CN104230847B - N-substituted benzoyl phenothiazine compound and its production and use - Google Patents
N-substituted benzoyl phenothiazine compound and its production and use Download PDFInfo
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- CN104230847B CN104230847B CN201410409024.2A CN201410409024A CN104230847B CN 104230847 B CN104230847 B CN 104230847B CN 201410409024 A CN201410409024 A CN 201410409024A CN 104230847 B CN104230847 B CN 104230847B
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- 0 C*1(C)C2=C[C@](C3)C3C=C2Nc2c1cccc2 Chemical compound C*1(C)C2=C[C@](C3)C3C=C2Nc2c1cccc2 0.000 description 2
- HXWQMQOJXDADTL-UHFFFAOYSA-N Cc1cc(S(Nc2cccc(C(N3c(cccc4)c4Sc4c3cccc4)=O)c2)(=O)=O)ccc1 Chemical compound Cc1cc(S(Nc2cccc(C(N3c(cccc4)c4Sc4c3cccc4)=O)c2)(=O)=O)ccc1 HXWQMQOJXDADTL-UHFFFAOYSA-N 0.000 description 1
- KFPMLWUKHQMEBU-UHFFFAOYSA-N Cc1cccc(S(Cl)(=O)=O)c1 Chemical compound Cc1cccc(S(Cl)(=O)=O)c1 KFPMLWUKHQMEBU-UHFFFAOYSA-N 0.000 description 1
- BQLSHZXNXHFBLN-UHFFFAOYSA-N Nc(cc1)ccc1C(N1c(cccc2)c2Sc2c1cccc2)=O Chemical compound Nc(cc1)ccc1C(N1c(cccc2)c2Sc2c1cccc2)=O BQLSHZXNXHFBLN-UHFFFAOYSA-N 0.000 description 1
- CPDCRMVLNNDSHL-UHFFFAOYSA-N Nc1cc(C(N2c(cccc3)c3Sc3c2cccc3)=O)ccc1 Chemical compound Nc1cc(C(N2c(cccc3)c3Sc3c2cccc3)=O)ccc1 CPDCRMVLNNDSHL-UHFFFAOYSA-N 0.000 description 1
- WPHUUIODWRNJLO-UHFFFAOYSA-N [O-][N+](c(cccc1)c1S(Cl)(=O)=O)=O Chemical compound [O-][N+](c(cccc1)c1S(Cl)(=O)=O)=O WPHUUIODWRNJLO-UHFFFAOYSA-N 0.000 description 1
- MWWNNNAOGWPTQY-UHFFFAOYSA-N [O-][N+](c1cccc(S(Cl)(=O)=O)c1)=O Chemical compound [O-][N+](c1cccc(S(Cl)(=O)=O)c1)=O MWWNNNAOGWPTQY-UHFFFAOYSA-N 0.000 description 1
- KDHKEVHNWUCVPZ-UHFFFAOYSA-N [O-][N+](c1ccccc1S(Nc(cc1)ccc1C(N1c(cccc2)c2Sc2c1cccc2)=O)(=O)=O)=O Chemical compound [O-][N+](c1ccccc1S(Nc(cc1)ccc1C(N1c(cccc2)c2Sc2c1cccc2)=O)(=O)=O)=O KDHKEVHNWUCVPZ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
- C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
- C07D279/18—[b, e]-condensed with two six-membered rings
- C07D279/22—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom
- C07D279/30—[b, e]-condensed with two six-membered rings with carbon atoms directly attached to the ring nitrogen atom with acyl radicals attached to the ring nitrogen atom
Abstract
The present invention relates to class N-substituted benzoyl phenothiazine compound and its production and use.Specifically; relating to class N-substituted benzoyl phenothiazine compound with Formulas I structure and preparation method thereof, the N-substituted benzoyl phenothiazine compound of Formulas I structure is as the pharmaceutical composition of active ingredients and the purposes in the disease that prevention or treatment are relevant to arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, arginine vasopressin V2 receptor, sympathetic nervous system or renin angiotensin aldosterone system thereof.
Description
Technical field
The invention belongs to pharmaceutical technology field, more precisely, relate to class N-substituted benzoyl phenothiazine compound and its production and use.
Background technology
Arginine vasopressin (argininevasopressin, AVP), is again vassopressin, vasopressin, is a kind of peptide hormone of pituitary secretion, through receptor G protein-second message,second messenger's approach, regulates the several functions such as body body fluid balance.AVP plays key player in regulating the secretion etc. of heavily absorption, the isotonic concentration of body fluid, volumetric blood, blood pressure, cellular contraction, cell proliferation and adrenocortical hormone of human body free water.
Arginine vasopressin by being combined the various physiological actions of performance with vasopressin receptor.Vasopressin receptor can be divided into three kinds of hypotypes of V1a, V1b and V2.V1a receptor is distributed in vascular smooth muscle, myocyte and platelet, participates in vasoconstriction, platelet aggregation and glycogenolysis；V1b receptor is distributed in anterior pituitary, the secretion of regulation and control adrenocortical hormone；V2 receptor is mainly distributed on the kidney collecting tubule of kidney, the heavily absorption of regulation and control free water.Suppress arginine vasopressin receptors, a series of physiological action can be produced.
Research shows, argnine vasopressin receptor antagonist is in prevention or treatment hypertension, thunder syndrome, dysmenorrhea, premature labor, corticotropin releasing hormone parasecretion, adrenal hyperplasia, depression, chronic heart failure, the hyponatremia that liver cirrhosis, antidiuretic hormone secretion disorder syndrome or chronic heart failure, liver cirrhosis and antidiuretic hormone secretion disorder cause there is positive role.Benzazepine compounds conivaptan, tolvaptan etc. have become the focus direction of above-mentioned disease therapeuticing medicine research and development.This compounds has the antagonistic activity to arginine vasopressin receptors, and therefore can be applicable to treat above-mentioned disease.
As the medicine of above-mentioned disease, benzazepine compounds is all to there is also certain deficiency in activity, side effect or in physicochemical characteristic.The present invention proposes N-substituted benzoyl phenothiazine compound, has arginine vasopressin antagonism, and the treatment and prevention of above-mentioned disease are had positive role.
Summary of the invention
It is an object of the present invention to provide a class N-substituted benzoyl phenothiazine compound.
The preparation method that it is a further object of the present invention to provide this compounds.
It is yet another object of the invention to provide the medical usage of this compounds, this compounds is generally of arginine vasopressin receptors antagonistic activity, can be used for preventing or treating hypertension, thunder syndrome, dysmenorrhea, premature labor, corticotropin releasing hormone parasecretion, adrenal hyperplasia, depression, the diseases such as the hyponatremia that chronic heart failure, liver cirrhosis, antidiuretic hormone secretion disorder syndrome or chronic heart failure, liver cirrhosis and antidiuretic hormone secretion disorder cause.
Another object of the present invention is in that, discloses the pharmaceutical composition being main active with this compounds.
In conjunction with the object of the invention, present invention is described in detail.
Present invention relates particularly to the compound with Formulas I structure:
Wherein,
R1For hydrogen atom, halogen atom, hydroxyl, low alkyl group, the low alkyl group of halogen substiuted, amino, nitro, alkoxyl, can arbitrarily with the amino of low-grade alkyl substituent；Such as: hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl group, normal-butyl, isopropyl, isobutyl group, the tert-butyl group, pi-allyl, 3-cyclobutenyl, cyclopropyl, ring the third methyl, one methyl fluoride, difluoromethyl, trifluoromethyl, 3-fluoropropyl, chloromethyl, bromomethyl, 4-brombutyl, 3-chlorobutyl, amino, nitro, methoxyl group, ethyoxyl, methylamino, dimethylamino, diethylin etc.；
R2For hydrogen atom, halogen atom, hydroxyl, low alkyl group, the low alkyl group of halogen substiuted, amino, nitro, alkoxyl, can arbitrarily with the amino of low-grade alkyl substituent；Such as: hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl group, normal-butyl, isopropyl, isobutyl group, the tert-butyl group, pi-allyl, 3-cyclobutenyl, cyclopropyl, ring the third methyl, one methyl fluoride, difluoromethyl, trifluoromethyl, 3-fluoropropyl, chloromethyl, bromomethyl, 4-brombutyl, 3-chlorobutyl, amino, nitro, methoxyl group, ethyoxyl, methylamino, dimethylamino, diethylin etc.；R2Replacement to phenyl ring can be monosubstituted or polysubstituted；
R3For low alkyl group, halogen or hydroxyl replace low alkyl group orGroup；Such as: methyl, ethyl, propyl group, normal-butyl, isopropyl, isobutyl group, the tert-butyl group, pi-allyl, 3-cyclobutenyl, cyclopropyl, ring the third methyl, a methyl fluoride, difluoromethyl, trifluoromethyl, 3-fluoropropyl, chloromethyl, bromomethyl, 4-brombutyl, 3-chlorobutyl andDeng；
R4For hydrogen atom, halogen atom, hydroxyl, low alkyl group, the low alkyl group of halogen substiuted, amino, nitro, alkoxyl, can arbitrarily with the amino of low-grade alkyl substituent；Such as: hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, methyl, ethyl, propyl group, normal-butyl, isopropyl, isobutyl group, the tert-butyl group, pi-allyl, 3-cyclobutenyl, cyclopropyl, ring the third methyl, one methyl fluoride, difluoromethyl, trifluoromethyl, 3-fluoropropyl, chloromethyl, bromomethyl, 4-brombutyl, 3-chlorobutyl, amino, nitro, methoxyl group, ethyoxyl, methylamino, dimethylamino, diethylin etc.；R4Replacement to phenyl ring can be monosubstituted or polysubstituted；
X is CO or SO2。
Preferably,
R1Low alkyl group for hydrogen atom, halogen, low alkyl group or halogen substiuted；
R2For hydrogen atom, halogen atom, low alkyl group, the low alkyl group of halogen substiuted, nitro, alkoxyl, can arbitrarily with the amino of low-grade alkyl substituent；R2The replacement of phenyl ring is preferably monosubstituted or two replacements；
R3For the low alkyl group of hydrogen atom, low alkyl group or halogen substiuted or such as formulaShown group；
R4For hydrogen atom, halogen atom, low alkyl group, the low alkyl group of halogen substiuted, nitro, alkoxyl, can arbitrarily with the amino of low-grade alkyl substituent；R4The replacement of phenyl ring is preferably monosubstituted or two replacements；
X is CO or SO2。
It is furthermore preferred that
R1For chlorine, fluorine, hydrogen, methyl or trifluoromethyl；
R2For hydrogen, fluorine, chlorine, C1～C4 alkyl, nitro, methoxyl group；R2The replacement of phenyl ring is preferably monosubstituted or two replacements；
R3For C1～C4 alkyl of hydrogen atom, C1～C4 alkyl or halogen substiuted or such as formulaShown group；
R4For hydrogen, fluorine, chlorine, C1～C4 alkyl, nitro, methoxyl group；R4The replacement of phenyl ring is preferably monosubstituted or two replacements；
X is CO or SO2。
Present invention provides applying equation I or comprise the pharmaceutical composition of this material, in order to prevent or to treat hypertension, thunder syndrome, dysmenorrhea, premature labor, corticotropin releasing hormone parasecretion, adrenal hyperplasia, depression, chronic heart failure, the diseases such as the hyponatremia that liver cirrhosis, antidiuretic hormone secretion disorder syndrome or chronic heart failure, liver cirrhosis and antidiuretic hormone secretion disorder cause.
The syntheti c route of the compound with Formulas I structure is as follows:
Wherein, the synthesis of II has seen bibliographical information.Such as Synlett, 2011 (1), 134-138. and AngewandteChemie, InternationalEdition, 2010,49 (7), 1291-1294. etc..According to the method for report in document, this specialty stakeholder all can prepare.
II is dissolved in the non-protonic solvents such as dichloromethane, chloroform, acetone, acetonitrile, oxolane, DMF, pyridine or toluene, it is dividedly in some parts III or the solution of its corresponding organic solvent, with triethylamine, pyridine, potassium alcoholate, sodium alkoxide, the organic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide or inorganic base are acid binding agent, and-5～60 DEG C of reactions prepare compound IV.
The preparation of V can adopt following methods: is dissolved in by IV in methanol or ethanol, adds the lower reduction of iron powder backflow and prepares V；Or, IV is dissolved in methanol or ethanol, adds iron chloride, activated carbon, and add hydrazine hydrate or ammonium formate as hydrogen donor, at 20-80 DEG C, reduction prepares V；Or, IV is dissolved in ethanol, methanol or ethyl acetate, adds palladium charcoal, add hydrazine hydrate or ammonium formate or be passed directly into hydrogen, at 0-80 DEG C, reduction prepares V.V can also pass through stannous chloride reduce in acid condition IV prepare.
V is dissolved in the non-protonic solvents such as dichloromethane, chloroform, acetone, acetonitrile, oxolane, DMF, pyridine or toluene, it is dividedly in some parts VI or the solution of its corresponding organic solvent, with triethylamine, pyridine, potassium alcoholate, sodium alkoxide, the organic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, sodium hydroxide or potassium hydroxide or inorganic base are acid binding agent, and-5～60 DEG C of reactions prepare compound I.
Although the compound of the present invention can be directly administered without any preparation, but described various compounds preferably use in the form of a pharmaceutical preparation, and route of administration can be parenteral route (such as vein, intramuscular delivery) and oral administration.
The pharmaceutical composition preparation of the compounds of this invention is as follows: use standard and conventional technology; make the compounds of this invention acceptable solid or liquid-carrier on galenic pharmacy be combined, and so as at random acceptable adjuvant and excipient are combined and prepare into microgranule or microsphere on galenic pharmacy.Solid dosage forms includes tablet, discrete particles, capsule, slow releasing tablet, slow-release micro-pill etc..Solid carrier can be at least one material, and it can serve as diluent, flavouring agent, solubilizing agent, lubricant, suspending agent, binding agent, disintegrating agent and coating agent.Inert solid carrier includes magnesium phosphate, magnesium stearate, smoothers sugar, lactose, pectin, propylene glycol, polyoxyethylene sorbitan monoleate, dextrin, starch, gelatin, cellulose substances such as methylcellulose, microcrystalline Cellulose, low melt point paraffin, Polyethylene Glycol, mannitol, cocoa butter etc..Liquid dosage form includes solvent, suspension such as injection, powder etc..
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, amount or the concentration of compound used regulate in a wider scope, generally, the weight range of reactive compound is the 0.5%-90% (weight) of compositions.Another preferably ranges for 0.5%-70%.
The compound with Formulas I structure that the present invention proposes, has arginine vasopressin receptors antagonism, especially V2 receptor antagonism is become apparent from.
People's arginine vasopressin receptors antagonistic experiment
The HeLa cell of people's AVP receptor is expressed in preparation, measure part of compounds in the present invention and the inhibition constant Ki of people's arginine vasopressin receptors (or is called Dissociation equilibrium constant, Ki value is more big, represents the affinity interaction of receptor is more little), concrete outcome is shown in following table:
Diuresis is tested
People's arginine vasopressin receptors antagonistic experiment shows that this compounds has the affinity interaction to vasopressin receptor, especially that vassopressin V2 receptor affinity interaction is notable.Antagonism V2 receptor can produce diuresis, therefore carries out again diuresis experiment.
Test-compound weighs appropriate compound before use and mills with 2% Tween 80, is suspended in 30%PEG.Dosage: 50mg/kg, matched group gives the solvent of same volume.
Tested SD rat body weight 260 ± 20g；Purchased from the red laboratory animal company limited in mountains and rivers, Tianjin, the quality certification number: SCXK (Tianjin) 2009-0001.Cage for animal is raised, and normal feedstuff is experimental mouse full-valence pellet feed, purchased from the red laboratory animal company limited in mountains and rivers, Tianjin, freely drinks water, humidity 60-80%, the light and shade cycle of natural lighting and about 12h.Before test, fasting is about 12h, but can freely drink water, and according to front 12h urine volume random packet, before administration, gavage increases Water l oad to the normal saline with 5% body weight, and to every rat in special time period chamber pot after gastric infusion, graduated cylinder is quantitative.
Experimental result is shown in following table.
Results of animal shows, compared with matched group, this compounds has obvious diuresis.This experiment has further demonstrated that this compounds in conjunction with arginine vasopressin receptors, thus producing antagonism, can show certain diuretic activity.
Above-mentioned two experiments show that, this compounds is generally of arginine vasopressin receptors antagonistic activity, there is again diuresis simultaneously, therefore, this compounds has prevention or treatment hypertension, thunder syndrome, dysmenorrhea, premature labor, corticotropin releasing hormone parasecretion, adrenal hyperplasia, depression, the potential use of the diseases such as the hyponatremia that chronic heart failure, liver cirrhosis, antidiuretic hormone secretion disorder syndrome or chronic heart failure, liver cirrhosis and antidiuretic hormone secretion disorder cause.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is further elaborated, but is not intended to the present invention.
Preparation embodiment
In the embodiment of the present invention, all solvents are before use all through redistillation, and the anhydrous solvent used all obtains by standard method dried；Except specified otherwise, being responded is all carry out under nitrogen protection and carry out TLC tracking, and the purification of product all uses silica gel (300-400 order) column chromatography except specified otherwise；Wherein silica gel (300-400 order) is produced by Haiyang Chemical Plant, Qingdao, and GF254 thin-layer silicon offset plate is produced by subsidiary factory of Haiyang Chemical Plant, Qingdao；Prepared compound is all confirmed through mass spectrum (MS).
Embodiment 1
The preparation of IV-1:
II-1 (100g, 500mmol) is placed in 1000mL reaction bulb, adds CH2Cl2(500mL) stirring makes it dissolve, add triethylamine (76g, 750mmol), stir under ice-water bath, it is dividedly in some parts intermediate III-1 (102g, 550mmol), temperature stirring 1h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 500ml cold water, fully shakes layering, divide and take organic layer, such continuous washing three times.By organic over anhydrous dried over sodium sulfate, place overnight.Filter, evaporated under reduced pressure solvent, obtain light yellow solid.Products therefrom ethyl alcohol recrystallization, obtains white solid 161g.Purity 98.4% (HPLC normalization method), yield 92.1%.ESI-MS ([M+H]+): 349.1.
Embodiment 2
The preparation of IV-2:
II-1 (20g, 100mmol) is placed in 250mL reaction bulb, adds CHCl3(100mL) stirring makes it dissolve, add pyridine (8.7g, 110mmol), stir at 50 DEG C molten clearly, it is dividedly in some parts intermediate III-2 (19.5g, 105mmol), temperature stirring 5h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 100ml cold water, fully shakes layering, divide and take organic layer, such continuous washing three times.By organic over anhydrous dried over sodium sulfate, stand overnight.Filter, evaporated under reduced pressure solvent, obtain light yellow solid crude product.Gained crude product purification by silica gel column chromatography, obtains white solid 29.8g.Purity 99.3% (HPLC normalization method), yield 85.3%.ESI-MS ([M+H]+): 349.1.
Embodiment 3
The preparation of IV-3:
II-2 (20g, 86mmol) it is placed in 250mL reaction bulb, add pyridine (60mL), stirring makes it dissolve, it is cooled to-5 DEG C, is dividedly in some parts intermediate III-3 (17.2g, 86mmol), temperature stirring 4h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 300ml cold water, stirring, there is solid to precipitate out.Filtering, filter cake is washed, is dried, and obtains yellow crude.By this crude product ethyl alcohol recrystallization, obtain white solid 32.2g.Purity 98.0% (HPLC normalization method), yield 94.8%.ESI-MS ([M+H]+): 397.0.
Embodiment 4
The preparation of IV-4:
II-3 (20g, 94mmol) it is placed in 250mL reaction bulb, adding oxolane (80mL) stirring makes it dissolve, add potassium tert-butoxide (15.7g, 141mmol), stir under ice-water bath, it is dividedly in some parts intermediate III-4 (21.7g, 98mmol), temperature stirring 2h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 200ml cold water, stirring, there is solid to precipitate out.Filtering, filter cake is washed, is dried, and obtains yellow-brown solid crude product.By this crude product purification by silica gel column chromatography, obtain white solid 22.3g.Purity 99.0% (HPLC normalization method), yield 59.7%.ESI-MS ([M+H]+): 397.0.
Embodiment 5
The preparation of IV-5:
II-4 (20g, 75mmol) it is placed in 100mL reaction bulb, adding DMF (60mL) stirring makes it dissolve, add potassium carbonate (15.5g, 113mmol), stir at 60 DEG C, intermediate III-5 (14g in batches, 75mmol), after reaction 1h, TLC detection display reaction terminates (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 200ml cold water, stirring, there is solid to precipitate out.Filtering, filter cake is washed, is dried, and obtains brown solid crude product.By this crude product ethyl alcohol recrystallization, obtain white solid 28.2g.Purity 98.7% (HPLC normalization method), yield 90.4%.ESI-MS ([M+H]+): 417.0.
Embodiment 6
The preparation of V-1:
Adding in 2000ml reaction bulb by IV-1 (100g, 287mmol), add 600ml ethanol, 150ml hydrochloric acid, heating makes it dissolve to 50 DEG C.Dropping SnCl2·2H2Ethanol (400ml) solution of O (226g, 1mol), system engenders white opacity.Dripping and finish, insulation reaction 7 hours, TLC detection display reaction terminates (developing solvent ethyl acetate: petroleum ether=1:2).
Reactant liquor is poured in 2000ml water, regulates pH to 8 by strong caustic, extract with dichloromethane (500ml × 3), merge organic facies, be dried overnight with anhydrous sodium sulfate.Filter, decompression distillation, obtain light yellow solid crude product, this crude product is placed in 500ml ethanol and refluxes refines, obtain V-1 white solid 71.4g, purity (HPLC normalization method) 98.6%, yield 92.7%.ESI-MS ([M+H]+): 319.1.
Embodiment 7
The preparation of V-2:
Adding in 500ml reaction bulb by IV-2 (20g, 57mmol), add 200ml methanol, heating is to 50 DEG C, and stirring makes it dissolve.Add 5% palladium charcoal 2g, drip hydrazine hydrate (7.2g, 143mmol) at this temperature.Continue reaction 3h, TLC detection display reaction and terminate (developing solvent ethyl acetate: petroleum ether=1:2).
Reacting liquid filtering removes solid insoluble, and filtrate decompression distillation obtains light yellow solid crude product, this crude product is placed in recrystallization in 100ml ethanol, obtains V-2 white solid 17.2g, purity 98.0% (HPLC normalization method), yield 94.7%.ESI-MS ([M+H]+): 319.1.
Embodiment 8
The preparation of V-3:
IV-3 (20g, 50mmol) is put in 500ml there-necked flask, adds 200ml ethanol, add thermosol clear.Iron chloride (1g), activated carbon (2g) are added in reaction system, continues heating to refluxing.Dripping hydrazine hydrate (7.5g, 150mmol) at this temperature, reaction 3h, TLC detection display reaction terminates (developing solvent ethyl acetate: petroleum ether=1:2).
Reacting liquid filtering removes solid insoluble, and decompression distillation obtains light yellow solid crude product.Column chromatography purification, obtains V-3 white solid 14.2g, purity 99.9% (HPLC normalization method), yield 77.4%.ESI-MS ([M+H]+): 367.1.
Embodiment 9
The preparation of V-4:
Putting in 500ml there-necked flask by reduced iron powder (8.4g, 150mmol), add 150ml ethanol, 50ml water, glacial acetic acid (0.6g, 10mmol), heating is to refluxing.IV-4 (20g, 50mmol) is dividedly in some parts in reaction system, continues to keep thermotonus 4h, TLC detection display reaction to terminate (developing solvent ethyl acetate: petroleum ether=1:2).
Reacting liquid filtering removes iron cement, and decompression distillation obtains brown yellow solid crude product, is dissolved in dichloromethane by this crude product thing, washes (100ml × 3), and anhydrous sodium sulfate is dried overnight.Filter, organic facies evaporated under reduced pressure, obtain light yellow crude product.Column chromatography purification, obtains V-4 white solid 15.7g, purity 98.7% (HPLC normalization method), yield 85.5%.ESI-MS ([M+H]+): 367.1.
Embodiment 10
The preparation of V-5:
Adding in 500ml reaction bulb by IV-5 (20g, 48mmol), add 200ml methanol, stirring makes it dissolve.Add 5% palladium charcoal 2g, be cooled to 0 DEG C.The continual hydrogen that passes at this temperature, sustained response 24h, system is re-absorption hydrogen not.Stopped reaction, TLC detection display reaction terminates (developing solvent ethyl acetate: petroleum ether=1:2).
Reacting liquid filtering removes solid insoluble, and filtrate decompression distillation obtains crude white solid, this crude product is placed in recrystallization in 80ml ethanol, obtains V-5 white solid 17.4g, purity 99.9% (HPLC normalization method), yield 93.6%.ESI-MS ([M+H]+): 387.1.
Embodiment 11:
The preparation of I-1
V-1 (5g, 16mmol) is placed in 100mL reaction bulb, adds CH2Cl2(50mL) stirring makes it dissolve, add triethylamine (2.4g, 24mmol), stir at-5 DEG C, dropping intermediate VI-1 (2.3g, 18mmol), temperature stirring 30min, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 50ml cold water, fully shakes layering, divide and take organic layer, such continuous washing three times.By organic over anhydrous dried over sodium sulfate, place overnight.Filter, evaporated under reduced pressure solvent, obtain light yellow solid crude product.Gained crude product silica gel column chromatography, obtains light yellow solid 5.7g.Purity 99.0% (HPLC normalization method), yield 86.3%, purity 99.7%, fusing point 212.4-213.7 DEG C,1HNMR(400MHz,DMSO-d6), 1.13 (t, J=7.2Hz, 3H), 3.09 (q, J=7.2Hz, 2H), 7.05 (d, J=8.8Hz, 2H), 7.21-7.27 (m, 6H), 7.43-7.45 (m, 2H), 7.55-7.58 (m, 2H), 10.04 (s, 1H) .ESI-MS ([M+H]+): 411.1.
Embodiment 12:
The preparation of I-2
V-1 (5g, 16mmol) it is placed in 100mL reaction bulb, adding oxolane (40mL) stirring makes it dissolve, add pyridine (2.5g, 32mmol), stir at 20 DEG C, dropping intermediate VI-2 (2.8g, 18mmol), temperature stirring 4h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 100ml cold water, stirring, there is yellow-brown solid to precipitate out.Filtering, filter cake is washed, is dried, and obtains yellow-brown solid crude product.By this crude product purification by silica gel column chromatography, obtain light yellow solid 5.3g.Purity 98.6% (HPLC normalization method), yield 76.1%.ESI-MS ([M+H]+): 439.1.
Embodiment 13:
The preparation of I-3
V-1 (5g, 16mmol) it is placed in 100mL reaction bulb, adding toluene (50mL) stirring makes it dissolve, add sodium bicarbonate (2.7g, 32mmol), stir at 30 DEG C, dropping intermediate VI-3 (2.9g, 18mmol), temperature stirring 8h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
By reacting liquid filtering, removing solid insoluble, filtrate is poured in 50ml cold water, fully shakes layering, divides and takes organic layer, such continuous washing three times.By organic over anhydrous dried over sodium sulfate, place overnight.Filter, evaporated under reduced pressure solvent, obtain light yellow solid.Products therefrom purification by silica gel column chromatography, obtains light yellow solid 5.9g.Purity 98.9% (HPLC normalization method), yield 82.7%, fusing point 213.8-216.3 DEG C,1HNMR(400MHz,DMSO-d6), 6.02-6.12 (m, 2H), 6.72-6.79 (m, 1H), 6.99 (d, J=8.4Hz, 1H), 7.20-7.27 (m, 6H), 7.42-7.44 (m, 2H), 7.54-7.58 (m, 2H), 10.28 (s, 1H) .ESI-MS ([M+H]+): 445.0.
Embodiment 14:
The preparation of I-4
V-1 (5g, 16mmol) it is placed in 100mL reaction bulb, adding DMF (50mL) stirring makes it dissolve, add potassium tert-butoxide (2.7g, 24mmol), stir under ice-water bath, it is dividedly in some parts intermediate VI-4 (3.2g, 18mmol), temperature stirring 2h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 200ml cold water, stirring, there is solid to precipitate out.Filtering, filter cake is washed, dry, obtains brown solid crude product.By this crude product silica gel column chromatography, obtain white solid 6.0g.Purity 98.8% (HPLC normalization method), yield 81.5%.ESI-MS ([M+H]+): 459.1.
Embodiment 15:
The preparation of I-5
V-1 (5g, 16mmol) is placed in 100mL reaction bulb, adds CHCl3(50mL) stirring makes it dissolve, add potassium carbonate (3.3g, 24mmol), it is warming up to 60 DEG C, it is dividedly in some parts intermediate VI-5 (3.2g, 17mmol), temperature stirring 3h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
By reacting liquid filtering, removing solid insoluble, filtrate is poured in 100ml cold water, fully shakes layering, divides and takes organic layer, such continuous washing three times.By organic over anhydrous dried over sodium sulfate, stand overnight.Filter, evaporated under reduced pressure solvent, obtain light yellow solid crude product.Gained crude product purification by silica gel column chromatography, obtains light yellow solid 5.5g.Purity 98.3% (HPLC normalization method), yield 72.5%, fusing point 224.2-225.1,1HNMR(400MHz,DMSO-d6), 2.34 (s, 3H), 6.94 (d, J=8.8Hz, 2H), 7.11-7.26 (m, 6H), 7.32-7.46 (m, 4H), 7.53-7.59 (m, 4H), 10.45 (s, 1H) .ESI-MS ([M+H]+): 473.1.
Embodiment 16:
The preparation of I-6
V-1 (5g, 16mmol) it is placed in 100mL reaction bulb, adding acetonitrile (50mL) stirring makes it dissolve, add sodium hydroxide (0.96g, 24mmol), stir under ice-water bath, it is dividedly in some parts intermediate VI-6 (3.1g, 16mmol), temperature stirring 4h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
By reacting liquid filtering, removing insoluble matter, filtrate is poured in 200ml cold water, and stirring has solid to precipitate out.Filtering, filter cake is washed, is dried, and obtains yellow solid crude product.By this crude product silica gel column chromatography, obtain slightly yellow solid 6.5g.Purity 98.8% (HPLC normalization method), yield 85.7%.ESI-MS ([M+H]+): 477.1.
Embodiment 17:
The preparation of I-7
V-1 (5g, 16mmol) it is placed in 100mL reaction bulb, adding dioxane (50mL) stirring makes it dissolve, add potassium hydroxide (1.3g, 24mmol), stir at 20 DEG C, it is dividedly in some parts intermediate VI-7 (3.4g, 16mmol), temperature stirring 2h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
By reacting liquid filtering, removing solid insoluble, filtrate is poured in 200ml cold water, and stirring has yellow solid to precipitate out.Filtering, filter cake is washed, is dried, and obtains yellow solid crude product.By this crude product silica gel column chromatography, obtain white solid 6.3g.Purity 99.3% (HPLC normalization method), yield 80%.ESI-MS ([M+H]+): 493.0.
Embodiment 18:
The preparation of I-8
V-1 (5g, 16mmol) it is placed in 100mL reaction bulb, add pyridine (20mL), stirring makes it dissolve, stir under room temperature, be dividedly in some parts intermediate VI-8 (2.5g, 18mmol), after reaction 2h, TLC detection display reaction terminates (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 200ml cold water, stirring, there is solid to precipitate out.Filtering, filter cake is washed, is dried, and obtains light yellow solid crude product.By this crude product purification by silica gel column chromatography, obtain slightly yellow solid 5.4g.Purity 98.3% (HPLC normalization method), yield 68.2%.ESI-MS ([M+H]+): 493.0.
Embodiment 19:
The preparation of I-9
V-1 (5g, 16mmol) is placed in 100mL reaction bulb, adds CH2Cl2(50mL) stirring makes it dissolve, and adds triethylamine (2.4g, 24mmol), it is warming up to 50 DEG C, is dividedly in some parts intermediate VI-9 (4g, 18mmol), temperature stirring 1h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 50ml cold water, fully shakes layering, divide and take organic layer, such continuous washing three times.By organic over anhydrous dried over sodium sulfate, place overnight.Filter, evaporated under reduced pressure solvent, obtain light yellow solid crude product.Gained crude product alcohol reflux is refined, and obtains light yellow solid 7.1g.Purity 99.0% (HPLC normalization method), yield 88.4%.1HNMR(400MHz,DMSO-d6), 6.97 (m, J=8.8Hz, 2H), 7.00-7.25 (m, 6H), 7.37 (dd, J1=0.8Hz, J2=8.0Hz, 1H), 7.52-7.56 (m, 2H), 7.76-7.98 (m, 4H), 10.95 (s, 1H) .ESI-MS ([M+H]+): 504.1.
Embodiment 20:
The preparation of I-10
V-1 (5g, 16mmol) is placed in 100mL reaction bulb, adds CH2Cl2(50mL) stirring makes it dissolve, and adds sodium carbonate (3.4g, 32mmol), it is warming up to 60 DEG C, adds intermediate VI-10 (4g, 18mmol) in batches, temperature stirring 1h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
By reacting liquid filtering, removing solid insoluble, filtrate is poured in 50ml cold water, fully shakes layering, divides and takes organic layer, such continuous washing three times.By organic over anhydrous dried over sodium sulfate, place overnight.Filter, evaporated under reduced pressure solvent, obtain light yellow solid crude product.Gained crude product alcohol reflux is refined, and obtains light yellow solid 7.5g.Purity 98.3% (HPLC normalization method), yield 93.3%.1HNMR(400MHz,DMSO-d6), 6.98 (d, J=8.4Hz, 2H), 7.13-7.23 (m, 6H), 7.35 (d, J=7.6Hz, 2H), 7.54 (dd, J1=1.0Hz, J2=7.8Hz, 2H), 7.85 (t, J=7.8Hz, 1H), 8.07 (d, J=8.0Hz, 1H), 8.45-8.48 (m, 2H), 10.79 (s, 1H) .ESI-MS ([M+H]+): 504.1.
Embodiment 21:
The preparation of I-11
V-1 (5g, 16mmol) it is placed in 100mL reaction bulb, adding oxolane (40mL), stirring makes it dissolve, and adds sodium hydrate solid (1g, 24mmol), stir under ice-water bath, dropping intermediate VI-11 (4g, 18mmol), temperature stirring 1h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 200ml cold water, stirring, there is solid to precipitate out.Filtering, filter cake is washed, is dried, and obtains light yellow solid crude product.By this crude product silica gel column chromatography, obtain light yellow solid 6.4g.Purity 99.4% (HPLC normalization method), yield 79.9%.1HNMR(400MHz,DMSO-d6), 6.97 (d, J=8.4Hz, 2H), 7.15-7.23 (m, 6H), 7.32-7.38 (m, 2H), 7.53-7.55 (m, 2H), 7.93-8.01 (m, 2H), 8.35 (d, J=8.8Hz, 2H), (10.83 s, 1H) .ESI-MS ([M+H]+): 504.1.
Embodiment 22:
The preparation of I-12
V-1 (5g, 16mmol) it is placed in 100mL reaction bulb, add pyridine (20mL), stirring makes it dissolve, stir at 20 DEG C, be dividedly in some parts intermediate VI-12 (3.9g, 16mmol), temperature stirring 1h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 200ml cold water, stirring, there is solid to precipitate out.Filtering, filter cake is washed, is dried, and obtains light yellow solid crude product.By this crude product silica gel column chromatography, obtain white solid 6.1g.Purity 99.5% (HPLC normalization method), yield 72.2%.1HNMR(400MHz,DMSO-d6), 6.96 (d, J=8.8Hz, 1H), 7.12-7.16 (m, 4H), 7.20-7.24 (m, 2H), 7.34 (d, J=7.6Hz, 2H), 7.54 (dd, J1=1.2Hz, J2=7.6Hz, 2H), 7.65 (d, J=8.8Hz, 1H), 7.76 (dd, J1=2.4Hz, J2=8.8Hz, 1H), 7.94 (d, J=2.8Hz, 1H), 11.01 (s, 1H) .ESI-MS ([M+H]+): 527.0.
Embodiment 23:
The preparation of I-13
V-2 (5g, 16mmol) is placed in 100mL reaction bulb, adds CH2Cl2(50mL) stirring makes it dissolve, and adds triethylamine (3.2g, 32mmol), at room temperature stir, dropping intermediate VI-13 (3.4g, 18mmol), temperature stirring 2h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 50ml cold water, fully shakes layering, divide and take organic layer, such continuous washing three times.By organic over anhydrous dried over sodium sulfate, place overnight.Filter, evaporated under reduced pressure solvent, obtain light yellow solid crude product.Gained crude product ethyl alcohol recrystallization, obtains light yellow solid 6.8g.Purity 98.6% (HPLC normalization method), yield 90.2%.ESI-MS ([M+H]+): 473.1.
Embodiment 24:
The preparation of I-14
V-2 (5g, 16mmol) it is placed in 100mL reaction bulb, add pyridine (40mL), stirring makes it dissolve, stir at 25 DEG C, be dividedly in some parts intermediate VI-14 (3.4g, 18mmol), after reaction 1h, TLC detection display reaction terminates (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 200ml cold water, stirring, there is solid to precipitate out.Filtering, filter cake is washed, is dried, and obtains light yellow solid crude product.By this crude product ethyl alcohol recrystallization, obtain slightly yellow solid 6.2g.Purity 98.9% (HPLC normalization method), yield 82.2%.ESI-MS ([M+H]+): 473.1.
Embodiment 25:
The preparation of I-15
V-3 (5g, 14mmol) is placed in 100mL reaction bulb, adds CH2Cl2(50mL) stirring makes it dissolve, add potassium bicarbonate (2.8g, 28mmol), heating is to 45 DEG C, add intermediate VI-15 (3.2g in batches, 15mmol), temperature stirring 2h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
By reacting liquid filtering elimination insoluble matter, filtrate is poured in 50ml cold water, fully shakes layering, divide and take organic layer, such continuous washing three times.By organic over anhydrous dried over sodium sulfate, place overnight.Filter, evaporated under reduced pressure solvent, obtain light yellow solid crude product.Gained crude product silica gel column chromatography, obtains white solid 6.1g.Purity 99.3% (HPLC normalization method), yield 80.7%.ESI-MS ([M+H]+): 541.0.
Embodiment 26:
The preparation of I-16
V-4 (5g, 14mmol) it is placed in 100mL reaction bulb, add pyridine (40mL), stirring makes it dissolve, stir under ice-water bath, be dividedly in some parts intermediate VI-16 (3.3g, 14mmol), after reaction 1h, TLC detection display reaction terminates (developing solvent ethyl acetate: petroleum ether=1:3).
Reactant liquor is poured in 200ml cold water, stirring, there is solid to precipitate out.Filtering, filter cake is washed, is dried, and obtains light yellow solid crude product.This crude product alcohol reflux is refined, obtains white solid 7.4g.Purity 99.2% (HPLC normalization method), yield 92.7%.ESI-MS ([M+H]+): 567.1.
Embodiment 27:
The preparation of I-17
V-5 (5g, 13mmol) it is placed in 100mL reaction bulb, adding acetonitrile (50mL) stirring makes it dissolve, add sodium hydroxide (0.84g, 26mmol), stir at-5 DEG C, dropping intermediate VI-17 (3.3g, 14mmol), temperature stirring 4h, TLC detection display reaction is kept to terminate (developing solvent ethyl acetate: petroleum ether=1:3).
By reacting liquid filtering, removing solid insoluble, filtrate is poured in 200ml cold water, and stirring has yellow solid to precipitate out.Filtering, filter cake is washed, is dried, and obtains yellow solid crude product.This crude product alcohol reflux is refined, obtains slightly yellow solid 6.8g.Purity 99.0% (HPLC normalization method), yield 88.9%.ESI-MS ([M+H]+): 586.1.
In order to be more fully explained the pharmaceutical composition of the present invention, providing below following example of formulations, described embodiment is merely to illustrate, rather than is used for limiting the scope of the present invention.Described preparation can use any reactive compound in the compounds of this invention and salt thereof, it is preferred to use the compound described in embodiment 11～27.
Embodiment 28:
Hard gelatin capsule is prepared by following compositions:
Preparation technology: dried in advance by supplementary material, crosses 100 mesh sieves standby.After mentioned component being mixed by recipe quantity, it is packed in hard gelatin capsule.
Embodiment 29:
Tablet is prepared by following compositions:
Preparation technology: dried in advance by supplementary material, crosses 100 mesh sieves standby.First the adjuvant of recipe quantity is fully mixed.Being added in adjuvant by crude drug with incremental dilution method, each added-time fully mixes 2～3 times, it is ensured that medicine and adjuvant fully mix, cross 20 mesh sieves, dry 2h in 55 DEG C of ventilated drying ovens, dry granule crosses 16 mesh sieve granulate, measure intermediates content, mix homogeneously, tabletting on tablet machine.
Embodiment 30:
The preparation of injection:
Preparation method: take in the water for injection that active component joins solubilized solution Polysorbate and propylene glycol, adds medicinal basic adjustment pH value and makes it dissolve to 4～8.Add activated carbon, stirring and adsorbing 30min, carbon removal, fine straining, embedding, sterilizing.
Embodiment 31:
The preparation of injection lyophilized powder:
Compound I-15100mg
Medicinal basic 0.1-7.0%
Mannitol 55-85%
Preparation method: take active component and add water for injection, regulates pH value with medicinal basic and makes it dissolve to 4-8.Adding mannitol, carry out autoclaving by the requirement of injection, add activated carbon, adopt filtering with microporous membrane, filtrate carries out subpackage, adopts freeze-drying, prepares loose block, sealing, to obtain final product.
Claims (7)
1. there is the compound of Formulas I structure:
Wherein,
R1For the amino that hydrogen atom, halogen atom, hydroxyl, C1-C4 alkyl, the C1-C4 alkyl of halogen substiuted, amino, nitro, C1-C4 alkoxyl, C1-C4 alkyl replace；
R2For the amino that hydrogen atom, halogen atom, hydroxyl, C1-C4 alkyl, the C1-C4 alkyl of halogen substiuted, amino, nitro, C1-C4 alkoxyl, C1-C4 alkyl replace；R2Replacement to phenyl ring can be monosubstituted or polysubstituted；
R3For the C1-C4 alkyl of hydrogen atom, C1-C4 alkyl, halogen or hydroxyl replacement or such as formulaShown group；
R4For the amino that hydrogen atom, halogen atom, hydroxyl, C1-C4 alkyl, the C1-C4 alkyl of halogen substiuted, amino, nitro, C1-C4 alkoxyl, C1-C4 alkyl replace；R4Replacement to phenyl ring can be monosubstituted or polysubstituted；
But wherein do not include following compound:
2. the compound with Formulas I structure according to claim 1, it is characterised in that in Formulas I:
R1It is preferably the C1-C4 alkyl of hydrogen atom, halogen atom, C1-C4 alkyl or halogen substiuted；
R2It is preferably the amino of hydrogen atom, halogen atom, C1-C4 alkyl, the C1-C4 alkyl of halogen substiuted, nitro, C1-C4 alkoxyl, the replacement of C1-C4 alkyl；R2The replacement of phenyl ring is preferably monosubstituted or two replacements；
R3It is preferably the C1-C4 alkyl of hydrogen atom, C1-C4 alkyl or halogen substiuted or such as formulaShown group；
R4It is preferably hydrogen atom, halogen atom, C1-C4 alkyl, the C1-C4 alkyl of halogen substiuted, nitro, C1-C4 alkoxyl, the amino that C1-C4 alkyl replaces；R4The replacement of phenyl ring is preferably monosubstituted or two replacements；
But wherein do not include following compound:
3. the compound with Formulas I structure according to claim 1 and 2, it is characterised in that in Formulas I:
R1It is preferably chlorine, fluorine, hydrogen, methyl or trifluoromethyl；
R2It is preferably hydrogen, fluorine, chlorine, C1～C4 alkyl, nitro, methoxyl group；R2The replacement of phenyl ring is preferably monosubstituted or two replacements；
R3It is preferably C1～C4 alkyl of hydrogen atom, C1～C4 alkyl or halogen substiuted or such as formulaShown group；
R4It is preferably hydrogen, fluorine, chlorine, C1～C4 alkyl, nitro, methoxyl group；R4The replacement of phenyl ring is preferably monosubstituted or two replacements；
But wherein do not include following compound:
4. the preparation method of the compound with Formulas I structure according to any one of claims 1 to 3, it is characterised in that:
Compound II per and Compound II per I are obtained by reacting compound IV, compound IV at-5～60 DEG C and reduces at 0～80 DEG C and obtain compound V, and compound V and compound VI is obtained by reacting compound I, above-mentioned R at-5～60 DEG C1、R2And R3Definition and claims 1 to 3 any one of identical.
5. the compound with Formulas I structure according to any one of right 1～3 preparation prevention or treatment and arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, disease that arginine vasopressin V2 receptor is relevant medicine in purposes.
6. purposes according to claim 5, it is characterized in that, described to arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, disease that arginine vasopressin V2 receptor is relevant include: hypertension, thunder syndrome, dysmenorrhea, premature labor, corticotropin releasing hormone parasecretion, adrenal hyperplasia, depression, the hyponatremia that chronic heart failure, liver cirrhosis, antidiuretic hormone secretion disorder syndrome or chronic heart failure, liver cirrhosis and antidiuretic hormone secretion disorder cause.
7. having a pharmaceutical composition for purposes described in any one of claim 5～6, what it comprised therapeutically effective amount has Formulas I structural compounds and one or more pharmaceutical carriers such as any one of claims 1 to 3.
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| 非肽类精氨酸加压素受体拮抗剂的研究进展;张大帅等;《中国药物化学杂志》;20140430;第24卷(第2期);第103-112页 * |
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