CN101318931B - Diaryl substituted pyrazole derivative, preparation method and application thereof - Google Patents
Diaryl substituted pyrazole derivative, preparation method and application thereof Download PDFInfo
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- CN101318931B CN101318931B CN200710041558A CN200710041558A CN101318931B CN 101318931 B CN101318931 B CN 101318931B CN 200710041558 A CN200710041558 A CN 200710041558A CN 200710041558 A CN200710041558 A CN 200710041558A CN 101318931 B CN101318931 B CN 101318931B
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Abstract
The invention relates to a novel antagonist and/or an inverse agonist of cannabinoide receptor-1 (cannabinoid receptor type 1, CB1) with a structural formula shown as a formula (I), a preparation method and an application thereof. In the structural formula, R1, R2, R3, R4, R5, R6, R7 and R8 are defined as the specification sheet. The compound of the invention can be used for treating, preventing or relieving diseases mediated by the CB1 receptor. The compound and pharmaceutically acceptable salt thereof can also be used for treating, preventing or relieving adiposity, diabetes mellitus, drug dependence, cognitive defect, nervous system diseases, diseases of gastrointestinal tract and cirrhosis.
Description
Technical field
The present invention relates to the novel diaryl substituted pyrazole derivative of a class, Preparation Method And The Use.Cannabined receptor-1 (the Cannabinoid receptor type 1 that the effect of can be used as of this compounds is powerful, CB1) receptor antagonist and/or inverse agonist and CB1 had highly selective, acceptable salt can be used for treatment, prevention or alleviation by the receptor-mediated disease of CB1, as obesity, diabetes, drug dependence, cognitive defect, nervous system disorders, gastrointestinal tract disease and liver cirrhosis on The compounds of this invention and the pharmacology thereof.
Background technology
Obesity is a kind of metabolic trouble of the multifactor complexity that causes, has become the health problem in the whole world.The energy that human body is taken in is greater than the energy generation obesity of human consumption, and it is to HUMAN HEALTH and keep good physical and mental statuse to produce totally unfavorable influence.According to the data of U.S.'s disease control with centre of prevention and cure, about 2/3rds overweight (IC BMI=25.5～29.9kg/m of U.S. adult
2), the fat (BMI 〉=30kg/M of U.S. adult over half
2).The World Health Organization estimates that the whole world has 700,000,000 people overweight at present, and expecting the whole world in 2025 has 300,000,000 people's obesities.The more important thing is that twenty or thirty in the past is in year, overweight and fat children and teenager's number have increased by 1 times.Obesity is the high risk factor that causes diseases such as coronary artery disease, hypertension, hyperlipidemia, diabetes, tumour, cardiovascular and cerebrovascular diseases, sacroiliitis and somnopathy.Only the U.S. annual with overweight and fat relevant death toll just greater than 300,000 [Drugs of Future 2005,30 (2): 128].
Overweight very complicated owing to causing with pathologic, physiologic factor obesity, also there is not the ideal methods of treatment at present, orlistat (Orlistat) and sibutramine (Sibutramine) only can produce medium (2.6～4.8kg) reduction body weight effect.It is Cannabined receptor-1 (CB1) and Cannabined receptor-2 (CB2) that Cannabined receptor (Cannabinoid receptor) has two kinds of hypotypes.The CB1 acceptor in the cerebral hippocampus district, there are high level expression in lamina corticalis, cerebellum, basic nervous center (basal ganglia) and some peripheral tissues as fat, gi tract, lung, reproductive system and cardiovascular systems, the CB2 acceptor is mainly expressed [J.Med.Chem.2004 in immunity system, 47,627].Studies show that CB1 receptor antagonist or inverse agonist (antagonist/inverse agonist) have the potentiality of a series of diseases relevant with the CB1 acceptor of treatment as obesity, diabetes, mental disorder, substance depilatory and gastrointestinal tract disease.As if particularly the CB1 acceptor has participated in the power balance of control human body, body weight balance and award, so the CB1 receptor antagonist can effectively reduce the picked-up of food, lowering blood glucose, withdrawal drug dependence (as smoking).
Existing document and patent [Expert.Opin.Ther.Patents 2002,12 (10), and 1475; IDrugs 2005,8 (1), and 53; Expert.Opin.Ther.Patents 2004,14 (10), and 1435; Current MedicinalChemistry, 2005,12,1361] a series of CB1 receptor antagonists or inverse agonist are disclosed.United States Patent (USP) 5624941 and WO 2006/074445 disclose pyrazole derivatives and to the CB1 receptor antagonist activity, WO 02/076949 discloses a class and has had the chirality 4 of very strong CB1 receptor antagonist activity, 5-pyrazoline derivative, WO 2006/074445 discloses the heterocycle pyrazole analogs of the novel CB1 of the acting on acceptor of a class, and WO 03/077847 discloses the substituted amide compound with CB1 receptor antagonist and/or reverse agonist activity.
Yet these compounds also exist avidity satisfactory inadequately in the prior art, to shortcomings such as the CB1 receptor-selective are lower, so this area presses for new antagonist and/or the inverse agonist that the CB1 acceptor is had highly selective of exploitation.
Summary of the invention
The purpose of this invention is to provide a kind ofly has the antagonist and/or the inverse agonist of highly selective and affinity and method for making and purposes to the CB1 acceptor.
A first aspect of the present invention provides compound shown in a kind of formula (I), or its crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate:
In the formula, R
1, R
2, R
3, R
4Independent respectively is hydrogen, chlorine, fluorine, bromine, hydroxyl, nitro, C
1-C
6Alkyl or C
1-C
6Alkoxyl group;
R
5, R
6, R
7Independent respectively is hydrogen, C
1-C
6Alkyl or C
3-C
6Cycloalkyl;
R
8, R
9Independent respectively is hydrogen, chlorine, fluorine, bromine, cyano group, nitro, trifluoromethyl, C
1-C
6Alkyl or C
1-C
6Alkoxyl group.
Wherein, described alkyl, cycloalkyl or alkoxyl group can have 1-3 substituting group that is selected from down group: halogen, hydroxyl, nitro or amino.
In another preference, R
1And R
2Be hydrogen or chlorine.
In another preference, R
3And R
4Be chlorine.
In another preference, R
5Be methyl.
In another preference, R
6And R
7At least one group is methyl or cyclopropyl.
In another preference, R
8And R
9In at least one group be chlorine or methyl.
In another preference, described compound is selected from down group:
N
1-methyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-1H-pyrazoles-1-carbonyl amidine (compound 4a);
N
1-methyl-N
2-(3-trifluoromethyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-1H-pyrazoles-1-carbonyl amidine (compound 4d);
N
1-methyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-1H-pyrazoles-1-carbonyl amidine (compound 4f);
N
1-methyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-1H-pyrazoles-1-carbonyl amidine (compound 4g);
N
1-methyl-N
2-(4-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-5-methyl isophthalic acid H-pyrazoles-1-carbonyl amidine (compound 19e);
N
1-methyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-5-methyl isophthalic acid H-pyrazoles-1-carbonyl amidine (compound 19g);
N
1-methyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (compound 27a);
N
1-methyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (compound 27c);
N
1-cyclopropyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (compound 27d);
N
1-methyl-N
2-(4-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (compound 27e); Or
N
1-cyclopropyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (compound 27h).
In a second aspect of the present invention, a kind of pharmaceutical composition is provided, it contains acceptable vehicle or carrier on the pharmacology, and the above-mentioned compound of the present invention or its crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate.
In a third aspect of the present invention, the present invention is provided above-mentioned compound, or the purposes of its crystal formation, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, they are used to prepare CB1 receptor antagonist and/or inverse agonist.
In a fourth aspect of the present invention, the present invention is provided above-mentioned compound, or the purposes of its crystal formation, pharmacy acceptable salt, hydrate or solvate, they are used to prepare treatment, prevention and the alleviation medicine by the receptor-mediated disease of CB1.
In another preference, describedly be selected from down group by the receptor-mediated disease of CB1:
(a) mental disorder, dysmnesia, cognitive illnesses, cerebrovascular disease, multiple sclerosis, anxiety disorder, epilepsy, Parkinson's disease, dyskinesia or schizophrenia;
(b) to the dependency of materials such as opium, alcohol, hemp and Nicotine;
(c) obesity, diabetes, hyperlipidemia, hypertension, constipation, chronic intestinal obstruction or liver cirrhosis.
In a fifth aspect of the present invention, the method for compound shown in a kind of preparation formula (I) is provided, comprise step:
(1) in the presence of alkali, in inert solvent,, forms compd B with the reaction of the sulfonamide compounds shown in compd A and the formula Z1;
(2) in inert solvent, the compound shown in compd B and the formula Z2 is carried out nucleophilic substitution reaction, form Compound C;
(3) in inert solvent, make Compound C remove a part water, form compound shown in the formula (I);
In above-mentioned each reaction formula, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, definition as mentioned above.
In another preference, step (1) is carried out in the presence of triethylamine.
In another preference, step (3) is at POCl
3Or dewater under the trifluoroacetic anhydride existence.
Embodiment
The inventor is through extensive and deep research, screened a large amount of compounds, discoverable type (I) compound not only has very strong avidity to the CB1 acceptor first, and the CB1 acceptor had high selectivity (promptly the avidity to the CB2 acceptor is very low), therefore be particularly suitable as the specific antagonists of CB1 acceptor.The inventor has finished the present invention on this basis.
Activeconstituents
" compound of the present invention " is meant the compound shown in the formula (I) herein.This term also comprises the various crystal formations of formula (I) compound, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate.
" pharmacy acceptable salt " as used herein so long as pharmaceutically acceptable salt just there is no particular limitation, can enumerate the salt that forms with acid particularly, be fit to salifiable acid and include, but is not limited to mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, acidic amino acids such as organic acid such as formic acid, acetate, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, Phenylsulfonic acid and aspartic acid, L-glutamic acid.
The preparation method
More specifically describe the preparation method of compound shown in the formula of the present invention (I) below, but these concrete grammars do not constitute any restriction to the present invention.Reaction conditions in addition, for example the amount of reactant, solvent, alkali, compound used therefor, temperature of reaction, reaction required time etc. are not limited to following explanation.
The compounds of this invention can also be chosen various synthetic methods that will describe in this manual or known in the art wantonly and combine and make easily, and such combination can be easy to carry out by those skilled in the art in the invention.
In preparation method of the present invention, each reaction in inert solvent, is carried out to solvent refluxing temperature (as 0 ℃～80 ℃, preferred 0 ℃～50 ℃) in room temperature usually.Reaction times was generally 0.1 hour-60 hours, preferably was 0.5-48 hour.
In a preference, formula of the present invention (I) compound can be by following flow preparation:
Reaction process I
Step 1. compound 1[J.Med.Chem.2004,47,627] and compound 7[Chem.Ber.1966,99,2885; J.Med.Chem.2004,47,627] in the presence of alkali, reaction can obtain compound 2 in appropriate solvent.
The alkali that is fit to above-mentioned reaction is organic bases and mineral alkali, and optimal alkali is triethylamine, pyridine, Dimethylamino pyridine; Be fit to above-mentioned reaction solvent be acetonitrile, DMF, pyridine, methylene dichloride, DMSO, tetrahydrofuran (THF), benzene, toluene.
Temperature of reaction from 0 ℃ to the solvent refluxing temperature, optimum temps is solvent refluxing temperature (DMF and DMSO 50-100 ℃ for good); Reaction times generally can finish at 1-10 hour from 30 minutes to 24 hours.
When aftertreatment, generally adopt column chromatography to separate and obtain target compound, also can not need careful purification sometimes, directly carry out the next step.
Step 2. compound 2 and various suitable substituted amine compound carry out nucleophilic substitution reaction in appropriate solvent can obtain compound 3.
Be fit to above-mentioned reaction solvent be the miscellany of methyl alcohol, ethanol, DMF, pyridine, methylene dichloride, DMSO, tetrahydrofuran (THF), benzene, toluene or above-mentioned solvent, optimum solvent is methyl alcohol and the mixed solvent of methylene chloride volume than 1: 1.
Temperature of reaction from-10 ℃ to the solvent refluxing temperature, optimum temps is a room temperature.When aftertreatment, generally adopt column chromatography to separate and obtain target compound, also can not need careful purification sometimes, directly carry out the next step.
Step 3. compound 3 removes a part water and forms azole compounds 4 under appropriate solvent and suitable temperature under the dewatering agent effect.
The dewatering agent that is fit to above-mentioned reaction is thionyl chloride, phosphorus oxychloride, trifluoroacetic anhydride, diacetyl oxide, the vitriol oil; The solvent that is fit to above-mentioned reaction is pyridine, tetrahydrofuran (THF), dioxane, glycol dimethyl ether, N-Methylimidazole, acetonitrile.
Temperature of reaction from-10 ℃ to the solvent refluxing temperature, the best is to continue stirring after 20 minutes, backflow 1-24 hour compound 3 and dewatering agent are mixed earlier under ice bath cooling.
The employing column chromatography separates purification or carries out recrystallization when aftertreatment.
Step 4. can randomly be prepared into corresponding pharmacy acceptable salt with formula (I) compound with ordinary method as required.
In another preference, formula of the present invention (I) compound can prepare by following flow process 2:
Reaction process 2:
Step 1. 4-Chlorophenylacetic acid and chloride reagent reaction obtain compound 8, and the acylating reagent that is fit to is thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, are best with the thionyl chloride.Compound 8 obtains compound 9 with benzene generation friedel-crafts acylation in the presence of the acid of Louis.Lewis acid comprises aluminum chloride, zinc chloride, iron(ic) chloride.
Step 2. is under common infrared searchlight light irradiation, and compound 9 obtains compound 10 with the bromide reagent back flow reaction in inert solvent.The inert solvent that is fit to is tetracol phenixin, benzene, toluene, hexanaphthene.The bromide reagent that is fit to comprises bromine and NBS, is best with the bromine.
Step 3. compound 11 is to be got with the strong alkaline substance back flow reaction in alcoholic solvent by compound 10.Alcohols material comprises methyl alcohol, ethanol.Strong alkaline substance such as sodium hydroxide, potassium hydroxide, lithium hydroxide.
Step 4. compound 11 makes compound 12 with grignard reagent reaction under refluxing.The solvent that this reaction is adopted is ether solvent such as ether, THF, dioxane, glycol dimethyl ether or aromatic hydrocarbon solvent such as benzene, toluene or their mixed solvent.
Step 5. compound 13 is by compound 12 oxidation gained.The organic solvent that is adopted during reaction can be halogenated hydrocarbon such as methylene dichloride, chloroform or ethers or DMF, DMSO, water, organic acid or their mixed solvent.The oxidising agent that is fit to is DMSO, Jones reagent, Collins reagent, PCC, PDC.
Step 6. compound 13 is sloughed a part water and is obtained compound 14 under the dehydrated reagent effect.The dehydrated reagent that is fit to comprises formic acid, sulfuric acid, trifluoroacetic acid.The last gains of this reaction need not purified and can directly be carried out the next step.
Step 7. compound 15 is by compound 14 gained under peroxide oxidation.The solvent that this reaction is fit to comprises acetonitrile, methyl alcohol, ethanol, methylene dichloride, chloroform.The oxygenant that is fit to is hydrogen peroxide, benzoyl hydroperoxide, monoperphthalic acid, Peracetic Acid, metachloroperbenzoic acid.
Step 8. compound 15 and hydrazine hydrate reaction obtain compound 16.The solvent that reaction is adopted is methyl alcohol, ethanol or ethers or amides.Reaction is at room temperature carried out.
Step 9. compound 16 obtains compound 17 with compound 7 reactions.Suitable solvent is acetonitrile, DMF, pyridine, benzene, tetrahydrofuran (THF), dioxane.The organic bases that is fit to is triethylamine, DBU, DMAP, salt of wormwood, yellow soda ash, cesium carbonate.Temperature of reaction is that room temperature arrives the solvent refluxing temperature, and the best is 90-110 ℃.
Step 10. compound 17 obtains compound 18 with the amine reaction that is fit to.What be fit to is methylamine, ethamine, dimethylamine, diethylamine, cyclopropylamine, aromatic amine, ammonia, hydrazine hydrate, oxyammonia.The solvent that reaction is adopted is various halohydrocarbon or various alcohol or their mixed solvent.Temperature of reaction is 0～100 ℃, and optimal temperature is a room temperature.
Step 11. compound 18 obtains compound 19 with various dewatering agent reactions in organic solvent.The organic solvent that is fit to comprises tetrahydrofuran (THF), dioxane, glycol dimethyl ether (DME), pyridine, N-Methylimidazole.The dewatering agent that is fit to comprises thionyl chloride, phosphorus oxychloride, trifluoroacetic anhydride, diacetyl oxide, formic acid, the vitriol oil.The temperature that reaction is fit to is 0 ℃ and arrives the solvent refluxing temperature that the best is 70-110 ℃.
Step 12. can randomly be prepared into corresponding pharmacy acceptable salt with formula (I) compound with ordinary method as required.
In another preference, formula of the present invention (I) compound can prepare by following flow process 3:
Reaction process 3:
Step 1.2,4-fenac and the reaction of chlorine acylating reagent obtain compound 20.
Acylating reagent comprises thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride.Compound 20 obtains compound 21 with benzene generation friedel-crafts acylation under the condition that Louis acid exists.The Lewis acid that is fit to comprises aluminum chloride, zinc chloride, iron(ic) chloride.Compound 21 obtains compound 22 with formaldehyde generation Mannich reaction.
Step 2. compound 13 is by compound 12 oxidation gained.The organic solvent that is adopted during reaction can be halogenated hydrocarbon such as methylene dichloride, chloroform or ethers or DMF, DMSO, water, organic acid or their mixed solvent.The oxidising agent that is fit to is DMSO, Jones reagent, Collins reagent, PCC or PDC.
Step 3. compound 23 is by gained under compound 22 oxidations.The organic solvent that is adopted during reaction can be halogenated hydrocarbon such as methylene dichloride, chloroform or ethers or DMF, DMSO, water, organic acid or their mixed solvent.The oxidising agent that is fit to is DMSO, Jones reagent, Collins reagent, PCC, PDC.
Step 4. compound 23 and hydrazine hydrate reaction obtain compound 24.The solvent that reaction is adopted is methyl alcohol, ethanol or ethers or amides.Reaction is at room temperature carried out.
Step 5. is to obtain compound 25 by compound 24 and compound 7 reactions.Suitable solvent is acetonitrile, DMF, pyridine, benzene, tetrahydrofuran (THF), dioxane.The organic bases that is fit to is triethylamine, DBU, DMAP, salt of wormwood, yellow soda ash, cesium carbonate.Temperature of reaction is that room temperature arrives the solvent refluxing temperature, and the best is 90-110 ℃.
Step 6. compound 25 obtains compound 26 with various suitable amine reactions in organic solvent.What be fit to is methylamine, ethamine, dimethylamine, diethylamine, cyclopropylamine, aromatic amine, ammonia, hydrazine hydrate, oxyammonia.The solvent that reaction is adopted is various halohydrocarbon or various alcohol or their mixed solvent.Temperature of reaction is 0～100 ℃, and optimal temperature is a room temperature.
Step 7. compound 27 is to be dewatered in organic solvent and got by compound 26.The organic solvent that is fit to comprises tetrahydrofuran (THF), dioxane, glycol dimethyl ether (DME), pyridine, N-Methylimidazole.The dewatering agent that is fit to comprises thionyl chloride, phosphorus oxychloride, trifluoroacetic anhydride, diacetyl oxide, formic acid, the vitriol oil.The temperature that reaction is fit to is 0 ℃ and arrives the solvent refluxing temperature that the best is 70-110 ℃.
Step 8. can randomly be prepared into corresponding pharmacy acceptable salt with formula (I) compound with ordinary method as required.
In the present invention, compound 7 can followingly make, but the method for making of compound 7 is not limited thereto:
Synthesizing of compound 7
At first, reference method [Collect.Czech.Chem.Commun.1984,49,1182] substituted aniline is through diazotization, and chlorosulfonylation gets compound 5 again.
Then, compound 5 is dissolved in acetone, tetrahydrofuran (THF), dioxane, the glycol dimethyl ether, under-10～0 ℃, is added drop-wise in the ammonia soln, stirring at room is 0.5～4 hour then.Reaction finishes, and under 0 ± 2 ℃, with the reaction system neutrality that neutralizes, filters the solid that generates with concentrated hydrochloric acid, and washing obtains compound 6.
At last, after compound 6 and the dithiocarbonic anhydride addition, under potassium hydroxide, sodium hydroxide, sodium hydride effect, methylate and obtain compound 7 with methyl iodide and methyl-sulfate.The solvent of reaction adopts water-soluble organic solvents such as DMF, DMSO, THF, dioxane.
Pharmaceutical composition and application process
Because The compounds of this invention has the avidity and the specificity of excellent CB1 acceptor, therefore The compounds of this invention and various crystal formation thereof, pharmaceutically acceptable inorganic or organic salt, hydrate or solvate, and to contain The compounds of this invention be that the pharmaceutical composition of main active ingredient can be used for treatment, prevention and alleviates by the receptor-mediated disease of CB1.According to prior art, it is following by the receptor-mediated disease of CB1 that The compounds of this invention can be used for treatment:
(a) be used for the treatment of mental disorder, dysmnesia, cognitive illnesses, cerebrovascular disease, multiple sclerosis, anxiety disorder, epilepsy, Parkinson's disease, dyskinesia, schizophrenia.
(b) treatment is to substance depilatories such as opium, alcohol, hemp and Nicotines.
(c) be used for the treatment of obesity, diabetes, hyperlipidemia, hypertension, constipation, chronic intestinal obstruction, liver cirrhosis etc.
Pharmaceutical composition of the present invention comprises on The compounds of this invention in the safety, significant quantity scope or its pharmacology acceptable vehicle or carrier on the acceptable salt and pharmacology.Wherein " safety, significant quantity " refers to: the amount of compound is enough to obviously improve the state of an illness, and is unlikely to produce severe side effect.Usually, pharmaceutical composition contains 1-1000mg The compounds of this invention/agent, and preferably 5-500mg The compounds of this invention/agent more preferably, contains 10-200mg The compounds of this invention/agent.
" pharmaceutically acceptable vehicle or carrier " refers to: one or more consistency solids or liquid filler or gelatinous mass, they are suitable for the people uses, and enough purity and enough low toxicity must be arranged." consistency " referred to herein as each component energy and compound of the present invention and blending mutually between them in the composition, and the drug effect of not obvious reduction compound.Pharmaceutically acceptable vehicle or carrier part example have Mierocrystalline cellulose and derivative (as Xylo-Mucine, ethyl cellulose sodium, cellulose ethanoate etc.) thereof, gelatin, talcum, solid lubricant (as stearic acid, Magnesium Stearate), calcium sulfate, vegetables oil (as soya-bean oil, sesame oil, peanut oil, olive wet goods), polyvalent alcohol (as propylene glycol, glycerine, N.F,USP MANNITOL, sorbyl alcohol etc.), emulsifying agent (as tween
), wetting agent (as sodium lauryl sulphate), tinting material, seasonings, stablizer, antioxidant, sanitas, apirogen water etc.
When using The compounds of this invention, can be oral, rectum, parenteral (intravenously, intramuscular or subcutaneous), topical.
The solid dosage that is used for oral administration comprises capsule, tablet, pill, powder and granule.In these solid dosages, active compound mixes with at least a conventional inert excipient (or carrier), as Trisodium Citrate or Lin Suanergai, or mixes with following compositions: (a) filler or expanding material, for example, starch, lactose, sucrose, glucose, N.F,USP MANNITOL and silicic acid; (b) tackiness agent, for example, Walocel MT 20.000PV, alginate, gelatin, Polyvinylpyrolidone (PVP), sucrose and gum arabic; (c) wetting Agent for Printing Inks, for example, glycerine; (d) disintegrating agent, for example, agar, lime carbonate, yam starch or tapioca (flour), alginic acid, some composition silicate and yellow soda ash; (e) retarding solvent, for example paraffin; (f) absorb accelerator, for example, quaternary ammonium compound; (g) wetting agent, for example hexadecanol and glyceryl monostearate; (h) sorbent material, for example, kaolin; (i) lubricant, for example, talcum, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate, or its mixture.In capsule, tablet and the pill, formulation also can comprise buffer reagent.
Solid dosage such as tablet, sugar-pill, capsule, pill and granule can adopt dressing and the preparation of shell material, as casing and other material well known in the art.They can comprise opacifying agent, and, discharge in the mode that the release of active compound or compound can postpone in this composition certain part in digestive tube.The example of adoptable embedding component is polymeric material and Wax.In case of necessity, active compound also can with above-mentioned vehicle in one or more form microencapsulation form.
The liquid dosage form that is used for oral administration comprises pharmaceutically acceptable emulsion, solution, suspension, syrup or tincture.Except the active ingredient beyond the region of objective existence, liquid dosage form can comprise the conventional inert diluent that adopts in this area, as water or other solvent, solubilizing agent and emulsifying agent, example is known, the mixture of ethanol, Virahol, ethyl-carbonate, ethyl acetate, propylene glycol, 1,3 butylene glycol, dimethyl formamide and oil, particularly Oleum Gossypii semen, peanut oil, maize germ, sweet oil, Viscotrol C and sesame oil or these materials etc.
Except these inert diluents, composition also can comprise auxiliary agent, as wetting agent, emulsifying agent and suspension agent, sweeting agent, the agent of tender flavor and spices.
Except the active ingredient beyond the region of objective existence, suspension can comprise suspension agent, for example, and the mixture of ethoxylation isooctadecane alcohol, polyoxyethylene sorbitol and Isosorbide Dinitrate, Microcrystalline Cellulose, aluminum methylate and agar or these materials etc.
The composition that is used for parenteral injection can comprise physiologically acceptable aseptic moisture or anhydrous solution, dispersion liquid, suspension or emulsion and be used for being dissolved into again the aseptic Injectable solution or the sterilized powder of dispersion liquid.Suitable moisture and nonaqueous carrier, thinner, solvent or vehicle comprise water, ethanol, polyvalent alcohol and suitable mixture thereof.
The formulation that is used for the The compounds of this invention of topical comprises ointment, powder, patch, propellant and inhalation.Activeconstituents under aseptic condition with physiologically acceptable carrier and any sanitas, buffer reagent, or the propelling agent that may need in case of necessity is mixed together.
The compounds of this invention can be individually dosed, perhaps with other pharmaceutically acceptable compound Combined Preparation.
When making pharmaceutical composition, it is the Mammals (as the people) that the The compounds of this invention of safe and effective amount is applicable to the needs treatment, the effective dosage of dosage for pharmaceutically thinking when wherein using, for the people of 60kg body weight, day dosage is generally 1～1000mg, preferred 20～500mg.Certainly, concrete dosage also should be considered factors such as route of administration, patient health situation, and these all are within the skilled practitioners skill.
Major advantage of the present invention comprises:
(1) The compounds of this invention has excellent avidity to the CB1 acceptor, and therefore stronger biological activity is arranged.
(2) The compounds of this invention has the selectivity of height to the CB1 acceptor.
(3) the The compounds of this invention preparation method is simple, low cost of manufacture.
Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to normal condition, or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise umber and per-cent are weight part and weight percent.
Among all embodiment, fusing point is measured with MEL-TEMP fusing point instrument, and thermometer is not proofreaied and correct;
1H-NMR VarianMercury 400 nuclear magnetic resonance analyser records, chemical shift is represented with δ (ppm); Separate and use silica gel, the undeclared 200-300 order that is, it is volume ratio that column chromatography and TLC detect the developping agent ratio.
Embodiment 1:3-(4-chloro-phenyl-)-N-(4-chloro-phenyl-alkylsulfonyl)-4-hydroxy-4-phenyl-4,5-dihydro-1 h-pyrazole-1-carbonyl imines thio-methyl ester (2a)
Compound 1 (12.75g, 46.8mmol) and compound 7a (17.73g 60.0mmol) is dissolved in the mixed solution of acetonitrile (200ml) and triethylamine (20ml) composition, and mixture heating up is back to till compound 1 reacts completely.Reaction mixture is concentrated into dried, adds methylene dichloride, wash twice with water, dried over sodium sulfate, concentrating residues thing column chromatography (developping agent: sherwood oil: ethyl acetate=8: 1) compound 2a (20.4g, 83.8%).
1NMR(CDCl
3)δ：2.31(s，3H)，4.62(d，1H，J＝12.18Hz)，4.83(d，1H，J＝12.18Hz)，7.20-7.40(m，9H)，7.66(dt，2H，J＝6.97Hz)，7.82(dt，2H，J＝6.78Hz)。
Embodiment 2:N
1-methyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxy-4-phenyl-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (3a)
(1.2g 2.3mmol) is dissolved in the mixing solutions of methyl alcohol (30ml) and methylene dichloride (30ml), at room temperature adds methylamine alcohol solution (18ml) (or other excessive amine), till at room temperature being stirred to compound 2a and reacting completely with compound 2a.Reaction mixture is concentrated into dried, residue directly carries out column chromatography and gets (developping agent: sherwood oil: ethyl acetate=5: 1) compound 3a (0.6g, 51.7%).
1NMR(DMSO)δ：2.95(s，3H)，4.13(d，1H，J＝12.18Hz)，4.30(d，1H，J＝12.18Hz)，7.27-7.57(m，9H)，7.65-7.68(m，1H)，7.76-7.85(m，4H)。
Embodiment 3:N
1-methyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-1H-pyrazoles-1-carbonyl amidine (4a)
With compound 3a (0.8g, 1.6mmol) under the ice bath cooling, be dissolved in the pyridine (8ml), slowly drip phosphorus oxychloride (0.5ml), drip off the back and under ice bath, continue to stir 20min, refluxed then 2 hours, after the reaction mixture cooling, pour in the frozen water, use extracted with diethyl ether 2 times, organic layer washs with 1 equivalent dilute hydrochloric acid, dried over sodium sulfate is concentrated into dried residue and carries out column chromatography and get compound 4a (0.35g, 45%).
Embodiment 4-15: the preparation of compound 4b-4m
The synthetic method of similar compound 4a can make compound 4b-4m.The preparation yield of compound 4b-4m, nuclear magnetic data sees Table 1.
Yield, the nuclear magnetic data of table 1 compound 4b～4m
Embodiment 16: substituted benzene SULPHURYL CHLORIDE (5)
The mixture of substituted aniline (0.25mol) and concentrated hydrochloric acid (85ml) is cooled to 0 ℃, drip sodium nitrite in aqueous solution (20 gram Sodium Nitrites are dissolved in 40ml water) under 5 ℃ the condition being no more than, dropwise, reaction mixture continues to make diazonium salt solution in 20 minutes to 2 hours 0 ℃ of stirring.Under 0～10 ℃, in the mixture of cuprous chloride (7g) and glacial acetic acid (200ml), feed sulfurous gas to saturated, then this saturated solution is added drop-wise to the diazonium salt solution that makes above, after dripping off with reaction mixture stirring at room 2 hours, the air bubbling is removed too much sulfurous gas.Ethyl acetate extraction (3 * 100mL) reaction solutions, extraction liquid merge after with the saturated sodium bicarbonate washing to neutral, organic phase Calcium Chloride Powder Anhydrous drying is evaporated to driedly, obtains compound 5 crude products, need not be further purified promptly to can be used for next step reaction.
Embodiment 17: substituted benzene sulfonic acid amide (6)
The product substituted benzene SULPHURYL CHLORIDE of gained of last step is dissolved in the small amount of acetone, under ice bath, be added drop-wise in the strong aqua (500ml), at room temperature stirred after dropwising 1 hour, it is extremely neutral to reaction mixture then to drip concentrated hydrochloric acid under ice bath, the solid that filtration is separated out, the washing solid obtains compound 6.Compound 6 need not be further purified, and can directly carry out the next step.
Embodiment 18: substituted benzene alkylsulfonyl two sulfilimine methylcarbonates (7)
Descend dithiocarbonic anhydride (4ml in room temperature, stirring, 0.066mol) join substituted benzene sulfonic acid amide compound 6 (0.060mol) and be dissolved in the solution of dimethyl formamide (60ml), finish, drip 45% potassium hydroxide (11.2ml) solution, dropwise back stirring at room reaction 0.5～2 hour.Control reaction temperature is lower than 15 ℃, drip methyl iodide (7.4ml, 0.12mol), add the afterreaction mixture stirring at room 2 hours, pour reaction mixture in the water (300ml), put into 0 ℃ of refrigerating chamber and spend the night, filter the solid chemical compound of separating out, solid is used sherwood oil, water, washing with alcohol successively, and drying obtains compound 7.Compound 7 can directly carry out the next step.
Yield, the nuclear magnetic data of compound 7a～7m see Table 2.
Yield, the nuclear magnetic data of table 2 compound 7a～7m
Embodiment 19:4-chlorobenzene Acetyl Chloride 98Min. (8)
4-chlorobenzene acetic acid (102.30g, 0.60mol) and thionyl chloride (87.60ml, 1.20mol) mixture stirring reaction 3 hours under the condition that refluxes, cool to room temperature, air distillation goes out excessive thionyl chloride, the residuum underpressure distillation gets pinkish liquid to chlorobenzene Acetyl Chloride 98Min. (87.30g, 77.0%).
1NMR(CDCl
3)：δ4.12(s，2H)，7.19(d，2H，J＝2.57Hz)，7.34(d，2H，J＝2.57Hz)。
Embodiment 20:2-(4-chloro-phenyl-)-1-methyl phenyl ketone (9)
Under ice bath, to chlorobenzene Acetyl Chloride 98Min. (64.60g, 0.34mol) be added drop-wise to benzene (136ml) and aluminum chloride (48.00g, 0.36mol) mixture in, after dropwising the reaction mixture intensification was stirred 3 hours about 70 ℃, reaction mixture is poured in the 500 gram mixture of ice and water, separated out yellowish green solid product 9 (74.20g, 94.2%).
1NMR(CDCl
3)：4.26(s，2H)，7.18-7.61(m，7H)，7.99-8.03(m，2H)。
Embodiment 21:2-bromo-2-(4-chloro-phenyl-)-1-methyl phenyl ketone (10)
Under the condition of illumination, backflow, with bromine (6.16ml, 0.12mol) tetracol phenixin (120ml) drips of solution be added to compound 9 (27.70g, 0.12mol) tetracol phenixin (300ml) solution in, continuation illumination (detects by TLC till being back to and reacting completely, developping agent sherwood oil: ethyl acetate=15: 1), reaction mixture is washed with saturated carbon acid gas sodium solution, dried over sodium sulfate, filtrate concentrates, residue adds an amount of sherwood oil recrystallization and gets white solid product 10 (22.30g, 60.0%).
1NMR(CDCl
3)：δ6.32(s，1H)，7.33-7.62(m，7H)，7.98-8.01(m，2H)。
Embodiment 22:2-hydroxyl-2-(4-chloro-phenyl-)-1-methyl phenyl ketone (11)
Compound 10 (6.19g 0.02mol) is dissolved in ethanol (20ml), is warming up to backflow, drip sodium ethylate (4.08g, 0.06mol) and the solution (also can directly add the solid sodium ethylate) of ethanol (35ml) composition.Reaction mixture continue to be stirred to raw material reaction fully till (needing 2 hours approximately).Add in the reaction system reaction mixture hydrochloric acid (15%, 200ml), be cooled to room temperature and separate out solid, filter washing, dry compound 11 (3.8g, 77.4%).
1NMR(CDCl
3)：δ4.56(br，s，1H)，5.93(s，1H)，7.27-7.56(m，7H)，7.87-7.90(m，2H)。
Embodiment 23:1-(4-chloro-phenyl-)-2-phenyl butane-1,2 glycol (12)
Drips of solution with the tetrahydrofuran (THF) (5ml) of monobromethane (6.60ml) under the room temperature is added to magnesium chips (2.00g, 83.00mmol) and the mixture of tetrahydrofuran (THF) (15ml), after dropwising, after reaction mixture continues to be stirred to magnesium chips and dissolves fully, drip compound 11 (2.47g, 0.01mol) tetrahydrofuran (THF) (20ml) solution, after dropwising, the reaction mixture reflux is spent the night, reaction mixture, drip saturated ammonium chloride solution to reaction mixture no longer till the bubbling, (2 * 100ml) extractions are washed organic layer, dried over sodium sulfate to reaction solution after then handling with ethyl acetate, adding sherwood oil crystallisation by cooling is separated out white solid product (1.20g, 43.4%) after concentrating most solvent.
1NMR(CDCl
3)：δ0.77(t，3H，J＝7.32Hz)，2.04(q，2H，J＝7.17Hz)，2.41(s，1H)，2.60(d，1H，J＝3.96Hz)，4.76(d，1H，J＝3.97Hz)，6.88-7.26(m，9H)。
Embodiment 24:1-(4-chloro-phenyl-)-2-hydroxyl-2-phenyl butanone (13)
Under-80～-60 ℃ the condition, solution to the methylene dichloride (160ml) of oxalyl chloride (2.62ml) drips dimethyl sulfoxide (DMSO) (2.42ml), drips compound 12 (5.53g, methylene dichloride 20mmol) (40ml) solution after 30 minutes, after continuing to stir 30min, add triethylamine (10.4ml), stir after 30 minutes, reaction mixture is warming up to room temperature, reaction mixture washes that (2 * 60ml) is inferior with water, dried over sodium sulfate is concentrated into dried faint yellow oily product (5.32g, 96.9%).
1NMR(CDCl
3)：δ0.84(t，3H，J＝7.32Hz)，2.38(q，2H，J＝7.32Hz)，4.51(s，1H)，7.25-7.46(m，7H)，7.61-7.66(m，2H)。
Embodiment 25:1-(4-chloro-phenyl-)-2-phenyl but-2-ene-1-ketone (14)
Compound 13 (2.75g, 0.01mol) be dissolved in formic acid (98%, 25ml), temperature rising reflux to raw material reaction fully till (needing 6-8 hour approximately), reaction mixture is concentrated into dried, add ether (20ml), wash to neutrality with sig water, the ether layer dried over sodium sulfate, filtrate is carried out column chromatography (developping agent: sherwood oil: ethyl acetate=25: 1) after concentrating, get oily matter (1.74g, 67.7%)
1NMR (CDCl
3): δ Z formula 1.75 (d, 3H, J=3.2Hz), 6.36 (q, 1H, J=14.33Hz), 7.23-7.43 (m, 7H), 7.88-7.93 (m, 2H) E formula 1.89 (d, 3H, J=4.73Hz), 6.60 (q, 1H, J=14.18Hz), 7.15-7.42 (m, 7H), 7.68-7.72 (m, 2H).
Embodiment 26:1-phenyl-1-(4-chloro-phenyl-carbonyl) propylene oxide
With compound 14 (1.70g, 6.63mmol), metachloroperbenzoic acid (3.00g, 17.40mmol), the mixture temperature rising reflux of methylene dichloride (20ml) to raw material reaction fully till (about 12 hours, separate out the solid of white this moment), then reaction mixture is washed with 5% diluted alkaline or saturated sodium bicarbonate solution, dried over sodium sulfate is filtered, the solvent decompression removes the back residue and carries out column chromatography (developping agent sherwood oil: ethyl acetate=25: 1) get oily product (1.50g, 83%).
1NMR(CDCl
3)：δ1.14-1.38(td，3H，J＝5.5Hz)，3.30-3.71(tq，1H，J＝5.32Hz)，7.38-7.59(m，7H)，7.96-8.06(m，2H)。
Embodiment 27:3-(4-chloro-phenyl-)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole (16)
Hydrazine hydrate with 85% (1ml) is added drop-wise to by compound 15 (1.50g, 5.50mmol), the mixture that ethanol (10ml) is formed, after dropwising, reaction mixture maintains 35 ℃ and (detects developping agent sherwood oil: ethyl acetate=3: 1 by TLC till continuing to be stirred to raw material and disappearing, reaction times needs about 20 hours approximately), reaction mixture sat, cooling are separated out the soft solid product 16 (0.42g, 26.9%) of white.
1NMR(DMSO-d
6)：δ1.05(d，3H，J＝6.6Hz)，3.50(q，1H，J＝13.2Hz)，7.17-7.46(m，9H)。
Embodiment 28:3-(4-chloro-phenyl-)-N-(4-chloro-phenyl-alkylsulfonyl)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole-1-carbonyl imines thio-methyl ester (17a)
With compound 16 (0.42g, 1.45mmol), 7a (0.43g, 1.45mmol), acetonitrile (6.2ml) and triethylamine (0.46ml) mix the back stirring and refluxing to raw material reaction fully till (about three days), reaction mixture is concentrated into dried, adds methylene dichloride, wash (2 * 40ml) organic layers with water, dried over sodium sulfate, carry out column chromatography (developping agent sherwood oil: ethyl acetate=8: 1), obtain little yellow solid product (0.474g, 61.3%).
1NMR(CDCl
3)：δ1.43(d，3H，J＝6.78Hz)，2.54(s，3H)，3.64(s，1H)，4.54(q，1H，J＝6.6Hz)，7.21-7.41(m，9H)，7.68-7.83(m，4H)。
Embodiment 29:3-(4-chloro-phenyl-)-N-(3-chloro-phenyl-alkylsulfonyl)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole-1-carbonyl imines thio-methyl ester (17b)
The preparation method of reference compound 17a, (2.5g, 8.73mmol) (2.6g, 8.73mmol) reaction obtains compound 17b (2.5g, 53.7%) with compound 7f to make compound 16
1NMR (CDCl
3): δ 1.46 (d, 3H, J=6.79Hz), 2.54 (s, 3H), 3.40 (br, s, 1H), 4.58 (q, 1H, J=6.79Hz), 7.22-7.48 (m, 9H), 7.68-7.92 (m, 4H).
Embodiment 30:3-(4-chloro-phenyl-)-N-(4-aminomethyl phenyl alkylsulfonyl)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole-1-carbonyl imines thio-methyl ester (17c)
Preparation method's reference compound 17a, (2g, 6.98mmol) (1.92g, 6.98mmol) reaction gets product 17c (2.1g, 58.2%) with compound 71 to make compound 16.
1NMR(CDCl
3)δ1.43(d，3H，J＝6.6Hz)，2.39(s，3H)，2.54(s，3H)，3.73(br，s，1H)，4.55(q，1H，J＝6.6Hz)，7.19-7.36(m，9H)，7.66-7.77(m，4H)。
Embodiment 31:3-(4-chloro-phenyl-)-N-(3-aminomethyl phenyl alkylsulfonyl)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole-1-carbonyl imines thio-methyl ester (17d)
Preparation method's reference compound 17a, make compound 16 (2.5g, 8.73mmol) and compound 7g (2.4g, 8.73mmol) reaction, 17d (2.89g, 64.4%),
1NMR (CDCl
3) δ 1.45 (d, 3H, J=6.77Hz), 2.38 (s, 3H), 2.54 (s, 3H), 4.57 (q, 1H, J=6.77Hz), 7.20-7.39 (m, 9H), 7.66-7.73 (m, 4H).
Embodiment 32:N
1-methyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (18a)
With compound 17a (0.47g 0.89mmol) is dissolved in methyl alcohol (20ml) and the methylene dichloride (20ml), adds methylamine alcohol solution (10ml), at room temperature be stirred to raw material reaction fully till (about 1 hour).Decompression removes solvent, and residue carries out column chromatography (developping agent sherwood oil: ethyl acetate=5: 1) get white solid product compound 18a (0.29g, 63.8%)
1NMR (CDCl
3): δ 1.25 (d, 3H, J=6.59Hz), 2.80 (br, s, 1H), 3.25 (d, 3H, J=5.3Hz), 4.31 (q, 1H, J=6.77Hz), 7.19-7.39 (m, 10H), 7.54-7.7.56 (m, 2H), 7.77-7.80 (m, 2H).
Embodiment 33:N
1-cyclopropyl-N
2-(4-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (18f)
Preparation process reference compound 18a, make compound 17c (1.00g, 1.95mmol) and cyclopropylamine (4ml) reaction, product 18f (1.00g, 98.3%),
1NMR (CDCl
3) δ 0.38-0.87 (4m, 4H), 1.26 (d, 3H, J=6.6Hz), 2..39 (s, 3H), 3.22-3.24 (m, 1H), 4.37 (q, 1H, 6.6Hz), 7.17-7.34 (m, 10H), 7.53-7.70 (m, 4H).
Embodiment 34:N
1-methyl-N
2-(4-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (18e)
Preparation process reference compound 18a, make compound 17c (1.00g, 1.95mmol) and methylamine alcohol solution (15ml) reaction, product 18e (0.92g, 95.3%) 1NMR (CDCl
3) δ 1.25 (d, 3H, J=6.58Hz), 2.38 (s, 3H), 3.22 (d, 3H, J=5.12Hz), 4.31 (q, 1H, J=6.58Hz), 7.16-7.37 (m, 10H), 7.53-7.55 (m, 2H), 7.73-7.75 (m, 2H).
Embodiment 35:N
1-cyclopropyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (18b)
Preparation process reference compound 18a, make compound 17a (1.45g, 2.72mmol) and cyclopropylamine (4ml) reaction, product 18b (1.25g, 84.8%).
1NMR(CDCl
3)δ0.47-0.91(4m，4H)，1.26(d，3H，J＝6.6Hz)，2.93(s，1H)，3.22-3.28(m，1H)，4.34(q，1H，J＝6.6Hz)，7.18-7.49(m，1H)，7.53-7.58(m，2H)，7.73-7.77(m，2H)。
Embodiment 36:N
1-methyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (18c)
Preparation process reference compound 18a, make compound 17b (1.28g, 2.40mmol) and methylamine alcohol solution (15ml) reaction, product 18c (0.94g, 75.7%).
1NMR(CDCl
3)δ1.26(d，3H，J＝6.6Hz)，3.25(d，2H，J＝5.13Hz)，4.33(q，1H，J＝6.59Hz)，7.17-7.45(m，10H)，7.54-7.59(m，2H)，7.71-7.74(m，1H)，7.85-7.85(m，1H)。
Embodiment 37:N
1-cyclopropyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (18d)
Preparation process is with reference to 18a, make compound 17b (1.40g, 2.62mmol) and cyclopropylamine (4ml) reaction, product 18d (1.16g, 81.5%)
1NMR (CDCl
3) δ 0.47-0.87 (4m, 4H), 1.27 (d, 3H, J=6.74Hz), 2.93 (br s, 1H), 3.24-3.25 (m, 1H), 4.37 (q, 1H, J=6.59Hz), 7.15-7.48 (m, 10H), 7.54-7.57 (m, 2H), 7.69-7.91 (m, 2H).
Embodiment 38:N
1-methyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (18g)
Preparation process reference compound 18a, make compound 17d (1.2g, 2.34mmol) and methylamine alcohol solution (15ml) reaction, product 18g (1.07g, 92.2%)
1NMR (CDCl
3) δ 1.25 (d, 3H, J=6.59Hz), 2.36 (s, 3H), 3.22 ((d, 3H, J=5.13Hz), 4.32 (q, 1H, J=6.74Hz), 7.14-7.41 (m, 10H), 7.53-7.57 (m, 2H), 7.62-7.72 (m, 2H).
Embodiment 39:N
1-cyclopropyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxy-4-phenyl-5-methyl-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (18h)
Preparation process reference compound 18a, make compound 17d (1.23g, 2.40mmol) and cyclopropylamine (4ml) reaction, product 18h (1.16g, 92.7%)
1NMR (CDCl
3) δ 0.38-0.86 (4m, 4H), 1.26 (d, 3H, J=6.6Hz), 2.36 (s, 3H), 3.22-3.25 (m, 1H), 4.38 (q, 1H, J=6.59Hz), 7.17-7.40 (m, 10H), 7.53-7.64 (m, 4H).
Embodiment 40:N
1-methyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-5-methyl isophthalic acid H-pyrazoles-1-carbonyl amidine (19a)
With compound 18a (0.29g, 0.57mmol) be dissolved in pyridine (6ml) after, under ice bath, drip phosphorus oxychloride (0.20ml) and continue to stir 30 minutes, with reaction mixture temperature rising reflux 3 hours, reaction mixture is poured in the ice bath, with extracted with diethyl ether (30ml), 1N salt acid elution is removed pyridine, the organic layer dried over sodium sulfate, filter, decompression removes solvent, and residue carries out column chromatography (developping agent sherwood oil: ethyl acetate=5: 1) get white solid product 19a (38mg, 72.1%)
1NMR (CDCl
3): δ 2.23 (s, 3H), 3.64 (s, 3H), 7.10-7.40 (m, 10H), 7.53-7.56 (m, 2H), 7.93-7.96 (m, 2H).
Embodiment 41:N
1-cyclopropyl-N
2-(4-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-5-methyl isophthalic acid H-pyrazoles-1-carbonyl amidine (19f)
Preparation process reference compound 19a, make compound 18f (0.3g, 0.57mmol) and phosphorus oxychloride (0.30ml) reaction, product 19f (65mg, 22.4%)
1NMR (CDCl
3): δ 1.09-1.23 (m, 2H), 2.21 (s, 3H), 2.43 (s, 3H), 3.58-3.59 (m, 1H), 7.08-7.39 (m, 11H), 7.87-7.90 (m, 2H).
Embodiment 42:N
1-cyclopropyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-5-methyl isophthalic acid H-pyrazoles-1-carbonyl amidine (19b)
Preparation process reference compound 19a, make compound 18b (0.96g, 1.77mmol) and phosphorus oxychloride (0.30ml) reaction, product 19b (0.79g, 85.2%)
1NMR (CDCl
3): δ 1.12-1.24 (m, 4H), 2.22 (s, 3H), 3.57-3.58 (m, 1H), 7.09-7.54 (m, 11H), 7.93-7.95 (m, 2H).
Embodiment 43:N
1-methyl-N
2-(4-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-5-methyl isophthalic acid H-pyrazoles-1-carbonyl amidine (19e)
Preparation process reference compound 19a, make compound 18e (0.89g, 1.79mmol) and phosphorus oxychloride (0.30ml) reaction, product 19e (0.19g, 22.1%)
1NMR (CDCl
3): δ 2.24 (s, 3H), 2.44 (s, 3H), 3.63 (s, 3H), 7.10-7.40 (m, 12H), 7.87-7.89 (m, 2H).
Embodiment 44:N
1-methyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-5-methyl isophthalic acid H-pyrazoles-1-carbonyl amidine (19g)
Preparation process reference compound 19a, make compound 18g (0.99g, 2.01mmol) and phosphorus oxychloride (0.30ml) reaction, product 19g (0.53g, 55.1%)
1NMR (CDCl
3): δ 2.25 (s, 3H), 2.44 (s, 3H), 3.64 (s, 3H), 7.10-7.45 (m, 12H), 7.79-7.82 (m, 2H).
Embodiment 45:N
1-methyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-5-methyl isophthalic acid H-pyrazoles-1-carbonyl amidine (19c)
Preparation process reference compound 19a, make compound 18c (0.89g, 1.72mmol) and phosphorus oxychloride (0.30ml) reaction, product 19c (0.14g, 15.8%).
1NMR(CDCl
3)：δ2.25(s，3H)，3.65(s，3H)，7.10-7.63(m，12H)，7.88-8.00(m，2H)。
Embodiment 46:N
1-cyclopropyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-5-methyl isophthalic acid H-pyrazoles-1-carbonyl amidine (19d)
Preparation process reference compound 19a, make compound 18d (1.06g, 1.95mmol) and phosphorus oxychloride (0.30ml) reaction, product 19d (0.45g, 43.9%).
1NMR(CDCl
3)：δ1.11-1.23(m，4H)，2.23(s，3H)，3.58(m，1H)，7.10-7.62(m，12H)，7.87-8.01(m，2H)。
Embodiment 47:N
1-cyclopropyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-5-methyl isophthalic acid H-pyrazoles-1-carbonyl amidine (19h)
Preparation process reference compound 19a, make compound 18h (1.03g, 1.97mmol) and phosphorus oxychloride (0.30ml) reaction, product 19h (0.52g, 52.4%).
1NMR(CDCl
3)：δ1.10-1.24(m，4H)，2.21(s，3H)，2.43(s，3H)，3.59(m，1H)，7.09-7.44(m，12H)，7.79-7.81(m，2H)。
Embodiment 48:2,4-dichloro phenyllacetyl chloride (20)
With 2,4 dichloro benzene acetate (20.50g 0.10mol) refluxed about 2 hours with thionyl chloride (20ml) mixture heating up, the thionyl chloride that underpressure distillation is excessive, the residuum underpressure distillation gets flaxen fluid cpds 20 (14.80g, 66.2%).
Embodiment 49:2-(2, the 4-chloro-phenyl-)-1-chloro-acetophenone (21)
At room temperature, compound 20 (14.80g, 0.07mol) be added drop-wise to aluminum chloride (10.00g, 0.08mol) and in the mixture of chlorobenzene (30ml), after adding reaction mixture is warmed up to 100 ℃ no longer include bubble and generate to reaction till, reaction mixture is poured in the tart frozen water, the solid that filtration is separated out, washing, drying, get white solid product 21 (17g, 85.7%).
1NMR(CDCl
3)：δ4.38(s，2H)，7.17-7.27(m，2H)，7.44-7.42(m，3H)，7.97-7.99(m，2H)。
Embodiment 50:1-(4-chloro-phenyl-)-2-(2,4 dichloro benzene base) propyl group-2-alkene-1-ketone (22)
With compound 21 (8.99g, 0.03mol) and after methyl alcohol (120ml) mixes, add piperidines (0.28ml), glacial acetic acid (0.28ml) successively, formalin solution (10ml), with the mixture temperature rising reflux of gained to raw material reaction fully till (about 4 hours), then reaction mixture is cooled off, separate out the crystalline product of white, filter, get compound 22 (6.2g, 66.3%).
1NMR(CDCl
3)：δ5.97(s，1H)，6.10(s，1H)，7.26-7.47(m，5H)，7.85-7.89(m，2H)。
Embodiment 51:1-(4-chloro-phenyl-carbonyl)-1-(2,4 dichloro benzene base) oxyethane (23)
With compound 22 (1.80g, 5.78mmol), methylene dichloride (15ml) and metachloroperbenzoic acid (1.76g, 10.2mmol) mix after, temperature rising reflux (about 16 hours) till react completely.With reaction mixture with the washing of the saturated sodium bicarbonate of capacity till no longer emit bubble.The organic layer dried over sodium sulfate of gained is carried out column chromatography (developping agent sherwood oil: ethyl acetate=30: 1) get faint yellow oily product (1.35g, 71.3%).
1NMR(CDCl
3)：δ3.08-3.76(4d，2H，J＝6.34Hz)，7.31-7.96(m，7H)。
Embodiment 52:3-(4-chloro-phenyl-)-4-hydroxyl-4-(2, the 4-chloro-phenyl-)-4,5-dihydro-1 h-pyrazole (24)
With compound 23 (0.60g, 1.83mmol) be dissolved in ethanol (5ml) after, add 85% hydrazine hydrate (1ml) under the room temperature, then 35 ℃ of following insulations till react completely (about about 20 hours), then reaction mixture sat is spent the night and separate out the solid product (0.32,51.1%) of white.
1NMR(DMSO-d
6)：δ3.54(d，1H，J＝12.02Hz)，3.82(d，1H，J＝12.02Hz)，7.22-7.52(m，6H)，8.02(d，1H，J＝8.5Hz)。
Embodiment 53:3-(4-chloro-phenyl-)-N-(4-chloro-phenyl-alkylsulfonyl)-4-hydroxyl-4-(2,4 dichloro benzene base)-4,5-dihydro-1 h-pyrazole-1-carbonyl imines thio-methyl ester (25a)
Make compound 24 (1.50g; 4.39mmol) and [(4-chloro-phenyl-) alkylsulfonyl] two sulfilimine methylcarbonate (7a) (1.30g; 4.39mmol), acetonitrile (18ml), the mixture of triethylamine (1.3ml) react under the condition that refluxes to raw material reaction fully till (about three days).Then reaction mixture is concentrated into driedly, adds methylene dichloride 30ml, the water thorough washing, the organic layer dried over sodium sulfate is concentrated into dried column chromatography (the developping agent sherwood oil: ethyl acetate=8: 1) must white solid 25a (2.11g, 81.6%) that carries out.
1NMR(CDCl
3)：δ2.31(s，3H)，4.82-4.92(d?br，3H)，7.21-7.57(m，6H)，7.55-7.57(m，2H)，7.81-7.84(m，2H)，8.00(d，1H，J＝8.43Hz)。
Embodiment 54:3-(4-chloro-phenyl-)-N-(4-aminomethyl phenyl alkylsulfonyl)-4-hydroxyl-4-(2,4 dichloro benzene base)-4,5-dihydro-1 h-pyrazole-1-carbonyl imines thio-methyl ester (25c)
Preparation process reference compound 25a, (1.50g, 4.39mmol) (1.21g, 4.39mmol) reaction gets product 25c (1.85g, 74%) with compound 71 to make compound 24.
1NMR(CDCl
3)：δ2.30(s，3H)，2.35(s，3H)，4.81-4.89(m，3H)，7.10-7.37(m，6H)，7.55-7.60(m，2H)，7.77-7.79(m，2H)，8.02(d，1H，J＝8.5Hz)。
Embodiment 55:3-(4-chloro-phenyl-)-N-(3-aminomethyl phenyl alkylsulfonyl)-4-hydroxyl-4-(2,4 dichloro benzene base)-4,5-dihydro-1 h-pyrazole-1-carbonyl imines thio-methyl ester (25d)
Preparation process reference compound 25a, (1g, 2.93mmol) (0.81g, 2.93mmol) reaction gets product 25d (0.98g, 59.1%) with compound 7g to make compound 24.
1NMR(CDCl
3)：δ2.29(s，3H)，2.32(s，3H)，4.85-4.87(m，2H)，5.11(br?s，1H)，7.18-7.36(m，6H)，7.55-7.59(m，2H)，7.69-7.73(m，2H)，8.01(d，1H，J＝8.61Hz)。
Embodiment 56:3-(4-chloro-phenyl-)-N-(3-chloro-phenyl-alkylsulfonyl)-4-hydroxyl-4-(2,4 dichloro benzene base)-4,5-dihydro-1 h-pyrazole-1-carbonyl imines thio-methyl ester (25b)
Preparation process reference compound 25a, (1.00g, 2.93mmol) (0.87g, 2.93mmol) reaction gets product 25b (0.98g, 56.6%) with compound 7f to make compound 24.
1NMR(CDCl
3)：δ2.33(s，3H)，4.80(br?s，2H)，5.18(br?s，1H)，7.19-7.42(m，6H)，7.58(d，2H，J＝8.61Hz)，7.76-7.78(m，1H)，7.94-7.95(m，1H)，8.00(d，1H，J＝8.61Hz)。
Embodiment 57:N
1-methyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxyl-4-(2,4 dichloro benzene base)-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (26a)
With compound 25a (1.00g, 1.70mmol) be dissolved in methyl alcohol (20ml), behind the methylene dichloride (20ml), under stirring at room, add methylamine alcohol solution (15ml), then be stirred to raw material reaction fully till, reaction mixture is concentrated into dried column chromatography (the developping agent sherwood oil: ethyl acetate=5: 1), get white solid product 26a (0.90g, 92.7%) that carries out.
1NMR(CDCl
3)：δ3.09(d，3H，J＝5.02Hz)，4.42-4.54(m，2H)，5.19(s，1H)，7.01(s，1H)，7.17-7.36(m，6H)，7.48-7.53(m，2H)，7.76-7.80(m，2H)，7.98-8.01(m，1H)。
Embodiment 58:N
1-cyclopropyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxyl-4-(2,4 dichloro benzene base)-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (26b)
Preparation process reference compound 26a, make compound 25a (1.00g, 1.70mmol) and cyclopropylamine (4ml) reaction, product 26b (0.88g, 86.8%).
1NMR(DMSO)：δ0.54-0.68(m，4H)，2.94-2.97(m，1H)，4.27(m，2H)，7.35(d，2H，J＝2.05Hz)，7.37-7.64(m，6H)，7.82-7.86(m，2H)，8.06(d，1H，J＝8.5Hz)。
Embodiment 59:N
1-methyl-N
2-(4-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxyl-4-(2,4 dichloro benzene base)-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (26e)
Preparation process reference compound 26a, make compound 25c (0.90g, 1.58mmol) and methylamine alcohol solution (15ml) reaction, product 26e (0.35g, 40.1%).
1NMR(CDCl
3)：δ2.36(s，3H)，3.11(d.3H，J＝4.94Hz)，4.43-4.54(m，2H)，5.24(br，s，1H)，7.11-7.33(m，6H)，7.43-7.51(m，2H)，7.73-7.80(m，2H)，8.01(d，1H，J＝8.61Hz)。
Embodiment 60:N
1-cyclopropyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxyl-4-(2,4 dichloro benzene base)-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (26h)
Preparation process reference compound 26a, make compound 25d (1.00g, 1.76mmol) and cyclopropylamine (3ml) reaction, product 26h (0.55g, 54.5%).
1NMR(CDCl
3)：δ0.33-0.77(m，4H)，2.36(s，3H)，3.15-3.16(m，1H)，4.40-4.61(m，2H)，5.20(br，s，1H)，7.15-7.35(m，6H)，7.49-7.52(m，2H)，7.62-7.64(m，2H)，8.04(d，1H，J＝8.62Hz)。
Embodiment 61:N
1-methyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxyl-4-(2,4 dichloro benzene base)-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (26g)
Preparation process reference compound 26a, make compound 25d (0.55g, 0.97mmol) and methylamine alcohol solution (15ml) reaction, product 26g (0.35g, 64.8%).
1NMR(CDCl
3)：δ2.34(s，3H)，3.10(d，3H，J＝4.77Hz)，4.46-4.57(m，2H)，5.23(s，1H)，7.08-7.34(m，6H)，7.50-7.53(m，2H)，7.64-7.67(m，2H)，8.02(d，1H，J＝8.62Hz)。
Embodiment 62:N
1-cyclopropyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxyl-4-(2,4 dichloro benzene base)-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (26d)
Preparation process reference compound 26a, make compound 25b (0.50g, 0.85mmol) and cyclopropylamine (3ml) reaction, product 26d (0.42g, 86.1%).
1NMR(CDCl
3)：δ0.36-0.64(m，4H)，3.14(m，1H)，4.41-4.57(m，2H)，5.07(br，s，1H)，7.18-7.45(m，6H)，7.50-7.53(m，2H)，7.72-7.74(m，1H)，7.86(br，s，1H)，8.04(d，1H，J＝8.65Hz)。
Embodiment 63:N
1-methyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxyl-4-(2,4 dichloro benzene base)-4,5-dihydro-1 h-pyrazole-1-carbonyl amidine (26c)
Preparation process reference compound 26a, make compound 25b (0.50g, 0.85mmol) and methylamine alcohol solution (15ml) reaction, product 26c (0.42g, 86.5%).
1NMR(CDCl
3)：δ3.11(d，3H，J＝4.98Hz)，4.45-4.56(m，2H)，5.18(br，s，1H)，7.05-7.44(m，6H)，7.51-7.54(m，2H)，7.74-7.77(m，1H)，7.86-7.87(m，1H)，8.02(d，1H，J＝8.5Hz)。
Embodiment 64:N
1-cyclopropyl-N
2-(4-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-hydroxyl-4-(2,4 dichloro benzene base)-4,5-dihydro-1 h-pyrazole-1-carboxylic amidine (26f)
Preparation process reference compound 26a, make compound 25c (0.85g, 1.50mmol) and cyclopropylamine (3ml) reaction, product 26f (0.83g, 96.1%).
1NMR(CDCl
3)：δ0.36-0.64(m，4H)，2.38(s，3H)，3.14-3.15(m，1H)，4.38-4.61(m，2H)，5.16(s，1H)，7.15-7.34(m，6H)，7.48-7.51(m，2H)，7.70-7.72(m，2H)，8.03(d，1H，J＝8.43Hz)。
Embodiment 65:N
1-methyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (27a)
With compound 26a (0.80g, 1.40mmol) be dissolved in pyridine (8ml) after, under ice bath, drip phosphorus oxychloride (0.40ml), drip off the back and under the condition that refluxes, stirred 2 hours, then reaction mixture is poured in the frozen water, use extracted with diethyl ether, organic layer 1N salt acid elution, the dried over sodium sulfate organic layer carries out column chromatography (sherwood oil: ethyl acetate=5: 1) get white solid product 27a (0.32g, 41.3%).
1NMR(CDCl
3)：δ3.51(d，3H，J＝4.03Hz)，7.15-7.93(m，12H)，8.21(s，1H)。
Embodiment 66:N
1-cyclopropyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (27b)
Preparation process reference compound 27a, make compound 26b (0.88g, 1.47mmol) and phosphorus oxychloride (0.30ml) reaction, product 27b (0.11g, 12.3%).
1NMR(CDCl
3)：δ0.91-1.12(dbr，s，4H)，3.50(br，1H)，7.14-7.93(m，12H)，8.15(s，1H)。
Embodiment 67:N
1-methyl-N
2-(4-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (27e)
Preparation process reference compound 27a, make compound 26e (0.40g, 1.47mmol) and phosphorus oxychloride (0.30ml) reaction, product 27e (0.13g, 33.6%).
1NMR(CDCl
3)：δ2.42(s，3H)，3.51(d，3H，J＝5.31Hz)，7.17-7.90(m，12H)，8.25(s，1H)。
Embodiment 68:N
1-cyclopropyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (27h)
Preparation process reference compound 27a, make compound 26h (0.50g, 0.87mmol) and phosphorus oxychloride (0.30ml) reaction, product 27h (0.20g, 42.1%).
1NMR(CDCl
3)：δ0.90-1.10(m，4H)，2.43(s，3H)，3.57(m，1H)，7.15-7.82(m，12H)，8.21(s，1H)。
Embodiment 69:N
1-methyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (27g)
Preparation process reference compound 27a, make compound 26g (0.34g, 0.62mmol) and phosphorus oxychloride (0.30ml) reaction, product 27g (0.19g, 58.3%).
1NMR(CDCl
3)：δ2.43(s，3H)，3.52(d，3H，J＝5.28Hz)，7.15-7.89(m，12H)，8.26(s，1H)。
Embodiment 70:N
1-cyclopropyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (27d)
Preparation process reference compound 27a, make compound 26d (0.45g, 0.78mmol) and phosphorus oxychloride (0.30ml) reaction, product 27d (46mg, 10.5%).
1NMR(CDCl
3)：δ0.92-1.13(m，4H)，3.51(m，1H)，7.14-8.01(m，12H)，8.18(s，1H)。
Embodiment 71:N
1-methyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (27c)
Preparation process reference compound 27a, make compound 26c (0.50g, 0.87mmol) and phosphorus oxychloride (0.30ml) reaction, product 27c (0.15g, 29.9%).
1NMR(CDCl
3)：δ3.52(d，3H，J＝5.32Hz)，7.16-8.00(m，11H)，8.23(s，1H)。
Embodiment 72:N
1-cyclopropyl-N
2-(4-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine (27f)
Preparation process reference compound 27a, make compound 26f (0.91g, 1.58mmol) and phosphorus oxychloride (0.30ml) reaction, product 27f (55mg, 6.2%).
1NMR(CDCl
3)δ：0.83-1.07(m，4H)，2.42(s，3H)，3.55-3.56(m，1H)，7.14-7.89(m，12H)，8.20(s，1H)。
Embodiment 73:CB1/CB2 receptor competition is in conjunction with experiment
Experimental principle
Utilize testing compound and isotope-labeled known ligand [
3H]-CP55940 to the competition of CB2 acceptor in conjunction with judging the affine degree of testing compound to acceptor.Testing compound is to the affine degree height of acceptor, a little less than the combination of isotropic substance part just, and the corresponding attenuating of reading; If instead testing compound is low to the affine degree of acceptor, then the combination of isotropic substance part is just strong, and reading is corresponding higher.
Experimentation:
With the Chinese hamster ovary celI kind of stably express CB1 or CB2 acceptor to 96 orifice plates, 37 ℃ of overnight incubation.Substitute normal substratum with serum free medium, hatched 2 hours for 37 ℃.
2. add certain density testing compound (each compound is got 8 concentration gradients, 3 multiple holes) or known CB
1Or CB
2Antagonist Rimonabant (positive control), incubated at room 10 minutes.The negative contrast of solvent DMSO.
3. add isotopic labeling part [3H]-CP55940 (available from PerkinElmer company), final concentration is 1.7nM, incubated at room 30 minutes.
4. wash cell 3 times with damping fluid.Lysing cell adds an amount of scintillation solution, reads plate on Micro-Beta liquid scintillation counter (available from PerkinElmer company).
5. data processing, with 200 μ M Rimonabant to 1.7nM[3H]-inhibiting rate of CP55940 is 100%, with testing compound and its relatively.Use GraphPad Prism software to carry out curve fitting, obtain the IC50 of testing compound, calculate its Ki value and 95% fiducial limit.
The molecular structural formula of representative compounds of the present invention and the biological activity test of part of compounds the results are shown in Table 3.
The molecular structural formula of table 3 representative compounds of the present invention
And part of compounds is to the avidity of CB1, CB2 acceptor
As known from Table 3, The compounds of this invention and to CB
1Acceptor has very strong avidity and high selectivity.And no matter be to the avidity of CB1 acceptor or to the selectivity of CB1 acceptor, all be far superior to positive control medicine Rimonabant.
Especially compound 4a, 27c and 27h obviously are better than Rimonabant to the avidity of CB1 acceptor; 4a, 4f, 19e, 27a, 27c, 27d, 27g and 27h are far superior to positive control medicine Rimonabant to the selectivity of CB1 acceptor.
4a particularly, 27c compare with Rimonabant the avidity of CB1 acceptor with 27h and have improved 3-5 doubly, and the selectivity of CB1 acceptor has been improved 5-7 respectively doubly.This explanation The compounds of this invention has stronger pharmacologically active and lower side effect.
Embodiment 74: pharmaceutical composition
Compound 4a 20g
Starch 140g
Microcrystalline Cellulose 60g
According to a conventional method, after above-mentioned substance mixed, the common gelatine capsule of packing into obtained 1000 capsules.
By similar approach, make the capsule that contains compound 27c or 27h respectively.
Embodiment 75: the preparation of capsule
Compound 4a 50g
Starch 400g
Microcrystalline Cellulose 200g
According to a conventional method, after the pharmaceutical composition of embodiment 74 gained mixed, the common gelatine capsule of packing into obtained 1000 capsules.
By similar approach, make the capsule that contains compound 27c or 27h respectively.
All quote in this application as a reference at all documents that the present invention mentions, just quoted as a reference separately as each piece document.Should be understood that in addition those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.
Claims (10)
1. compound shown in the formula (I), or its pharmaceutically acceptable inorganic or organic salt:
In the formula, R
1, R
2, R
3, R
4Independent respectively is hydrogen, chlorine, fluorine, bromine, hydroxyl, nitro, C
1-C
6Alkyl or C
1-C
6Alkoxyl group;
R
5, R
6, R
7Independent respectively is hydrogen, C
1-C
6Alkyl or C
3-C
6Cycloalkyl;
R
8, R
9Independent respectively is hydrogen, chlorine, fluorine, bromine, cyano group, nitro, trifluoromethyl, C
1-C
6Alkyl or C
1-C
6Alkoxyl group;
Wherein, described alkyl, cycloalkyl or alkoxyl group can have 1-3 substituting group that is selected from down group: halogen, hydroxyl, nitro or amino.
2. compound as claimed in claim 1 is characterized in that R
1And R
2Be hydrogen or chlorine.
3. compound as claimed in claim 1 is characterized in that R
3And R
4Be chlorine; And/or R
5Be methyl.
4. compound as claimed in claim 1 is characterized in that R
6And R
7At least one group is methyl or cyclopropyl; And/or R
8And R
9In at least one group be chlorine or methyl.
5. compound as claimed in claim 1 is characterized in that, described compound is selected from down group:
N
1-methyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-1H-pyrazoles-1-carbonyl amidine;
N
1-methyl-N
2-(3-trifluoromethyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-1H-pyrazoles-1-carbonyl amidine;
N
1-methyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-1H-pyrazoles-1-carbonyl amidine;
N
1-methyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-1H-pyrazoles-1-carbonyl amidine;
N
1-methyl-N
2-(4-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-5-methyl isophthalic acid H-pyrazoles-1-carbonyl amidine;
N
1-methyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-phenyl-5-methyl isophthalic acid H-pyrazoles-1-carbonyl amidine;
N
1-methyl-N
2-(4-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine;
N
1-methyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine;
N
1-cyclopropyl-N
2-(3-chloro-phenyl-alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine;
N
1-methyl-N
2-(4-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine; Or
N
1-cyclopropyl-N
2-(3-aminomethyl phenyl alkylsulfonyl)-3-(4-chloro-phenyl-)-4-(2,4 dichloro benzene base)-1H-pyrazoles-1-carbonyl amidine.
6. a pharmaceutical composition is characterized in that, it contains acceptable vehicle or carrier on the pharmacology, and the described compound of claim 1 or its pharmaceutically acceptable inorganic or organic salt.
7. described compound of claim 1, or the purposes of its pharmaceutically acceptable inorganic or organic salt is characterized in that, are used to prepare CB1 receptor antagonist and/or inverse agonist.
8. described compound of claim 1, or the purposes of its pharmaceutically acceptable inorganic or organic salt is characterized in that, are used to prepare treatment, prevention and alleviate medicine by the receptor-mediated disease of CB1.
9. purposes as claimed in claim 8 is characterized in that, describedly is selected from down group by the receptor-mediated disease of CB1:
Obesity, diabetes, hyperlipidemia, hypertension, constipation, chronic intestinal obstruction or liver cirrhosis.
10. the method for compound shown in the preparation formula (I) is characterized in that, comprises step:
(1) in the presence of alkali, in inert solvent,, forms compd B with the reaction of the sulfonamide compounds shown in compd A and the formula Z1;
(2) in inert solvent, the compound shown in compd B and the formula Z2 is carried out nucleophilic substitution reaction, form Compound C;
(3) in inert solvent, make Compound C remove a part water, form compound shown in the formula (I),
In above-mentioned each reaction formula, R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8And R
9Definition according to claim 1.
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| Publication Number | Publication Date |
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| CN101318931B true CN101318931B (en) | 2010-05-19 |
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| CN200710041558A Expired - Fee Related CN101318931B (en) | 2007-06-04 | 2007-06-04 | Diaryl substituted pyrazole derivative, preparation method and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1486301A (en) * | 2001-03-22 | 2004-03-31 | ������ҩ������˾ | 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity |
| CN1529595A (en) * | 2001-09-21 | 2004-09-15 | ������ҩ������˾ | 4,5-hydro-1H-pyrazole derivative having protent CB1-antagonistic |
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2007
- 2007-06-04 CN CN200710041558A patent/CN101318931B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1486301A (en) * | 2001-03-22 | 2004-03-31 | ������ҩ������˾ | 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity |
| CN1529595A (en) * | 2001-09-21 | 2004-09-15 | ������ҩ������˾ | 4,5-hydro-1H-pyrazole derivative having protent CB1-antagonistic |
Non-Patent Citations (2)
| Title |
|---|
| Jos H. M. Lange,et al.Synthesis, Biological Properties, and Molecular ModelingInvestigations of Novel 3,4-Diarylpyrazolines as Potent andSelective CB1 Cannabinoid Receptor Antagonists.J. Med. Chem47 3.2003,47(3),627-643. |
| Jos H.M.Lange,et al.Synthesis,Biological Properties,and Molecular ModelingInvestigations of Novel 3,4-Diarylpyrazolines as Potent andSelective CB1 Cannabinoid Receptor Antagonists.J.Med.Chem47 3.2003,47(3),627-643. * |
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| CN101318931A (en) | 2008-12-10 |
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