CN101314591B - Novel pyrazoles highly-selective marijuana acceptor-1antagon and/or reversed activation agent - Google Patents
Novel pyrazoles highly-selective marijuana acceptor-1antagon and/or reversed activation agent Download PDFInfo
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- CN101314591B CN101314591B CN200710041437XA CN200710041437A CN101314591B CN 101314591 B CN101314591 B CN 101314591B CN 200710041437X A CN200710041437X A CN 200710041437XA CN 200710041437 A CN200710041437 A CN 200710041437A CN 101314591 B CN101314591 B CN 101314591B
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Abstract
The invention relates to a constitutional formula of receptor antagonist and/or inverse agonist of novel cannabinoid receptor type 1 (CB1) receptor shown in the right formula (I), the preparation method and the application thereof. The compounds can be used for curing, preventing or relieving CB1 receptor mediated diseases. The compounds and the pharmaceutically-acceptable salts thereof can be used for curing, preventing or relieving obesity, diabetes, drug dependence, cognitive deficit, neurological disease, gastrointestinal tract disease and liver cirrhosis.
Description
Technical field
The present invention relates to the novel diaryl substituted pyrazole derivative of a class, Preparation Method And The Use.This compounds has very strong Cannabined receptor-1 (Cannabinoid receptor type1, CB1) receptor antagonist and/or inverse agonist and have very high CB2/CB1 to select ratio, acceptable salt can be used for treatment, prevention or alleviates that the receptor-mediated disease of CB1 is arranged on The compounds of this invention and the pharmacology thereof, as obesity, diabetes, drug dependence, cognitive defect, nervous system disorders, gastrointestinal tract disease and liver cirrhosis.
Background technology
Obesity is a kind of complexity, the multifactor metabolic trouble 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 to cause coronary artery disease, hypertension, hyperlipidemia, diabetes, tumour, cardiovascular and cerebrovascular diseases, the high risk factor of diseases such as sacroiliitis and somnopathy.Only the U.S. annual with overweight and fat relevant death toll with regard to big by 300,000 [Drugs of Future2005,30 (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 is in the cerebral hippocampus district, lamina corticalis, cerebellum, basic nervous center (basal ganglia) and some peripheral tissues such as fat, gi tract, lung, reproductive system and cardiovascular systems have high level expression, the CB2 acceptor is mainly expressed [J.Med.Chem.2004,47,627] in immunity system.Studies show that CB1 receptor-blocking agent or inverse agonist (antagonist/inverse agonist) have treatment a series of disease such as the obesities relevant with the CB1 acceptor, diabetes, mental disorder, the potentiality of 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-blocking agent can effectively reduce the picked-up of food, lowering blood glucose, withdrawal drug dependence (as smoking).
Existing document and patent [Expert.Opin.Ther.Patents2002,12 (10), 1475; IDrugs2005,8 (1), 53; Expert.Opin.Ther.Patents2004,14 (10), 1435; Current Medicinal Chemistry, 2005,12,1361] a series of CB1 receptor-blocking agent or inverse agonist are disclosed.United States Patent (USP) 5624941 and WO2006/074445 disclose pyrazole derivatives and CB1 acceptor blocking activity thereof, WO02/076949 discloses a class and has had the chirality 4 of very strong CB1 acceptor blocking activity, 5-pyrazoline derivative, the novel heterocycle pyrazole analogs that acts on the CB1 acceptor of WO2006/074445 one class, WO03/077847 disclose the substituted amide compound with the retardance of CB1 acceptor and/or reverse agonist activity.
Yet these compounds also exist avidity satisfactory inadequately in the prior art, and to shortcomings such as the CB1 receptor-selective are lower, so to press for exploitation new for CB in this area
1Acceptor has the antagonist and/or the inverse agonist of highly selective.
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 method for making and purposes to the CB1 acceptor.
In a first aspect of the present invention, provide novel highly selective CB1 receptor-blocking agent and/or the inverse agonist shown in a kind of formula (I), i.e. compound shown in the formula (I), or its crystal formation, pharmacy acceptable salt, hydrate or solvate:
In the formula, R is n-propyl or sec.-propyl;
X
1, X
2Independent respectively is chlorine or bromine.
In another preference, X
2Be chlorine.
In another preference, R is a sec.-propyl.
In another preference, described compound is selected from down group:
5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-propyl group-N-(piperidino)-1H-pyrazole-3-formamide (Ia);
5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-propyl group-N-(piperidino)-1H-pyrazole-3-formamide (Ib);
5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-sec.-propyl-N-(piperidino)-1H-pyrazole-3-formamide (Ic); Or
5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-sec.-propyl-N-(piperidino)-1H-pyrazole-3-formamide (Id).
In a second aspect of the present invention, the method for the compound shown in a kind of preparation formula (I) is provided, comprise step:
(1) in inert organic solvents, in the presence of sodium iodide and alkali,, forms compound 2 with compound 1 and the reaction of trimethylammonium halosilanes;
(2) compound 2 and chloroformyl ethyl formate react under Louis acid catalysis, form compound 3;
(3) in inert solvent, under the catalysis of tosic acid, Phenylsulfonic acid and/or methylsulfonic acid, compound 3 and the reaction of 2,4 dichloro benzene hydrazonium salt hydrochlorate generation cyclodehydration form compound 4;
(4) compound 4 hydrolysis under the effect of alkali forms compound 5;
(5) compound 5 and acylating reagent generation acylation reaction with the reaction of 1-anilinic piperidines, form formula (I) compound then:
Wherein, in above-mentioned each reaction formula, R is n-propyl or sec.-propyl; And X
1, X
2Independent respectively is chlorine or bromine.
In another preference, described method also comprises step: isolate the compound shown in the formula (I) from reaction mixture.
In third aspect present invention, provide and contained that compound is the pharmaceutical composition of main active ingredient shown in the formula (I).Particularly, provide a kind of pharmaceutical composition, it contains pharmaceutically acceptable carrier and the above-mentioned compound of the present invention, or its crystal formation, pharmacy acceptable salt, hydrate or solvate.
In a fourth aspect of the present invention, compound compound shown in the formula (I) is provided, or the purposes of its crystal formation, pharmacy acceptable salt, hydrate or solvate, they are used to prepare CB1 receptor antagonist and/or inverse agonist, and/or are used to treatment, prevention and alleviation by CB
1The medicine of receptor-mediated disease.
In another preference, described by CB
1Receptor-mediated disease is selected from down group:
(a) mental disorder, dysmnesia, cognitive illnesses, cerebrovascular disease, multiple sclerosis, anxiety disorder, epilepsy, Parkinson's disease, dyskinesia or schizophrenia;
(b) to the abuse of materials such as opium, alcohol, hemp and Nicotine;
(c) obesity, diabetes, hyperlipidemia, hypertension are with constipation, chronic intestinal obstruction or liver cirrhosis.
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
As used herein, term " The compounds of this invention " refers to the compound shown in the formula (I).This term also comprises and various crystalline forms, pharmacy acceptable salt, hydrate or the solvate of formula (I) compound.
As used herein, term " pharmacy acceptable salt " refers to the formed salt that is suitable as medicine of The compounds of this invention and acid or alkali.Pharmacy acceptable salt comprises inorganic salt and organic salt.The preferred salt of one class is The compounds of this invention and the sour salt that forms.Being fit to the salifiable acid of shape includes, but are not limited to: mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, organic acids 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 acidic amino acid such as aspartic acid, L-glutamic acid.
The preparation method
The preparation method of formula of the present invention (I) structural compounds is more specifically described below, but these concrete grammars do not constitute any restriction to the present invention, in addition, reaction conditions, 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 a preference, formula of the present invention (I) compound can be by following flow preparation:
Wherein, rt is a room temperature; Reflux is for refluxing; Toluenen is a toluene, and PTSA is a tosic acid.
In this flow process, each reaction in inert solvent, is carried out to reflux 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.
Step 1. compound 1[can be available from Aldrich company] with the trimethylammonium halosilanes in the presence of sodium iodide and alkali, in appropriate solvent, react and can obtain compound 2.
The trimethyl silicane alkyl halide that is fit to above-mentioned reaction is bromotrimethylsilane, trimethylchlorosilane or Iodotrimethylsilane; The alkali that is fit to above-mentioned reaction is organic bases and mineral alkali, and optimal alkali is triethylamine or pyridine.
The solvent that is fit to above-mentioned reaction is acetonitrile, methylene dichloride, chloroform, ether, tetrahydrofuran (THF), benzene, toluene.
Temperature of reaction is in-10 ℃～solvent refluxing temperature; Reaction times is 8-48 hour, generally can finish at 12 hours.
When aftertreatment, generally adopt column chromatography to separate and obtain target compound, sometimes also can not need purify, directly carry out the next step.
Step 2. compound 2 and chloroformyl ethyl formate react under Louis acid catalysis and obtain compound 3.
The Lewis acid that is fit to is Zinc Chloride Anhydrous, aluminum chloride, titanium tetrachloride or boron trichloride.
Be fit to above-mentioned reaction solvent be the miscellany of ether, methylene dichloride, benzene, toluene, tetrahydrofuran (THF) or above-mentioned solvent.A kind of optimum solvent is the mixed solvent that the volume ratio of toluene/ether/methylene dichloride is about 7:1:2.
Temperature of reaction is in-10 ℃～solvent refluxing temperature.
Step 3. compound 3 and 2,4 dichloro benzene hydrazonium salt hydrochlorate are under the catalysis of appropriate solvent and temperature and PTSA (tosic acid) or Phenylsulfonic acid or methylsulfonic acid, and cyclodehydration obtains compound 4.
The solvent that is fit to above-mentioned reaction is the miscellany of benzene, toluene, acetonitrile, methyl alcohol, ethanol, glycol dimethyl ether or above-mentioned solvent, and optimum solvent is a toluene.
Temperature of reaction is 5 ℃ and arrives the solvent refluxing temperature.In another preference, optimal reaction temperature is 5～50 ℃ for adding before the PTSA, is elevated to the solvent refluxing temperature after adding PTSA.
Do not need to purify when aftertreatment, the crude product that obtains directly carries out next step reaction.
Step 4. compound 4 hydrolysis under the effect of suitable alkali obtains compound 5.
The solvent that is fit to above-mentioned reaction is the miscellany of water, methyl alcohol, ethanol or above-mentioned solvent.A kind of optimum solvent is that the volume ratio of water and methyl alcohol is 1:1.
The temperature that is fit to above-mentioned reaction is 5 ℃ and arrives the solvent refluxing temperature.
The alkali that is fit to above-mentioned reaction is salt of wormwood, yellow soda ash, sodium hydroxide, potassium hydroxide, lithium hydroxide, and the alkali of optimum response reaction is potassium hydroxide.
Adopt crystallization or column chromatography to separate and obtain target compound.
Step 5. compound 5 at first in appropriate solvent with acylating reagent generation acylation reaction, under the effect of suitable alkali, generate target product (I) then with the effect of 1-anilinic piperidines.
The solvent that is fit to above-mentioned reaction is the miscellany of DMF, methylene dichloride, chloroform, acetonitrile, tetrahydrofuran (THF), ether or above-mentioned solvent; the acylating reagent that is fit to is thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, is the best with oxalyl chloride and thionyl chloride.Optimum solvent is methylene dichloride (can add several DMF in right amount).
The temperature that is fit to above-mentioned reaction is 0-50 ℃;
The best alkali that is fit to above-mentioned reaction is triethylamine and pyridine.
When aftertreatment, adopt column chromatography to separate and obtain target compound.
Step 6. can randomly be made corresponding pharmacy acceptable salt with formula (I) compound as required.
Pharmaceutical composition and application process
Because The compounds of this invention has excellent avidity and specificity at the CB1 acceptor, so 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) be used for the treatment of abuse to materials such as opium, alcohol, hemp and Nicotines.
(c) be used for the treatment of obesity, diabetes, hyperlipidemia, hypertension with constipation, chronic intestinal obstruction, liver cirrhosis etc.
Pharmaceutical composition of the present invention comprises on The compounds of this invention in the safe and effective weight range or its pharmacology acceptable vehicle or carrier on the acceptable salt and pharmacology.Wherein " safe and effective amount " 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, more preferably, contains 20-200mg The compounds of this invention/agent.
" pharmaceutically acceptable 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 carrier part example has 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 to tell
), 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 Varian Mercury400 nuclear magnetic resonance analyser record, 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 1:5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-propyl group-N-(piperidino)-1H-pyrazole-3-formamide (Ia)
A) trimethyl silane (2a) 1-(4-chloro-phenyl-) amyl group-1-enol base)
At N
2Protection down, with compound 1a (19.7g, 0.10mol) and triethylamine (13.9mL; 0.10mol) mixed; (12.7mL 0.10mol), drips and finishes slowly to drip trimethylchlorosilane down at 0 ℃; at following sodium iodide (15.0g of this temperature; 0.10mol) second eyeball (150mL) solution slowly splash in the reactor, spend the night 45-50 ℃ of heated and stirred, reaction finishes; the reaction solution concentrating under reduced pressure; add toluene (160mL) in the residue, pressure reducing and steaming toluene (approximately 60mL) removes by filter insolubles again; toluene wash filter cake three times; the filtrate that obtains is used anhydrous sodium sulfate drying, filters, and filtrate decompression concentrates; obtain product 2a (21.0g, 78%).
1H?NMR(CDCl
3)δ0.97(t，J＝7.50Hz，3H)，1.48-1.39(m，2H)，2.17(q，J＝7.51，7.31Hz，2H)，5.24(t，J＝7.14Hz，1H)，7.26(d，J＝11.16Hz，2H)，7.39(d，J＝11.16Hz，2H).
B) 3-propyl group-2,4-dicarbapentaborane-4-(4-chloro-phenyl-) butyric acid (5a)
At dry, N
2Protection down; (13.0g 95mmol) and toluene (98mL), refluxed 1～3 hour to add zinc chloride in there-necked flask; divide the moisture that goes wherein; drop to room temperature, add anhydrous diethyl ether (14mL), be cooled to 0 ℃; drip chloroformyl ethyl formate (17.4mL; methylene dichloride 156mmol) (26mL) solution dropwises reaction 10-20 minute, drips 2a (21.0g; 78mmol); after dripping off, be heated to 45 ℃, reacting 16 hours; the slow sodium bicarbonate aqueous solution that adds; regulate pH=7～8, with ethyl acetate (100mL * 3) extraction, organic phase water (40mL * 2) washing; saturated sodium-chloride water solution (40mL * 2) is washed; anhydrous magnesium sulfate drying filters the back and concentrates and obtain crude product 3a (21.8g, 94%) and can directly drop into next step reaction.
(29.7g 100mmol) is dissolved in the toluene (580mL), adds 2 in batches will to go up step product 3a, (21.4g 100mmol), at room temperature stirred 18 hours the 4-dichloride phenyl hydrazine hydrochloric acid salt, add PTSA (1.4g, 8.34mmol) refluxed 12 hours, question response liquid cool to room temperature removes by filter insolubles, filtrate water (50mL * 3) washing, anhydrous sodium sulfate drying filters the concentrated 4a (31.5g, 72%) that obtains in back.
To go up step product 4a (31.5g) and be dissolved in the methyl alcohol (340mL), add entry (340mL), stir, slowly add again potassium hydroxide (17.6g, 312mmol), back flow reaction 3 hours, pressure reducing and steaming methyl alcohol, regulate pH=1 with hydrochloric acid (5M),, merge organic phase with methylene dichloride (300mL * 3) extraction, use anhydrous sodium sulfate drying, filter, revolving desolvates obtains crude product (ethyl acetate: sherwood oil=8:1) obtains white solid product 5a (3.2g, 11%) through recrystallization.M.p.＝174-176℃；
1H?NMR(CDCl
3)δ0.87(t，J＝7.43Hz，3H)，1.62-1.57(m，2H)，2.71(t，J＝7.83Hz，2H
2)，7.08-8.08(m，7H).
C) compound (Ia)
At dry, N
2Protection is compound 5a (410mg down; 1.0mmol) and methylene dichloride (20mL) mixed, add a DMF (N, dinethylformamide) solution; slowly drip oxalyl chloride (0.45mL after the stirring and dissolving; 5.3mmol), finish, stirred 3 hours under the room temperature; concentrating under reduced pressure; residue is with methylene dichloride (20mL) dissolving, while stir slowly drip successively triethylamine (0.25mL, 1.7mmol) and anilinic piperidines (0.37g; 3.7mmol); drip off at room temperature react 13 hours after, wash reaction solution with water (10mL) once, anhydrous sodium sulfate drying; filter; concentrate, the residue column chromatography obtains Compound I a (339mg, 69%).M.p.＝214-217℃；
1H?NMR(CDCl
3)δ0.85(t，J＝7.33Hz，3H)，1.42(s，2H)，1.59(m，2H)，1.76(m，4H)，2.70(m，2H)，2.86(s，4H)，7.07(m，2H)，7.30-7.26(m，4H)，7.41(s，1H)，7.64(s，1H).
Embodiment 2:5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-propyl group-N-(piperidino)-1H-pyrazole-3-formamide (Ib)
A) trimethyl silane (2b) 1-(4-bromophenyl) amyl group-1-enol base)
Preparation process is with reference to 2a, and (24.1g 0.10mol) with the trimethylchlorosilane reaction, gets product 2b (28.0g, 90%) to compound 1b.
1H?NMR(CDCl
3)δ0.96(t，J＝7.44Hz，3H)，1.43(q，J＝7.04，7.44Hz，2H)，2.14(q，J＝7.44，7.43Hz，2H)5.25(t，J＝，7.04Hz，1H)，7.34(d，J＝10.95Hz，2H)，7.40(d，J＝10.57Hz，2H).
B) 3-propyl group-2,4-dicarbapentaborane-4-(4-bromophenyl) butyric acid (5b)
Preparation process is with reference to 5a, and (12.0g 26mmol) reacts with the chloroformyl ethyl formate earlier compound 2b, obtains compound 3b, again with 2,4 dichloro benzene hydrazonium salt hydrochlorate reacting generating compound 4b, obtains white solid product 5b (2.1g, 12%) through hydrolysis at last.M.p.＝168-170℃；
1H?NMR(CDCl
3)δ0.87(t，J＝7.33Hz，3H)，1.65-1.55(m，2H)，2.71(t，J＝7.70Hz，2H)，7.00-7.50(m，7H).
C) compound (Ib)
Preparation process reference compound Ia, (0.45g 1.00mmol) with the reaction of 1-anilinic piperidines, gets white solid product Ib (330mg, 62%) to compound 5b.M.P.＝176-178℃；
1H?NMR(CDCl
3)δ0.86(t，J＝7.34Hz，3H)，1.43(s，2H)，1.60(m，4H)，1.75(m，4H)，2.70(m，2H)，2.86(s，4H)，7.00(d，J＝8.42Hz，2H)，7.28(m，2H)，7.45-7.42(m，3H)，7.64(s，1H).
Embodiment 3:5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-sec.-propyl-N-(piperidino)-1H-pyrazole-3-formamide (Ic)
A) trimethyl silane (2c) 1-(4-chloro-phenyl-) isopentyl-1-enol base)
Preparation process is with reference to 2a, and (39.3g 0.20mol) with the trimethylchlorosilane reaction, gets product 2c (38.7g, 72%) to compound 1c.
1H?NMR(CDCl
3)δ1.04(d，J＝6.78Hz，6H)，2.75-2.85(m，1H)，5.04(d，J＝9.53Hz，1H)，7.26(d，J＝8.61Hz，2H)，7.39(d，J＝8.61Hz，2H).
B) 3-sec.-propyl-2,4-dicarbapentaborane-4-(4-chloro-phenyl-) butyric acid (5c)
Preparation process is with reference to 5a, and (25.1g 248mmol) reacts with the chloroformyl ethyl formate earlier compound 2c, obtain compound 3c, again with 2,4 dichloro benzene hydrazonium salt hydrochlorate reacting generating compound 4c, obtain white solid product 5c (0.66g, 1.5%) through hydrolysis at last.M.p.＝222-224℃；
1H?NMR(CDCl
3)δ1.25(d，J＝7.03Hz，6H)，3.37-3.28(m，1H)，7.22-7.56(m，7H).
C) compound (Ic)
Preparation process reference compound Ia, (0.50g 1.22mmol) with the reaction of 1-anilinic piperidines, gets white solid product Ic (311mg, 52%) to compound 5c.M.P.＝208-211℃；
1H?NMR(CDCl
3)δ1.28(d，J＝6.95Hz，6H)，1.43(m，2H)，1.78-1.73(m，4H)，2.86(m，4H)，3.31-3.24(m，1H)，7.06-7.10(m，2H)，7.20-7.30(m，4H)，7.40(d，J＝2.01Hz，1H)，7.67(s，1H).
Embodiment 4:5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-sec.-propyl-N-(piperidino)-1H-pyrazole-3-formamide (Id)
A) trimethyl silane (2d) 1-(4-bromophenyl) isopentyl-1-enol base)
Preparation process is with reference to 2a, and (24.1g 0.10mol) with the trimethylchlorosilane reaction, gets product 2d (20.3g, 65%) to compound 1d.
1H?NMR(CDCl
3)δ0.98(d，J＝7.38Hz，6H)，2.76-2.84(m，1H)，5.07(d，J＝9.53Hz，1H)，7.35(d，J＝8.58Hz，2H)，7.41(d，J＝8.59Hz，2H).
B) 3-sec.-propyl-2,4-dicarbapentaborane-4-(4-chloro-phenyl-) butyric acid (5d)
Preparation process is with reference to 5a, and (24.1g 52mmol) reacts with the chloroformyl ethyl formate earlier compound 2d, obtains compound 3d, again with 2,4 dichloro benzene hydrazonium salt hydrochlorate reacting generating compound 4d, obtains white solid product 5d (0.21g, 1.2%) through hydrolysis at last.
1H?NMR(CDCl
3)δ1.26(t，J＝7.13Hz，6H，2CH
3)，3.41-3.27(m，1H，CH)，7.20-7.62(m，7H，ArH).
C) compound (Id)
Preparation process reference compound Ia, (0.20g 0.44mmol) with the reaction of 1-anilinic piperidines, gets white solid product Id (80mg, 34%) to compound 5d.M.P.＝168-171℃；
1H?NMR(CDCl
3)δ1.27(d，J＝6.95Hz，6H)，1.43(m，2H)，1.78-1.72(m，4H)，2.87(m，4H)，3.28(m，1H)，7.05-7.11(m，2H)，7.18-7.30(m，4H)，7.45(d，J＝2.01Hz，1H)，7.66(s，1H).
Embodiment 5: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:
1. with stably express CB1 or CB
2The Chinese hamster ovary celI kind of 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 CB1 or CB2 antagonist Rimonabant (positive control), incubated at room 10 minutes.The negative contrast of solvent DMSO.
3. add the 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 Mi cro-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 IC of testing compound
50, calculate its Ki value and 95% fiducial limit.
Representative compounds biological activity test of the present invention the results are shown in Table 1.
Table 1 representative compounds of the present invention and to the avidity of CB1, CB2 acceptor
As known from Table 1, The compounds of this invention has the selectivity of very strong avidity and height to the CB1 acceptor, and no matter is to the avidity of CB1 acceptor or to the selectivity of CB1 acceptor, all is far superior to positive control medicine Rimonabant.
Particularly Ib compares with Rimonabant the avidity of CB1 acceptor with Id and has improved 2 times and 8 times respectively, and the selectivity of CB1 acceptor has been improved 13 times and 32 times respectively.This explanation The compounds of this invention has stronger pharmacologically active and lower side effect.
Embodiment 6 pharmaceutical compositions
Compound I d 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 I a or Ic respectively.
Embodiment 7 pharmaceutical compositions
Compound I d 50g
Starch 400g
Microcrystalline Cellulose 200g
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 I a or Ic 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 (11)
1. the compound shown in the formula (I), or its pharmacy acceptable salt:
In the formula, R is n-propyl or sec.-propyl;
X
1, X
2Independent respectively is chlorine or bromine.
2. compound as claimed in claim 1 is characterized in that X
2Be chlorine.
3. compound as claimed in claim 1 is characterized in that, R is a sec.-propyl.
4. compound as claimed in claim 1 is characterized in that, described compound is selected from down group:
5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-propyl group-N-(piperidino)-1H-pyrazole-3-formamide (Ia);
5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-propyl group-N-(piperidino)-1H-pyrazole-3-formamide (Ib);
5-(4-chloro-phenyl-)-1-(2,4 dichloro benzene base)-4-sec.-propyl-N-(piperidino)-1H-pyrazole-3-formamide (Ic); Or
5-(4-bromophenyl)-1-(2,4 dichloro benzene base)-4-sec.-propyl-N-(piperidino)-1H-pyrazole-3-formamide (Id).
5. the method for the compound shown in the preparation formula (I) is characterized in that, comprises step:
(1) in inert organic solvents, in the presence of sodium iodide and alkali,, forms compound 2 with compound 1 and the reaction of trimethylammonium halosilanes;
(2) compound 2 and chloroformyl ethyl formate react under Louis acid catalysis, form compound 3;
(3) in inert solvent, under the catalysis of tosic acid, Phenylsulfonic acid and/or methylsulfonic acid, compound 3 with
The reaction of generation cyclodehydration forms compound 4;
(4) compound 4 hydrolysis under the effect of alkali forms compound 5;
(5) compound 5 and acylating reagent generation acylation reaction with the reaction of 1-amino piperidine, form formula (I) compound then:
Wherein, in above-mentioned each reaction formula, R is n-propyl or sec.-propyl; And X
1, X
2Independent respectively is chlorine or bromine.
6. method as claimed in claim 5 is characterized in that, also comprises step: isolate the compound shown in the formula (I) from reaction mixture.
7. a pharmaceutical composition is characterized in that, it contains arbitrary described compound among pharmaceutically acceptable carrier and the claim 1-4, or its pharmacy acceptable salt.
8. described compound of claim 1, or the purposes of its pharmacy acceptable salt is characterized in that, is used to prepare CB1 receptor antagonist and/or inverse agonist.
9. described compound of claim 1, or the purposes of its pharmacy acceptable salt is characterized in that, the medicine that preparation is used for the treatment of, prevents and alleviates the disease that is mediated by Cannabined receptor-1.
10. purposes as claimed in claim 9 is characterized in that, described disease by Cannabined receptor-1 mediation is selected from down group:
(a) mental disorder, dysmnesia, cognitive illnesses, cerebrovascular disease, multiple sclerosis, epilepsy, Parkinson's disease or dyskinesia;
(b) to the abuse of opium, alcohol, hemp and Nicotine;
(c) obesity, diabetes, hyperlipidemia, hypertension, constipation, chronic intestinal obstruction or liver cirrhosis.
11. purposes as claimed in claim 10 is characterized in that, described is anxiety disorder or schizophrenia by the receptor-mediated disease of Cannabined receptor-1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0576357A1 (en) * | 1992-06-23 | 1993-12-29 | Sanofi | Pyrazole derivatives, process for their preparation and pharmaceutical compositions containing them |
| CN1207731A (en) * | 1995-12-08 | 1999-02-10 | 萨诺费公司 | 3-pyrazolecarboxamide derivs. having cannabinoid receptor affinity |
| CN1827603A (en) * | 2004-03-01 | 2006-09-06 | 康涅狄格大学 | Novel pyrazole analogs acting on cannabinoid receptors |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0576357A1 (en) * | 1992-06-23 | 1993-12-29 | Sanofi | Pyrazole derivatives, process for their preparation and pharmaceutical compositions containing them |
| US5624941A (en) * | 1992-06-23 | 1997-04-29 | Sanofi | Pyrazole derivatives, method of preparing them and pharmaceutical compositions in which they are present |
| CN1207731A (en) * | 1995-12-08 | 1999-02-10 | 萨诺费公司 | 3-pyrazolecarboxamide derivs. having cannabinoid receptor affinity |
| CN1827603A (en) * | 2004-03-01 | 2006-09-06 | 康涅狄格大学 | Novel pyrazole analogs acting on cannabinoid receptors |
Non-Patent Citations (2)
| Title |
|---|
| Murielle Rinaldi-Carmona et al..SR141716A, a potent and selective antagonist ofthe brain cannabinoid receptor.FEBS Letters350.1994,350240-244. * |
| MurielleRinaldi-Carmonaetal..SR141716A a potent and selective antagonist ofthe brain cannabinoid receptor.FEBS Letters350.1994 |
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