as far as possible.

Claims (25)

1. formula I compound R wherein 1Be meant heterocyclic radical; R 2Be meant hydrogen, low alkyl group, lower alkoxy, lower alkylthio, lower alkoxy low alkyl group, low alkyl group alkylsulfonyl lower alkoxy, phenyl, low alkyl group phenyl, lower alkoxyphenyl, low-grade alkylidene dioxy base phenyl, phenyl lower alkyl, low alkyl group phenyl lower alkyl, lower alkoxyphenyl low alkyl group, low-grade alkylidene dioxy base phenyl lower alkyl, heterocyclic radical or heterocyclic radical low alkyl group; R 3Be meant low alkyl group, lower alkoxy, formyl radical, junior alkyl halides, hydroxyl low-grade alkyl, amino low alkyl group or-CH 2The O-A-low alkyl group ,-(CH 2) m-O-(CR aR b) nOH ,-(CH 2) m-O-(CR aR b) nOR 9,-(CH 2) m-O-(CR aR b) nNH 2,-(CH 2) m-O-(CR aR b) n-B-R 9R 4-R 8Be meant hydrogen, lower alkoxy or halogen; R 9Be meant heterocyclic radical; Phenyl or the phenyl that is replaced by low alkyl group, lower alkoxy and/or halogen, or low alkyl group; R aAnd R bBe meant hydrogen or low alkyl group; A is meant ketone acetalization 1,2-dihydroxyl-ethylidene; B is meant-OC (O) O-, OC (O) NH-,-NHC (O) NH-or-NHC (O) O-; N is meant 2,3 or 4; Be meant 0 or 1 with m.
2. according to the compound of claim 1, R wherein 2Be hydrogen, low alkyl group, lower alkoxy, lower alkylthio, lower alkoxy low alkyl group, low alkyl group alkylsulfonyl lower alkoxy, phenyl, lower alkoxyphenyl, low-grade alkylidene two oxa-phenyl or heterocyclic radicals, R 3Be low alkyl group, lower alkoxy, formyl radical, junior alkyl halides, hydroxyl low-grade alkyl, amino low alkyl group or-CH 2The O-A-low alkyl group ,-(CH 2) m-O-(CR aR b) nOH ,-(CH 2) m-O-(CR aR b) nNH 2Or-(CH 2) m-O-(CR aR b) n-B-R 9And R 1, R 4-R 9, R a, R b, A, B, n and m such as claim 1 definition.
3. according to the compound of claim 1, R wherein 1Be pyridyl, pyrimidyl, isoxazolyl, furyl or thienyl, they are unsubstituted or by low alkyl group, halogen, amino, single low-grade alkyl amino or two elementary alkyl amido or lower alkane acyl substituted.
4. according to any one compound, wherein R among the claim 1-3 2Be hydrogen, pyrimidyl, pyridyl, morpholino, thiomorpholine generation, piperidino-(1-position only), pyrrolidino, benzo dioxolyl, lower alkoxyphenyl or lower alkylthio.
5. according to any one compound, wherein R among the claim 1-3 3Be-O-(CR aR b) nOH ,-O-(CR aR b) nNH 2Or-O (CH 2) 2-B-R 9, and R 9Be pyridyl, pyrimidyl or furyl.
6. according to the compound of claim 5, R wherein 3Be-O (CH 2) 2-B-R 9, and B is-(O) C (O) NH-.
7. according to the compound of claim 6, R wherein 9It is the 2-pyridyl.
8. according to the compound of claim 7, be pyridine-2-aminocarbamic acid 2-[6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base oxygen] ethyl ester.
9. according to the compound of claim 7, be
Pyridine-2-aminocarbamic acid 2-[6-(the 5-tertiary butyl-thiophene-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2,2 '-Lian pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[5-(2-methoxyl group-phenoxy group)-6-(5-amyl group-thiophene-2-ylsulfonylamino)-2,2 ＇-Lian pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[6-[5-(2,2-dimethyl propylene acyl group)-thiophene-2-ylsulfonylamino]-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2,2 '-Lian pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[5-(2-methoxyl group-phenoxy group)-6-pyridine-2-ylsulfonylamino)-2,2 '-Lian pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[5-(2-methoxyl group-phenoxy group)-6-pyridin-3-yl sulfonamido)-2,2 '-Lian pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[6-(the 5-tertiary butyl-thiophene-2-ylsulfonylamino)-5-(2-chloro-5-methoxyl group-phenoxy group)-pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2-(3-methoxyl group-phenyl)-pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2-methyl sulfane base-pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[2-(1,3-benzo dioxole-5-yl)-6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[5-(2-chloro-5-methoxyl group-phenoxy group)-6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-2-morpholine-4-yl pyrimidines-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[5-(2-methoxyl group-phenoxy group)-6-(5-methyl-pyridine-2-ylsulfonylamino)-2,2 ＇-Lian pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[5-(2-methoxyl group-phenoxy group)-6-(5-methyl-pyridine-2-ylsulfonylamino)-2-morpholine-4-yl pyrimidines-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[5-(2-chloro-5-methoxyl group-phenoxy group)-6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-2-morpholine-4-yl pyrimidines-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 5-(2-chloro-5-methoxyl group-phenoxy group)-6-(5-sec.-propyl-pyridine-2-ylsulfonylamino)-2-morpholine-4-yl pyrimidines-4-ylmethyl ester,
Pyridine-2-aminocarbamic acid 2-[6-(2,5-dichloro-thiophene-3-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2,2 '-Lian pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[5-(2-methoxyl group-phenoxy group)-6-(3,5-dimethyl-isoxzzole-4-ylsulfonylamino)-2,2 ＇-Lian pyrimidine-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[6-(5-tertiary butyl thiophene-2-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-yl pyrimidines-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[6-(2,5-dichloro-thiophene-3-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-yl pyrimidines-4-base oxygen] ethyl ester,
Pyridine-2-aminocarbamic acid 2-[6-(3,5-dimethyl-isoxzzole-4-ylsulfonylamino)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-yl pyrimidines-4-base oxygen] ethyl ester.
10. according to the compound of claim 6, R wherein 9It is the 4-pyridyl.
11., be pyridin-4-yl carboxylamine 2-[6-(the 5-tertiary butyl-thiophene-2-ylsulfonylamino)-5-(2-chloro-5-methoxyl group-phenoxy group)-pyrimidine-4-base oxygen according to the compound of claim 10] ethyl ester.
12. according to the compound of claim 5, wherein R 3Be-O (CH 2) 2-B-R 9, and B is-(O) C (O) O-.
13. the compound according to claim 12 is
Formic acid furans-3-ylmethyl ester 2-[5-(2-methoxyl group-phenoxy group)-6-(5-methyl-pyridine-2-sulfuryl amino)-2-morpholine-4-yl pyrimidines-4-base oxygen] ethyl ester,
5-sec.-propyl-pyridine-2-sulfonic acid 5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-6-[2-(pyrimidine-2-base oxygen)-oxyethyl group]-pyrimidine-4-yl }-acid amides.
14. according to the compound of claim 5, wherein R 3Be-O (CH 2) 2-B-R 9, and B is-NHC (O) NH-.
15. the compound according to claim 14 is
The 5-tertiary butyl-thiophene-2-sulfonic acid 5-(2-methoxyl group-phenoxy group)-6-[2-(3-pyridine-2-base-urea groups)-oxyethyl group]-2,2 ＇-Lian pyrimidine-4-base acid amides,
5-sec.-propyl-pyridine-2-sulfonic acid 5-(2-methoxyl group-phenoxy group)-6-[2-(3-pyridine-2-base-urea groups)-oxyethyl group]-2,2 ＇-Lian pyrimidine-4-base acid amides.
16. according to each compound among the claim 1-3, wherein R 3It is hydroxyl-oxethyl.
17. the compound according to claim 16 is
The 5-tertiary butyl-thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 '-Lian pyrimidine-4-base acid amides,
5-amyl group-thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides,
5-(2,2-dimethyl-propionyl)-thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 '-Lian pyrimidine-4-base acid amides,
5-sec.-propyl-pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 '-Lian pyrimidine-4-base acid amides,
Pyridine-3-sulphonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides,
The 5-tertiary butyl-thiophene-2-sulfonic acid 5-(2-chloro-5-methoxyl group-phenoxy group)-6-(2-hydroxyl-oxyethyl group)-pyrimidine-4-base acid amides,
The 5-tertiary butyl-thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-base acid amides,
N-[5-(2-chloro-5-methoxyl group-phenoxy group)-6-(2-hydroxyl-oxyethyl group)-pyrimidine-4-yl]-5-sec.-propyl-pyridine-2-sulfuryl amine,
5-sec.-propyl-N-[6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-(3-methoxyl group-phenyl)-pyrimidine-4-yl]-pyridine-2-sulfuryl amine,
5-sec.-propyl-N-[6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-methyl sulfane base-pyrimidine-4-yl]-pyridine-2-sulfuryl amine,
N-[2-(1,3-benzo dioxole-5-yl)-6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-yl]-5-sec.-propyl-pyridine-2-sulfuryl amine,
N-[5-(2-chloro-5-methoxyl group-phenoxy group)-6-(2-hydroxyl-oxyethyl group)-2-morpholine-4-base-pyrimidine-4-yl]-5-sec.-propyl-pyridine-2-sulfuryl amine,
5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides,
5-methyl-pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides,
5-sec.-propyl-pyridine-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides, 5-tertiary butyl thiophene-2-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides, 2,5-dichloro-thiophene-3-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides
3,5-dimethyl isoxazole-4-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2-morpholine-4-base-pyrimidine-4-base acid amides, 2,5-dichloro-thiophene-3-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 ＇-Lian pyrimidine-4-base acid amides
3,5-dimethyl isoxazole-4-sulfonic acid 6-(2-hydroxyl-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 '-Lian pyrimidine-4-base acid amides,
5-sec.-propyl-pyridine-2-sulfonic acid [6-(2-hydroxyl-oxyethyl group)-2-(3-methoxyl group-benzyl)-5-(2-methoxyl group-phenoxy group)-pyrimidine-4-yl]-acid amides,
5-sec.-propyl-pyridine-2-sulfonic acid [6-(2-hydroxyl-oxyethyl group)-2-(3-methoxyl group-benzyl)-5-phenoxy group-pyrimidine-4-base acid amides,
5-sec.-propyl-pyridine-2-sulfonic acid [2-(3-hydroxyl-benzyl)-6-(2-hydroxyl-oxyethyl group)-5-phenoxy group-pyrimidine-4-yl]-acid amides.
18. require among the 1-3 each compound, wherein R according to power 3It is amino ethoxy.
19. the compound according to claim 18 is
The 5-tertiary butyl-thiophene-2-sulfonic acid 6-(2-amino-oxyethyl group)-5-(2-methoxyl group-phenoxy group)-2,2 '-Lian pyrimidine-4-base acid amides.
20. according to each compound among the claim 1-3, wherein R 3Be low alkyl group, lower alkoxy, formyl radical, junior alkyl halides, hydroxyl low-grade alkyl or-CH 2The O-A-low alkyl group.
21. the compound according to claim 20 is
5-sec.-propyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxyl group-phenoxy group)-6-methyl-2-morpholine-4-base-pyrimidine-4-base acid amides,
5-(2-chloro-5-methoxyl group-phenoxy group)-6-formyl radical-2-morpholine-4-base-pyrimidine-4-base acid amides,
5-sec.-propyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxyl group-phenoxy group)-6-methylol-2-morpholine-4-base-pyrimidine-4-base acid amides,
5-sec.-propyl-pyridine-2-sulfonic acid 5-(2-chloro-5-methoxyl group-phenoxy group)-6-chloromethyl-2-morpholine-4-base-pyrimidine-4-base acid amides,
5-(2-chloro-5-methoxyl group-phenoxy group)-6-(2-hydroxyl-ethoxyl methyl)-2-morpholine-4-base-pyrimidine-4-base acid amides.
22. containing among the claim 1-21, pharmaceutical composition, said composition appoint-compound of item and carrier and the assistant agent of using always.
23. appoint among the claim 1-21-the preparation method of compound, it is characterized in that: a) with formula II compound
R wherein 1, R 2And R 4-R 8Implication defines as respective items in the claim 1-21 item respectively, and Hal is halogen, reacts with following formula: compound
HO(CR aR b) nXH
Wherein n, R aAnd R bImplication defines as respective items in the claim 1-21 item respectively, and X is meant O or NH, perhaps b) with formula III compound
Figure 9512025000111
R wherein 2-R 8Implication defines as respective items in the claim 1-21 item respectively, reacts with following formula: compound
R 1SO 2Z
R wherein 1Implication defines as respective items in the claim 1-21 item respectively, and therefore Y represents that halogen and Z represent amino, and perhaps Y represents that amino and Z represent halogen, perhaps c) with formula IV compound
Figure 9512025000112
R wherein 1, R 2, R 4-R 8, R a, R b, X, m and n implication define as respective items in the claim 1-21 item respectively, c1) with formula R 9The isocyanic ester of NCO or formula R 9The urea chloride reaction of NCOCl, wherein R 9Respective items defines in implication such as the claim 1-21 item, perhaps c2) and phosgene reaction, then with formula R 9The alcohol reaction of OH; Perhaps with formula R 9The chloro-formic ester reaction of OC (O) Cl; Perhaps d) R wherein 3The formula I compound of expression junior alkyl halides and following formula: compound reaction
HO (CH) 2-A-low alkyl group
Wherein A represents ketone acetalization 1,2-dihydroxyl-ethylidene, and, if desired, can change the substituting group that exists on the gained formula I compound and/or gained formula I compound is converted into salt.
24. each compound is used for the purposes of the medicine of the active diseases related of production for treating and endothelin as activeconstituents among the claim 1-21, described disease is a circulatory diseases.
25. the purposes of claim 24, wherein said circulatory diseases are hypertension, local asphyxia, vasospasm and stenocardia.
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