CN101735213A - Optical isomer of penehyclidine and medicinal composition and application thereof - Google Patents

Optical isomer of penehyclidine and medicinal composition and application thereof Download PDF

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CN101735213A
CN101735213A CN200810178611A CN200810178611A CN101735213A CN 101735213 A CN101735213 A CN 101735213A CN 200810178611 A CN200810178611 A CN 200810178611A CN 200810178611 A CN200810178611 A CN 200810178611A CN 101735213 A CN101735213 A CN 101735213A
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medicine
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acid
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CN101735213B (en
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仲伯华
郑建全
李美英
何新华
刘克良
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Yunnan Green Wildlife Medicine Co ltd
Institute of Pharmacology and Toxicology of AMMS
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Yunnan Green Wildlife Medicine Co ltd
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Abstract

The invention relates to an optical isomer of penehyclidine and a medicinal composition and application thereof, in particular to a compound shown in a formula Ia or Ib of basic optical voidness or a pharmaceutically acceptable salt or solvate. The invention also relates to a method for preparing the compound, the application of the compound serving as a selective M receptor antagonist, particularly serving as a selective M3 receptor antagonist, and the medicinal composition comprising the compound.

Description

The optical isomer of amyl ethyl quin ether and pharmaceutical composition thereof and purposes
Technical field
The present invention relates to compound shown in pure formula Ia of basic optical or the formula Ib, or its pharmacologically acceptable salts or solvate.The invention still further relates to the preparation method of described compound, as selectivity m receptor antagonist selectivity M particularly 3The purposes of receptor antagonist, and the pharmaceutical composition that comprises described compound.
Background technology
Penequine hydrochloride [English name: Penehyclidine Hydrochloride; Chemical name: 3-(2 '-hydroxyl-2 '-cyclopentyl-2 '-phenyl ethoxy) quinuclidine hydrochloride], its structure is as shown in the formula shown in the I
Figure G200810178611XD0000011
Amyl ethyl quin ether shown in the formula I belongs to ethyl cyclic hydrocarbon amido ether compounds, be a kind of m receptor antagonist class of novel texture anticholinergic agent (woods is forged etc. forever. institute of Military Medical Science Institute periodical, 1987,11,356.), clinically aspects such as organophosphate poisoning successfully have been used to give treatment to, its antitoxin height of tiring, effect is lasting, undesirable action is less (Ceng Fanzhong etc. CHINESE JOURNAL OF INTERNAL MEDICINE .1993,32,838; Qiao Jianzhong etc. Chinese Pharmaceutical Journal .2003,38,942.).In the evaluation study of cholinolytic effect, compare anti-nerve poison effect with instrument medicine QNB (3-Quinuclidine benziate) with Isodose level, its anti-methylarecaidin is caused tremble and flow the birth effect respectively than QNB strong 10 times and 2 times (Shen Shuying etc. Acta Pharmacologica Sinica .1985,6,158.).Existing medicinal its racemic modification.
The M cholinocepter is crucial pharmacological agent target.The anticholinergic drug of m receptor antagonist class has the effect of bronchiectatic activity, secretion inhibition and reduction vagal tone, can effectively treat chronic obstructive pulmonary disease; By suppressing the respiratory tract glandular secretion, effectively alleviate the runny nose and the nasal congestion symptom of flu; The m receptor antagonist can also reduce the respiratory tract secretion, keeps respiratory passage unblocked, is usually used in sucking prenarcotic premedicate.Therefore from the m receptor antagonist, develop the focus that medicine has become each big pharmaceuticals new drug research of the world.
But non-selective m receptor antagonist can produce side effects such as dry, tachycardia, constipation, uroschesis, mydriasis and central nervous system symptom; Even the different subtype of m receptor has different pharmacological properties in the same tissue.At respiratory tract, M 2The function of acceptor and M 1And M 3The function of acceptor is completely contradicted.Therefore, the selectivity to the m receptor of different subtype is the key of decision anticholinergic agent application prospect.
Therefore, the present effective as selective antagonist that still needs to seek at the m receptor different subtype.
Summary of the invention
Technical problem to be solved by this invention provides the effective as selective antagonist to the concrete hypotype of m receptor.
Investigator of the present invention is through intensive discovering, the different optical isomer of amyl ethyl quin ether is to the selectivity difference of the m receptor of different subtype, and the optical isomer of the amyl ethyl quin ether of its Chinese style Ia and formula Ib representative is to M 3The selectivity of acceptor is higher than raceme; Investigator of the present invention also finds, the optical isomer of the amyl ethyl quin ether of formula Ia and formula Ib representative when suppressing glandular secretion, to the side effect of heart less than raceme.Based on above discovery, finish the present invention.
Summary of the invention:
One aspect of the present invention provides compound shown in pure formula Ia of basic optical or the formula Ib,
Figure G200810178611XD0000021
Or its pharmacologically acceptable salts or solvate.
Further, compound shown in formula Ia of the present invention and the formula Ib in methyl alcohol at 20 ℃ of [α] that measure down D 20Value is about respectively+and 8.3 ° and+44.3 °.Art technology is clear, owing to measure the difference of factors such as environment, used instrument, operator, is somebody's turn to do [α] D 20Suitable deviation may appear in value, but these deviations usually can be in the scope that it will be appreciated by those skilled in the art that and accept.
According to above-mentioned or following each the described compound of first aspect present invention, its optical purity is preferably greater than 95% greater than 90%, is preferably greater than 98%, is preferably greater than 99%, is preferably greater than 99.5%.
According to above-mentioned or following each the compound of first aspect present invention, its useful as selective m receptor antagonist, preferred useful as selective M 3Receptor antagonist.
According to above-mentioned or following each the described compound of first aspect present invention, it can be used as the medicine for the treatment of chronic obstructive pulmonary disease, the medicine of treatment flu and/or the medicine of preanesthetic medication.
Second aspect present invention provides the method for preparing each described compound of first aspect present invention, and it may further comprise the steps:
I) make (R)-amygdalic acid and special valeral carry out aldol reaction; [preferably in this step use catalyzer, and this catalyzer trifluoromethanesulfonic acid (TfOH) preferably]
Ii) make step I) in hydroxyl and carboxyl in the hemiacetal molecule that forms carry out intramolecular condensation, obtain lactone compound;
Iii) making cyclopentanone and step I i) lactone compound of gained carries out the Michael addition reaction, and products therefrom obtains the oxyacetic acid compound through dehydration, deprotection, hydrogenation; [can add metallic lithium reagent in the Michael addition reaction, preferably use two (front three is silica-based) Lithamide]
Iv) make the ii) oxyacetic acid compound reduction of gained of step I, obtain dihydroxyl compound, react then with to toluene sulphur chlorine, obtain and the tosic acid monoester compound;
V) make step I v) the monoester compound of gained react through intramolecular cyclization, obtain (R)-1-phenyl-1-cyclopentyl-1,2-oxyethane;
Vi) make (R)-1-phenyl-1-cyclopentyl-1,2-oxyethane reacts with 3-(R)-quinine cyclol or 3-(S)-quinine cyclol respectively, obtains optical isomer Ia or Ib.
The present invention three aspects provide each described compound of first aspect present invention preparing as selectivity m receptor antagonist, preferably as selectivity M 3Purposes in the medicine of receptor antagonist.
The present invention four aspects provide the purposes of each described compound of first aspect present invention in the medicine of medicine, the medicine for the treatment of flu and/or the preanesthetic medication of preparation conduct treatment chronic obstructive pulmonary disease.
Fifth aspect present invention provides a kind of pharmaceutical composition, and it comprises as each described compound of first aspect present invention of the treatment significant quantity of activeconstituents and optional pharmaceutically acceptable carrier or vehicle.Pharmaceutical composition of the present invention can be used for as selectivity m receptor antagonist, preferably as selectivity M 3The medicine of receptor antagonist.Pharmaceutical composition of the present invention also can be used for as the medicine of treatment chronic obstructive pulmonary disease, the medicine of treatment flu and/or the medicine of preanesthetic medication.
According to above-mentioned or following each the described pharmaceutical composition of fifth aspect present invention, the optical purity of optical isomer or its pharmacologically acceptable salts or solvate is greater than 95% shown in wherein said formula Ia or the formula Ib, be preferably greater than 98%, be preferably greater than 99%, be preferably greater than 99.5%.
According to above-mentioned or following each the described pharmaceutical composition of fifth aspect present invention, it is tablet, capsule, injection, sprays, aerosol, nasal drop or powder inhalation.
According to above-mentioned or following each the described pharmaceutical composition of fifth aspect present invention, wherein comprise in the per unit dosage as optical isomer or its pharmacologically acceptable salts or solvate shown in 0.005 to 50mg the formula Ia of activeconstituents, perhaps wherein comprise in the per unit dosage as optical isomer or its pharmacologically acceptable salts or solvate shown in 0.05 to 100mg the formula Ib of activeconstituents.
Detailed Description Of The Invention:
Below the features and advantages of the present invention are further described.
One aspect of the present invention provides compound shown in pure formula Ia of basic optical or the formula Ib, or its pharmacologically acceptable salts or solvate.The chemical name of its Chinese style Ia and formula Ib is respectively:
Ia:3-(R)-[2 '-(R)-2 '-hydroxyl-2 '-cyclopentyl-2 '-phenyl ethoxy]-quinuclidine
Ib:3-(S)-[2 '-(R)-2 '-hydroxyl-2 '-cyclopentyl-2 '-phenyl ethoxy]-quinuclidine
As be used for this paper, term " basic optical is pure " is meant that optical isomer is purified basically shown in formula Ia of the present invention or the formula Ib, so that its optical purity is greater than 90%, be that the shared weight percentage of optical isomer shown in formula Ia in the formula I compound or the formula Ib is more than 90%, be preferably greater than 95%, be preferably greater than 98%, be preferably greater than 99%, be preferably greater than 99.5%.Though the present invention has obtained optical purity at the key intermediate more than 98% (IX) when described formula Ia of preparation or formula Ib compound, and can obtain optical purity at formula Ia more than 98% or formula Ib compound according to standard operation known in the art and instruction of the present invention further; But, it will be apparent to those skilled in the art that by suitable method, for example fractional crystallization, chiral column chromatography etc., can further obtain the formula Ia of high-optical-purity more or formula Ib compound with and pharmacologically acceptable salts or solvate.Certainly, those skilled in the art know that, the acquisition optical purity also is easy greater than 90% formula Ia or formula Ib compound, and its using value is arranged also, for example optical purity can be used for preparing its salt or solvate greater than 90% formula Ia or formula Ib compound approximately and is further purified in this salt of preparation or solvate process, to obtain more highly purified optical isomer.
M receptor has this area implication the most widely, and typically refers to M 1Acceptor, M 2Acceptor, M 3Acceptor, M 4Acceptor, M 5Acceptor is meant M in the present invention especially 3Acceptor.
As be used for this paper, term " pharmacy is acceptable " typically refers to and can be used on the pharmacopedics or available medically, though perhaps can not be directly used in pharmacopedics or medical science, but can utilize when can be used as preparation pharmacopedics or medical product intermediate, and in the end be used for removing by suitable method before pharmacopedics or the medical science.For example pharmacologically acceptable salts not only comprises can be used for clinical pharmaceutical salts, also comprise can not be directly used in clinical, but the salt that can use and in technological process subsequently, remove during The compounds of this invention in preparation.
As be used for this paper, and term " pharmaceutically acceptable carrier or vehicle " is meant the pharmaceutical excipient that the preparation industrial circle is commonly used, for example at Luo Mingsheng, etc. pharmaceutical necessities complete works, Sichuan science tech publishing house is enumerated in 1995.
Pharmaceutical composition of the present invention can be with optical isomer shown in the formula Ia or its pharmacologically acceptable salts or solvate as unique activeconstituents, also can be with optical isomer shown in the formula Ib or its pharmacologically acceptable salts or solvate as unique activeconstituents, can also be with two kinds of optical isomers shown in formula Ia and the formula Ib or its pharmacologically acceptable salts or solvate with arbitrary proportion as activeconstituents.In addition, can also contain at least a other activeconstituents in the drug regimen of the present invention, can also contain the pyraloxime methyl-chloride (PAM-CL) for the treatment of significant quantity in the pharmaceutical composition for example of the present invention, so that form compound preparation for clinical using with The compounds of this invention.Under the situation of above-mentioned use pyraloxime methyl-chloride (PAM-CL), the consumption of pyraloxime methyl-chloride (PAM-CL) with and can determine easily according to various factors such as the concrete state of an illness according to the clinician with the proportioning of optical isomer shown in formula Ia of the present invention or the formula Ib or its pharmacologically acceptable salts or solvate.
According to pharmaceutical composition of the present invention, it can be for example following formulation: tablet is such as but not limited to fast-release tablet, slowly sheet, controlled release tablet, film coated tablet, coated tablet, buccal tablet, Sublingual tablet, biological adhesive tablet etc.; Capsule is such as but not limited to hard capsule, soft capsule etc.; Injection is such as but not limited to water type injection aseptic or bacteriostatic agent, oleo-injection, lyophilize powder injection, injectable microsphere etc.; The sprays that sprays is used etc. with, local skin spraying with, nasal spray such as but not limited to mouth spray; Aerosol sucks with aerosol, local skin with aerosol such as but not limited to lung etc.; Nasal drop such as but not limited to collunarium with solution, collunarium with gel etc.; Powder inhalation such as but not limited to the oral cavity with powder inhalation, nasal cavity with powder inhalation, local skin with powder inhalation etc.The preparation technology of these preparations is that the art technology people can prepare according to its existing knowledge or with reference to being correlated with textbook or reference book.
Though the amount of the activeconstituents that is comprised in the per unit dosage of pharmaceutical composition of the present invention can be determined with reference to the clinical medicine dose of formula I compound, but under particular case of the present invention, the amount of this activeconstituents obviously can be done further expansion, implements to be suitable for invention.
As described herein, chronic obstructive pulmonary disease (COPD) is meant one group of clinical disease that is feature with irreversible substantially CAO.The main pathophysiological mechanism of COPD bronchial obstruction comprises by the high secretion of mucous membrane of vagus nerve control and by the bronchial smooth muscle tension force that cholinergic mechanism is brought out to be increased.Anticholinergic drug has the effect of bronchiectatic activity, secretion inhibition and reduction vagal tone, and pulmonary function, exercise tolerance, the living quality that can effectively improve COPD patient reduce acute exacerbation frequency (Han Wei.The effect of anticholinergic drug in the COPD treatment.World's clinical medicine, 2003,24 (2): 85-88).
As described herein, flu is modal human diseases.Owing to lack effective preventive means and antiviral, main methods of treatment to flu is a symptomatic treatment, promptly suppresses runny nose, suppresses cough or remove nasal congestion to alleviate cold symptoms by using antihistamine drug inhibition, antitussive medicine or peripheral blood vessel to shrink medicine.Anticholinergic agent such as ipratropium bromide can be by suppressing the respiratory tract glandular secretion, effectively alleviate runny nose and nasal congestion symptom (Hayden FG, Diamond L, Wood PB, Korts DC, Wecker MT.Effectiveness and safety of intranasalipratropium bromide in common colds.A randomized, double-blind, placebo-controlled trial.Ann Intern Med 1996; 125:89-97.).
As described herein, term " preanesthetic medication " is meant by using stable tranquilizer, soporific, anodyne and/or anticholinergic drug etc. to make patient's mood stable before anesthesia, reduce the consumption of narcotic, reduce side effect, reduce the secretory product of the upper respiratory tract, suppress to feel sick and vomiting, strengthen anaesthetic effect.Anticholinergic drug such as coromegine and eastern Liang alkali etc. can reduce the respiratory tract secretion, keep respiratory passage unblocked, are usually used in sucking prenarcotic premedicate.
One aspect of the present invention relates to and contains the pharmaceutical composition of the optical isomer of penehyclidine shown in formula Ia or the formula Ib as activeconstituents.This pharmaceutical composition can be made into various suitable formulations according to route of administration.Use acceptable carrier on one or more physiology, comprise vehicle and auxiliary agent, they help active compound is processed into can be at the preparation that pharmaceutically uses.The appropriate formulations form depends on selected route of administration, can make according to general knowledge well known in the art.
Another aspect of the present invention relates to and contains the optical isomer of penehyclidine shown in formula Ia or the formula Ib and pharmacologically acceptable salts thereof as the pharmaceutical composition of the activeconstituents medicinal use as chronic obstructive pulmonary disease medicine, common cold treatment medicine, preanesthetic medication etc.Can be by the mode administration of oral, non-enteron aisle or topical.Can comprise capsule and tablet etc. by oral pharmaceutical preparation; Patient swallows when having any problem, and also can adopt Sublingual tablet or other non-mode administrations of swallowing.Non-parenteral dosage forms can be injection or powder injection.The formulation of topical can make sprays, drops or powder inhalation.
Compound of the present invention can exist with the form of non-solvent compound and solvate, comprises hydrated form, for example semihydrate.In general, for purpose of the present invention, suitable with non-solvent compound form with the solvate form thereof of pharmacy acceptable solvent such as water, ethanol etc.
Compound of the present invention also can form pharmacologically acceptable salts, for example acid salt.For example, nitrogen-atoms can with sour salify.The example that is used for salifiable appropriate acid is hydrochloric acid, sulfuric acid, phosphoric acid, acetate, citric acid, oxalic acid, propanedioic acid, Whitfield's ointment, oxysuccinic acid, fumaric acid, succsinic acid, xitix, toxilic acid, methylsulfonic acid, Hydrogen bromide, tartrate, gluconic acid, tosic acid, phenylformic acid, lactic acid and well known to a person skilled in the art other mineral acids and carboxylic acid.These salt are to prepare by free alkali form being contacted with the required acid of capacity produce salt.Handle the salt of gained with the dilute aqueous soln of suitable dilute alkaline aqueous solution such as potassium hydroxide, salt of wormwood, ammoniacal liquor and sodium bicarbonate, can make free alkali form regeneration.Each free alkali form and they salt form is separately gone up slightly different in some physical properties (as the solubleness in polar solvent), but for the object of the invention, each acid salt and they free alkali form separately is suitable.(referring to for example S.M.Berge, etal., " Pharmaceutical Salts, " J.Pharm.Sci., 66:1-19 (1977), it incorporates this paper by reference into.
Term used herein " composition " means and comprises the product of respectively specifying composition that comprises specified amount, and directly or indirectly from any product of the combination results of respectively specifying composition of specified amount.
Compound of the present invention can use with the form derived from mineral acid or organic acid drug acceptable salt.Word " pharmacologically acceptable salts " refers in reliable medical judgment scope, be suitable for contacting with zootic tissue and over-drastic toxicity, stimulation, anaphylaxis etc. do not occur with the mankind, and with rational effect/risk than the salt that matches.Pharmacologically acceptable salts is well known in the art.For example, S.M.Berge etc. is at J. Pharmaceutical Sciences,1977, among the 66:1 pharmacologically acceptable salts is described in detail.Described salt can be by free alkali functionality and the appropriate organic reaction that makes The compounds of this invention, in final separation and the purge process made acid-stable in situ or the preparation separately of The compounds of this invention.Representational acid salt includes but not limited to acetate, adipate, alginates, Citrate trianion, aspartate, benzoate, benzene sulfonate, hydrosulfate, butyrates, camphorate, camsilate, digluconate, glycerophosphate, Hemisulphate, enanthate, hexanoate, fumarate, hydrochloride, hydrobromate, hydriodate, the 2-isethionate (different thiosulphate, isothionate), lactic acid salt, maleate, mesylate, nicotinate, the 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulphate, 3-phenylpropionic acid salt, picrate, Pivalate, propionic salt, succinate, tartrate, thiocyanate-, phosphoric acid salt, glutaminate, supercarbonate, tosilate and undecane hydrochlorate.Equally, alkaline nitrogen-containing group can be quaternized with following material: the muriate of elementary alkyl halide such as methyl, ethyl, propyl group and butyl, bromide and iodide; Sulfuric acid dialkyl such as methyl-sulfate, diethyl ester, dibutylester and diamyl ester; The muriate of long-chain halogenide such as decyl, dodecyl, tetradecyl and octadecyl, bromide and iodide; Arylalkyl halogenide such as bromotoluene and phenethyl bromide and other.Therefore dissolved in or be scattered in the product of water or oil.The sour example that can be used to form the acceptable acid salt of pharmacy comprises mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid and phosphoric acid, and organic acid such as oxalic acid, toxilic acid, succsinic acid and citric acid.
Dosage form for the topical administration The compounds of this invention comprises powder, sprays, ointment and inhalation.Under aseptic condition with active compound and pharmaceutically acceptable carrier and any required sanitas, buffer reagent or propellant mixing.Ophthalmic preparation, eye ointment, powder and solution also are considered within the scope of the present invention.
The active compound amount of gained can change the actual dose level of each activeconstituents in the pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response at concrete patient, composition and administering mode.The dosage level fibrous root is selected according to activity, route of administration, the severity of the patient's condition for the treatment of and the patient's to be treated patient's condition and the medical history of particular compound.But the way of this area is that the dosage of compound increases dosage gradually from being lower than for obtaining the level that required result of treatment requires, up to obtaining required effect.
When being used for above-mentioned treatment or other treatment, a kind of The compounds of this invention of treatment significant quantity can be used with pure form, perhaps uses with pharmacologically acceptable salts, ester or prodrug forms (under the situation that has these forms).Perhaps, described compound can be accepted the pharmaceutical composition administration of vehicle to contain this purpose compound and one or more medicines.The The compounds of this invention of word " treatment significant quantity " refers to the compound of the reasonable effect that is applicable to any therapeutic treatment/risk than the q.s of treatment obstacle.But the total daily dosage portion that it should be understood that The compounds of this invention and composition must be examined the doctor by the master and maked decision in the medical judgment scope reliably.For any concrete patient, the concrete horizontal fibrous root of treatment effective dose is decided according to multiple factor, and described factor comprises the severity of the obstacle of being treated and this obstacle; The activity of the particular compound that is adopted; The concrete composition that is adopted; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound that is adopted, route of administration and excretion rate; The treatment time length; The medicine that is used in combination or uses simultaneously with the particular compound that is adopted; And the known similar factor of medical field.For example, the way of this area is that the dosage of compound increases dosage gradually from being lower than for obtaining the level that required result of treatment requires, up to obtaining required effect.
The dosage of the The compounds of this invention Ia of administration of human can be in about 0.005 to about 50mg/ time scope, and more preferably dosage can be about 0.05 to about 10mg/ time scope; The dosage of the The compounds of this invention Ib of administration of human can be in about 0.05 to about 100mg/ time scope, and more preferably dosage can be about 0.5 to about 50mg/ time scope; Be administered once every day or repeatedly.If desired, effectively per daily dose can be divided into multiple doses for the administration purpose; Therefore, unit-dose composition can contain this quantity or its divided dose, to constitute per daily dose.The administration frequency of above-mentioned formula Ia or formula Ib compound can be determined according to clinician's experience with such as factors such as the type of patient age, body weight, sex, general health situation and disease and seriousness, for example give every day 1 time, 2 times, 3 times, 4 times, 5 inferior, perhaps per 2 days once, per 3 days once, per 1 week once, per 2 Mondays are inferior.
The present invention also provides the pharmaceutical composition that comprises with one or more nontoxic drug acceptable carriers The compounds of this invention formulated together.That described pharmaceutical composition can be mixed with especially specially is for oral administration with solid or liquid form, for the parenteral injection or for rectal administration.
Pharmaceutical composition of the present invention can by in oral, rectum, parenteral, the pond, intravaginal, intraperitoneal, part (as by powder, ointment or drops), a mouthful cheek give the mankind and other Mammalss, perhaps give as oral spray or nasal mist.Term used herein " parenteral " refers to comprise intravenously, intramuscular, intraperitoneal, breastbone is interior, subcutaneous and the administering mode of intra-articular injection and transfusion.
In yet another aspect, the invention provides and comprise the pharmaceutical composition that composition of the present invention and physiology can tolerate thinner.The present invention includes one or more above-claimed cpds, its can tolerance with one or more nontoxic physiology or acceptable diluent, carrier, auxiliary material or vehicle (this paper is referred to as thinner with them) be mixed with composition, for transmit in parenteral injection, the nose, with solid or liquid form oral administration, rectum or topical or the like.
The composition that is suitable for the parenteral injection can comprise physiologically acceptable aseptic moisture or non-aqueous solution agent, dispersion agent, suspensoid or emulsion, and for the aseptic powder that reconstitutes sterile injectable solution agent or dispersion agent.Suitable moisture or nonaqueous carrier, thinner, solvent or vectorial example comprise water, ethanol, polyvalent alcohol (propylene glycol, polyoxyethylene glycol, glycerine etc.), vegetables oil (as sweet oil), injectable organic ester such as ethyl oleate and their suitable mixture.
These compositions also can contain auxiliary material, as sanitas, wetting agent, emulsifying agent and dispersion agent.By various antibacterial agents and anti-mycotic agent, for example parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc. can guarantee to prevent action of microorganisms.Also expectation comprises isotonic agent, for example carbohydrate, sodium-chlor etc.By using the material that can postpone absorption, for example aluminum monostearate and gelatin can reach the prolongation absorption of injectable drug form.
Remove the active ingredient beyond the region of objective existence in the suspensoid and also can contain suspension agent, for example ethoxylation i-octadecanol, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, Microcrystalline Cellulose, the mixture etc. of aluminium hydroxide, wilkinite, agar and tragacanth gum or these materials partially.
In some cases, be the effect of prolong drug, expect to slow down absorption subcutaneous or the intramuscularly medicine.This can realize by the crystal of use poorly water-soluble or the liquid suspension of amorphous substance.Like this, the absorption rate of medicine depends on its dissolution rate, and dissolution rate can be depending on crystallographic dimension and crystal formation.Perhaps, the delay of the medicament forms of parenteral admin absorb by with this medicine dissolution in or be suspended in the oily vehicle and realize.
The injectable depot formulations form can prepare by the microcapsule matrix that forms medicine in biodegradable polymer such as polylactide-poly-glycollide (polylactide-polyglycolide).Can drug releasing rate be controlled according to the character of medicine with ratio with the concrete polymkeric substance that is adopted of polymkeric substance.The example of other biological degradable polymer comprises poe class (poly (orthoesters)) and polyanhydrides (poly (anhydrides)).Injectable depot formulations also can by pharmaceutical pack is embedded in can be compatible with bodily tissue liposome or micro emulsion in prepare.
Injectable formulation can be for example by filtering with bacterial filter or sterilizing by the disinfectant that mixes the aseptic solid composite form, and described solids composition can face with before being dissolved or dispersed in sterilized water or other sterile injectable medium.
Solid dosage for oral administration comprises capsule, tablet, pill, powder and granule.In this type of solid dosage, active compound can be accepted vehicle or carrier such as Trisodium Citrate or Lin Suanergai and/or following material with at least a inert medicine and mix: a) weighting agent or extender such as starch, lactose, sucrose, glucose, mannitol and silicic acid; B) tackiness agent such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Sudan Gum-arabic; C) wetting Agent for Printing Inks such as glycerine; D) disintegrating agent such as agar, lime carbonate, potato or tapioca (flour), Lalgine, some silicate and yellow soda ash; E) solution retarding agent such as paraffin; F) absorb accelerator such as quaternary ammonium compound; G) wetting agent such as hexadecanol and Zerol; H) sorbent material such as kaolin and wilkinite and i) lubricant such as talcum powder, calcium stearate, Magnesium Stearate, solid polyethylene glycol, sodium lauryl sulphate and their mixture.Under the situation of capsule, tablet and pill, also can comprise buffer reagent in the described formulation.
The solids composition of similar type uses vehicle for example lactose and high molecular weight polyethylene glycol etc., also can be used as the weighting material in soft capsule and the hard capsule.
The solid dosage of tablet, dragee (dragees), capsule, pill and granule can prepare with dressing and shell material such as enteric coating material and known other clothing materials of field of medicine preparations.These solid dosages can be chosen wantonly and contain opalizer, and its composition also can make it just or preferentially choose wantonly with the delayed mode release of active ingredients at certain position of enteron aisle.The example of operable embedding composition comprises polymer substance and wax class.
If be fit to, active compound also can be made into the micro-capsule form with one or more above-mentioned vehicle.
Liquid dosage form for oral administration comprises the acceptable emulsion of pharmacy, solution, suspensoid, syrup and elixir.Liquid dosage form also can contain this area inert diluent commonly used except that containing the active ingredient beyond the region of objective existence, for example water or other solvents, solubilizing agent and emulsifying agent be ethanol, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1,3 butylene glycol, dimethyl formamide, oils (particularly Oleum Gossypii semen, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), polyoxyethylene glycol and the fatty acid ester of sorbitan and their mixture for example.
Oral compositions also can comprise auxiliary material except that comprising inert diluent, for example wetting agent, emulsification and suspension agent, sweeting agent, correctives and flavouring agent.
The composition of confession rectum or vagina administration is suppository preferably.Suppository can be by for example theobroma oil, polyoxyethylene glycol or suppository wax are mixed and prepared with The compounds of this invention and suitable non-irritating excipient or carrier, they at room temperature are solid, therefore but next at body temperature is liquid, can melt in rectal cavity or vaginal canal and discharges active compound.
The compounds of this invention also can the liposome form administration.As known in the art, liposome makes with phosphatide or other lipid materials usually.Liposome is formed by the single or multiple lift aquation liquid crystal that is scattered in the water-bearing media.Can accept on any nontoxic, physiology that can form liposome and metabolizable lipid all can use.The present composition of liposome form also can contain stablizer, sanitas, vehicle etc. except that containing The compounds of this invention.Preferred lipid is natural and synthetic phosphatide and phosphatidylcholine (Yelkin TTS), and they can use separately or together.The method that forms liposome is well known in the art.Referring to for example Prescott, Ed., Methods in Cell Biology,Volume XIV, Academic Press, New York, N.Y. (1976), p.33.
The prodrug of The compounds of this invention represented in term used herein " pharmacy acceptable prodrugs ", it is suitable for contacting with zootic tissue with the mankind in reliable medical judgment scope and over-drastic toxicity, stimulation, anaphylaxis etc. do not occur, match with rational effect/risk ratio and effective, under possible situation, also represent the zwitterionic form of The compounds of this invention its intended purpose.Prodrug of the present invention can for example change into the parent compound of following formula in vivo fast by hydrolysis in blood.Discuss fully and be provided in T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems,V.14 of the A.C.S.Symposium Series and Edward B.Roche, ed., Bioreversible Carriers in Drug Design,AmericanPharmaceutical Association and Pergamon Press (1987), it incorporates this paper by reference into.
The optical isomer of formula Ia of the present invention and formula Ib preferably can synthesize with reference to following route:
Figure G200810178611XD0000131
Can be chiral template with (R)-amygdalic acid, with trifluoromethanesulfonic acid (TfOH) as catalyzer, under 30～35 ℃, hydroxyl in the amygdalic acid molecule at first carries out aldol condensation with special valeral (Pivaldehyde), and the hydroxyl in the hemiacetal molecule of formation carries out intramolecular condensation with carboxyl again, reacts 5～10 hours, stereoselectivity obtains interior ester products (2R, 5R)-and 2-tertiary butyl-5-phenyl-1,3-diox-4-ketone (II), solvent Skellysolve A.Then, the II of cyclopentanone and enol form carries out three-dimensional controlled Michael addition reaction under-78 ℃, adds metallic lithium reagent and (preferably uses two (front three is silica-based) Lithamide, LHMDS), obtain adduct III; Compound III obtains (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy acetate (VI) behind dehydration, deprotection, hydrogenation; VI uses LiAlH in tetrahydrofuran (THF) 4Reduction obtains dihydroxyl compound VII; VII and the synthetic tosic acid mono-esterification thing of Tosyl chloride reaction through intramolecular ring closure reaction, obtain optical purity at the synthetic key intermediate (R) more than 98%-1-phenyl-1-cyclopentyl-1,2-oxyethane (IX); IX with 3-(R)-quinine cyclol or 3-(S)-quinine cyclol reaction, obtains optical isomer Ia or Ib respectively under the sodium hydride effect.
Though the invention provides above-mentioned preferred synthetic schemes,, it will be apparent to those skilled in the art that the present invention does not get rid of any other feasible mode.
Embodiment
Further specify the present invention below by specific embodiment, still, should be understood to, these embodiment are only used for the more detailed usefulness that specifically describes, and are used for limiting in any form the present invention and should not be construed as.
The present invention carries out generality and/or concrete description to the material and the test method that are used in the test.Though for realizing that employed many materials of the object of the invention and working method are well known in the art, the present invention still does to describe in detail as far as possible at this.It will be apparent to those skilled in the art that hereinafter, if do not specify that material therefor of the present invention and working method are well known in the art.
Embodiment 1,(R)-and 1-phenyl-1-cyclopentyl-1, the preparation of 2-oxyethane (IX)
1.1,(2R, 5R)-2-tertiary butyl-5-phenyl-1, the preparation of 3-diox-4-ketone (II)
R-amygdalic acid 20g (0.13mol) is added in the 200mL Skellysolve A, add special valeral 21.2mL (content 80%, 0.16mol is available from Fluka company) then, add trifluoromethanesulfonic acid 0.5mL again, this mixture was refluxed 6 hours.Remove the water of generation with water trap.Be cooled to room temperature, add 8% sodium hydrogen carbonate solution 100mL, Skellysolve A is removed in underpressure distillation, filters, obtain (2R, 5R)-2-tertiary butyl-5-phenyl-1,3-diox-4-ketone (II), output 27.1g, fusing point 100-102 ℃, productive rate 95%, ultimate analysis, theoretical value %:C 70.89, and H 7.32; Experimental value %:C 70.81, H 7.39. 1H-NMR：δ(ppm，CDCl 3)，1.10(s，9H)，5.25(s，1H)，5.38(s，1H)，7.47(m，5H)。
1.2,(2R, 5S)-2-tertiary butyl-5-phenyl-5-(cyclopentyl-1-hydroxyl)-1, the preparation of 3-diox-4-ketone (III)
With 10g (45mmol) (2S, 5S)-2-tertiary butyl-5-phenyl-1,3-diox-4-ketone (II) is dissolved in the 70mL dry tetrahydrofuran, is cooled to-78 ℃, add 60mL two (front three is silica-based) Lithamide (solution in tetrahydrofuran (THF), 1.0M).Stir down and drip cyclopentanone 65mmol, will react and stir 2 hours, drip saturated sodium hydrogen phosphate solution of 15mL and 200mL saturated ammonium chloride solution.Separate organic layer, the water layer ethyl acetate extraction.With the organic layer drying that merges, distillation removes and desolvates, obtain (2R, 5S)-2-tertiary butyl-5-phenyl-5-(cyclopentyl-1-hydroxyl)-1,3-diox-4-ketone (III), output 10.5g, productive rate 74%. 1H-NMR：δ(ppm，CDCl 3)，0.88(s，9H)，1.52-2.06(m，8H)，5.52(s，1H)，7.31(m，3H)，7.78(dd，J＝1.5，8.3Hz，2H)。
1.3,(2R, 5R)-2-tertiary butyl-5-phenyl-5-(1-cyclopentenyl)-1, the preparation of 3-diox-4-ketone (IV)
(2S with 3.6g (10mmol), 5R)-and 2-tertiary butyl-5-phenyl-5-(cyclopentyl-1-hydroxyl)-1,3-diox-4-ketone (III) is dissolved in the 70mL dry tetrahydrofuran solution, is cooled to 0 ℃, add 2mL sulfur oxychloride and 3mL pyridine, will react and stir 1 hour.Add the 60mL saturated ammonium chloride solution, tell organic layer, the water layer ethyl acetate extraction merges organic layer, drying, distillation removes and desolvates, and obtains (2R, 5R)-and 2-tertiary butyl-5-phenyl-5-(1-cyclopentenyl)-1,3-diox-4-ketone (IV), output 3.7g, productive rate 95%. 1H-NMR：δ(ppm，CDCl 3)，1.07(s，9H)，1.92-2.50(m，6H)，5.22(s，1H)，6.03(m，1H)，7.25(m，4H)，7.59(m，1H)。
1.4,(R)-preparation of α-phenyl-α-cyclopentyl-Alpha-hydroxy acetate (VI)
With 2.34g (8.18mmol) (2R, 5R)-2-tertiary butyl-5-phenyl-5-(1-cyclopentenyl)-1,3-diox-4-ketone (IV) is dissolved in the mixing solutions of 20mL methyl alcohol and 10mL water.The KOH that adds 4.58g under agitation makes reaction reflux 3 hours.Be cooled to room temperature, with the normal heptane extraction, water is used ethyl acetate extraction again with 1N HCl acidifying, drying, and distillation removes and desolvates, and obtains (R)-α-phenyl-α-cyclopentenyl-Alpha-hydroxy acetate (V), output 1.64g, productive rate 92%, 1H NMR (CDCl3) 1.81 (m, 2H), 2.29 (m, 4H), 5.59 (s, 1H), 7.24 (t, J=6.8Hz, 1H), 7.32 (t, J=7.1Hz, 2H), 7.48 (d, J=7.8Hz, 1H).(R)-α-phenyl-α-cyclopentenyl-Alpha-hydroxy acetate (V) of 1.16g (5.3mmol) is dissolved in the 50mL methyl alcohol, adds the 10%Pd/C of 0.2g, under 1atm, use H 2Reduced 8 hours.Filter, underpressure distillation removes and desolvates, and obtains (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy acetate (VI) 1.08g, yield 93%.
Figure G200810178611XD0000161
(MeOH, c=3), fusing point: 118-119 ℃.
1.5,(R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy ethyl p-toluenesulfonate (VIII) synthetic
At N 2Under the protection, (R)-α-phenyl-α-cyclopentyl-10mL anhydrous THF solution of Alpha-hydroxy acetate (VI) that will contain 2.2g (0.01mol) slowly is added drop-wise to and contains LiAlH 4In the 20mL anhydrous THF solution (0.02mol), stir and slowly be warming up to backflow down, reaction 3h.Cooling carefully drips the saturated NaHCO of 2mL 3Solution drips the NaOH solution of the 2N of 10mL again.Separate organic phase, the water ether extraction.With the organic phase saturated common salt water washing that merges, use anhydrous sodium sulfate drying.Underpressure distillation removes and desolvates, and obtaining (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy ethanol (VII) is colourless acicular crystal, 2.06g, yield 100% fusing point: 49-50 ℃. 1H?NMR(CDCl 3)1.23-1.71(m，8H)，2.02(brs，1H)，2.20-2.28(m，1H)，3.76(d，J＝11Hz，1H)，3.94(d，J＝11Hz，1H)，7.23-7.27(m，1H)，7.34-7.44(m，4H)。
In exsiccant 100mL there-necked flask, add (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy ethanol (VII) and 50mL exsiccant CH of 1.89g 2Cl 2, be cooled to 0 ℃, add tosic acid 3.42g (18mmol).Stir and drip triethylamine 2.43g (24mmol) down.Dropwise, stir 2h down at 0 ℃, the mixed liquid of reaction slightly is yellow.The saturated NaHCO of careful then adding 3Solution will react rotary evaporation to remove CH 2Cl 2, use extracted with diethyl ether, drying, the sherwood oil recrystallization, obtaining (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy ethyl p-toluenesulfonate (VIII) is white cotton-shaped solid, 2.61g, yield 79%. 1H?NMR(CDCl 3)1.21-1.27(m，2H)，1.35-1.70(m，6H)，2.17(s，1H)，2.24(m，1H)2.40(s，3H)，7.21-7.27(m，8H)，7.58(d，J＝8Hz?2H)。
1.6,(R)-and 1-phenyl-1-cyclopentyl-1, the preparation of 2-oxyethane (IX)
In exsiccant 50mL there-necked flask, add (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy ethyl p-toluenesulfonate (VIII) and 20mL anhydrous methanol of 1.0g.Under agitation, add excessive anhydrous K 2CO 3At room temperature will react and stir 30min, thin up is used extracted with diethyl ether, drying, and steaming desolventizes, and obtains (R)-1-phenyl-1-cyclopentyl-1,2-oxyethane (IX), colourless liquid, 0.5g, yield 100%. 1H?NMR(CDCl 3)1.25-1.68(m，8H)，2.58-2.63(m，1H)，2.66(d，J＝5Hz，1H)，2.97(d，J＝5Hz，1H)，7.23-7.40(m，5H)。
Embodiment 2,3-(R)-[2 '-(R)-2 '-hydroxyl-2 '-cyclopentyl-2 '-phenyl ethoxy]-preparation of quinuclidine (Ia)
Under nitrogen protection; the NaH of 0.6g (15mmol) is placed the exsiccant there-necked flask, add the anhydrous DMSO of 10mL, behind the stirring 5min; dropping contains the 10mL DMSO solution of 3-(R)-quinine cyclol 1.8g (14.2mmol), will react under 60 ℃ and stir 1h.Be chilled to room temperature, slowly drip (R)-1-phenyl-1-cyclopentyl-1, the solution of 2-oxyethane (IX) 2.61g (14mmol) in the DMSO of 10mL.To react under 50 ℃ and stir 3h, cooling carefully drips 20mL water.Use ether extraction, wash with water, with 10% hydrochloric acid soln washing ether layer, merge water again; The hydrochloric acid extraction liquid of the NaOH alkalization gained with 40% is used extracted with diethyl ether, uses anhydrous sodium sulfate drying, and distillation removes and desolvates, and obtains containing the colourless liquid of Ia, 2.84g, and yield 65%,
Figure G200810178611XD0000171
(MeOH, c=0.35). 1HNMR(CDCl 3)1.23-1.75(m，13H)，1.96-1.99(m，2H)，2.26-2.32(m，1H)，2.52-2.77(m，5H)，2.71(s，-OH，1H)，2.89-2.95(m，1H)，3.35-3.38(m，1H)，3.58(d，J＝9Hz，1H)，3.71(d，J＝9Hz，1H)，7.29-7.42(m，5H)。
The colourless liquid that contains Ia of gained is dissolved with anhydrous diethyl ether, drip hydrogenchloride-diethyl ether solution, separate out white solid; Filter, with acetone recrystallization, obtain the hydrochloride of Ia, fusing point 160-162 ℃.
Embodiment 3,3-(S)-[2 '-(R)-2 '-hydroxyl-2 '-cyclopentyl-2 '-phenyl ethoxy]-preparation of quinuclidine (Ib)
Under nitrogen protection; the NaH of 0.6g (15mmol) is placed the exsiccant there-necked flask, add the anhydrous DMSO of 10mL, behind the stirring 5min; dropping contains the 10mL DMSO solution of 3-(S)-quinine cyclol 1.8g (14.2mmol), will react under 60 ℃ and stir 1h.Be chilled to room temperature, slowly drip (R)-1-phenyl-1-cyclopentyl-1, the solution among the DMSO of the 10mL of 2-oxyethane (IX) 2.61g (14mmol).To react under 50 ℃ and stir 3h, cooling carefully drips 20mL water.Use ether extraction, wash with water, with 10% hydrochloric acid soln washing ether layer, merge water again; The hydrochloric acid extraction liquid of the NaOH alkalization gained with 40% is used extracted with diethyl ether, uses anhydrous sodium sulfate drying, and distillation removes and desolvates, and obtains containing the colourless liquid of Ib, 2.82g, and yield 65%,
Figure G200810178611XD0000181
(MeOH, c=0.60). 1HNMR(CDCl 3)1.20-1.73(m，13H)，1.98-1.99(m，1H)，2.26-2.32(m，1H)，2.52-2.77(m，5H)，2.83(s，-OH，1H)，2.93-2.96(m，1H)，3.38-3.40(m，1H)，3.59(d，J＝9Hz，1H)，3.71(d，J＝9Hz，1H)，7.20-7.44(m，5H)。
The colourless liquid that contains Ib of gained is dissolved with anhydrous diethyl ether, drip hydrogenchloride-diethyl ether solution, separate out white solid; Filter, with acetone recrystallization, obtain the hydrochloride of Ib, fusing point 158-160 ℃.
Embodiment 4,The competitive binding experiment of m receptor
Utilize stably express M 1To M 5The Chinese hamster ovary celI of receptor subtype prepares membranin, with [ 3H]-N-epoxytropine tropate (NMS) for being at war with property of aglucon in conjunction with experiment, measure the IC of amyl ethyl quin ether and optical isomer Ia and Ib competitive inhibitory effect 50, compare its avidity to the different subtype m receptor, its experiment the results are shown in Table shown in 1.
Table 1: amyl ethyl quin ether and optical isomer thereof
Competitive binding experiment result (IC to the different subtype m receptor 50, M)
Figure G200810178611XD0000182
Experimental result shows that optical isomer Ia and Ib are to M 3Subtype acceptor shows higher selectivity, and Ia is to M 3The avidity of acceptor is respectively M 118.9 times, M of acceptor 2389.5 times, M of acceptor 443.7 times, M of acceptor 548.4 times of acceptor; Ib is to M 3The affinity of acceptor is respectively M 120.0 times, M of acceptor 21781.8 times, M of acceptor 436.4 times, M of acceptor 5107.3 times of acceptor; Particularly to the higher M that distributes at heart 2The avidity minimum of acceptor, Ia and Ib are to M 3The avidity of acceptor is respectively M 2389.5 times and 1781.8 times of acceptor, and amyl ethyl quin ether is to M 3The avidity of acceptor is M 29.8 times of acceptor.Therefore Ia and Ib are as selectivity M 3Receptor antagonist will have less cardiac side effects.
Embodiment 5,Restraining effect to salivary gland secretion
Get Kunming mouse, male and female half and half, body weight 18-22g, random packet, 10 every group.Inject amyl ethyl quin ether or its optical isomer of various dose in advance, behind the 15min, the subcutaneous oxotremorine (3mg/kg) that gives, observe the having or not of mouse salivary gland secretion (after the administration in the 15-40min, be stained with mouse lip portion with filter paper, become wet positive index with filter paper), control group only gives the physiological saline and the Isodose oxotremorine of equal volume, and the Bliss method is calculated ED 50
Subcutaneous injection oxotremorine 3mg/kg can obviously can cause the salivary gland secretion effect (n=50) of mouse.Inject amyl ethyl quin ether or its optical isomer in advance, along with the increase of drug dose to be tested, oxotremorine causes mouse salivation rate can be reduced on dose-dependently ground.The median effective dose of salivary gland secretion effect is respectively (ED due to amyl ethyl quin ether and its optical isomer Ia and the Ib inhibited oxidation tremorine 50) be respectively 0.57 ± 0.11mg/kg, 0.10 ± 0.03mg/kg and 6.68 ± 0.82mg/kg.
Embodiment 6,Influence to rat heart rate and blood pressure
With Wistar rat random packet, 10/group, male and female half and half are with 30mg/kg Sodital sodium solution intravenous injection anesthesia.Separate the left side femoral artery,common and make the artery intubate, connect the arterial pressure probe, upper right, bottom right and the subcutaneous insertion needle electrode of left lower extremity.Subcutaneous injection amyl ethyl quin ether and optical isomer Ia and Ib, dosage are respectively its ED that suppresses the salivation effect 50(amyl ethyl quin ether: 0.57mg/kg, Ia:0.10mg/kg, Ib:6.68 ± 0.82mg/kg).30 minutes blood pressure and heart rate after the record administration.As evaluation index, test is carried out for 22～23 ℃ in room temperature with mean value in the 60s.
Table 2: amyl ethyl quin ether and optical isomer thereof are to the influence of rat heart rate and blood pressure
Testing index Solvent control ??Ia ??Ib Amyl ethyl quin ether
Heart rate (inferior/second) ??343.7±58.4 ??335.3±51.8 ??329.5±31.7 ??283.4±20.0
Systolic pressure (mmHg) ??138.5±13.5 ??136.5±18.7 ??131.6±6.3 ??122.1±14.5
Diastolic pressure (mmHg) ??94.7±12.2 ??93.3±13.0 ??94.5±7.6 ??91.7±23.7
By the result of table 2 as seen, (be the ED of respective compound at the dose,equivalent that suppresses salivation 50Value) under, amyl ethyl quin ether can significantly reduce heart rate and the systolic pressure of rat, and optical isomer Ia and Ib do not make significant difference to heart rate and systolic pressure; The three does not all make significant difference to diastolic pressure.Therefore, optical isomer Ia and Ib are less as the cardiac side effects of common cold treatment medicine or preanesthetic medication.

Claims (10)

1. compound shown in pure formula Ia of basic optical or the formula Ib,
Figure F200810178611XC0000011
Or its pharmacologically acceptable salts or solvate.
2. the described compound of claim 1, its optical purity is preferably greater than 95% greater than 90%, is preferably greater than 98%, is preferably greater than 99%, is preferably greater than 99.5%.
3. claim 1 or 2 described compounds, its useful as selective m receptor antagonist, preferred useful as selective M 3Receptor antagonist.
4. claim 1 or 2 described compounds, it can be used as the medicine for the treatment of chronic obstructive pulmonary disease, the medicine of treatment flu and/or the medicine of preanesthetic medication.
5. prepare the method for each described compound of claim 1 to 4, it may further comprise the steps:
I) make (R)-amygdalic acid and special valeral carry out aldol reaction;
Ii) make step I) in hydroxyl and carboxyl in the hemiacetal molecule that forms carry out intramolecular condensation, obtain lactone compound;
Iii) making cyclopentanone and step I i) lactone compound of gained carries out the Michael addition reaction, and products therefrom obtains the oxyacetic acid compound through dehydration, deprotection, hydrogenation;
Iv) make the ii) oxyacetic acid compound reduction of gained of step I, obtain dihydroxyl compound, react then with to toluene sulphur chlorine, obtain and the tosic acid monoester compound;
V) make step I v) the monoester compound of gained react through intramolecular cyclization, obtain (R)-1-phenyl-1-cyclopentyl-1,2-oxyethane;
Vi) make (R)-1-phenyl-1-cyclopentyl-1,2-oxyethane reacts with 3-(R)-quinine cyclol or 3-(S)-quinine cyclol respectively, obtains optical isomer Ia or Ib.
6. each described compound of claim 1 to 4 is preparing as selectivity m receptor antagonist, preferably as selectivity M 3Purposes in the medicine of receptor antagonist.
7. each described compound of claim 1 to 4 is preparing as the purposes in the medicine of the medicine for the treatment of chronic obstructive pulmonary disease, the medicine for the treatment of flu and/or preanesthetic medication.
8. pharmaceutical composition, it comprises as each described compound of claim 1 to 4 of the treatment significant quantity of activeconstituents and optional pharmaceutically acceptable carrier or vehicle.
9. the described pharmaceutical composition of claim 8, the optical purity of optical isomer or its pharmacologically acceptable salts or solvate is preferably greater than 98% greater than 95% shown in wherein said formula Ia or the formula Ib, is preferably greater than 99%, is preferably greater than 99.5%.
10. claim 8 or 9 described pharmaceutical compositions, it is tablet, capsule, injection, sprays, aerosol, nasal drop or powder inhalation.
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WO2011160252A1 (en) * 2010-06-21 2011-12-29 中国人民解放军军事医学科学院毒物药物研究所 Organic acid salts of penehyclidine optical isomer
CN102702187A (en) * 2011-06-29 2012-10-03 成都自豪药业有限公司 New crystal form of penehyclidine hydrochloride and preparation method of new crystal form
CN102850344A (en) * 2011-06-28 2013-01-02 中国人民解放军军事医学科学院毒物药物研究所 Medicinal application of penehyclidine optical isomer derivative in anti-tumor
CN108569943A (en) * 2017-03-07 2018-09-25 中国科学院大连化学物理研究所 A method of using cyclopentanone as Material synthesis high density aviation fuel
CN114306331A (en) * 2020-10-10 2022-04-12 远大生命科学(武汉)有限公司 Use of penehyclidine in treating or preventing vision-impaired eye diseases

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011160252A1 (en) * 2010-06-21 2011-12-29 中国人民解放军军事医学科学院毒物药物研究所 Organic acid salts of penehyclidine optical isomer
CN102850344A (en) * 2011-06-28 2013-01-02 中国人民解放军军事医学科学院毒物药物研究所 Medicinal application of penehyclidine optical isomer derivative in anti-tumor
CN102702187A (en) * 2011-06-29 2012-10-03 成都自豪药业有限公司 New crystal form of penehyclidine hydrochloride and preparation method of new crystal form
CN108569943A (en) * 2017-03-07 2018-09-25 中国科学院大连化学物理研究所 A method of using cyclopentanone as Material synthesis high density aviation fuel
CN114306331A (en) * 2020-10-10 2022-04-12 远大生命科学(武汉)有限公司 Use of penehyclidine in treating or preventing vision-impaired eye diseases
CN114306331B (en) * 2020-10-10 2023-07-18 远大生命科学(武汉)有限公司 Use of penehyclidine in the treatment or prevention of vision-damaging ocular disorders

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Inventor after: Li Meiying

Inventor after: He Xinhua

Inventor after: Liu Keliang

Inventor after: Shi Weiguo

Inventor after: Zhang Zhenqing

Inventor after: Xie Jianwei

Inventor before: Zhong Bohua

Inventor before: Zheng Jianquan

Inventor before: Li Meiying

Inventor before: He Xinhua

Inventor before: Liu Keliang

COR Change of bibliographic data

Free format text: CORRECT: INVENTOR; FROM: ZHONG BOHUA ZHENG JIANQUAN LI MEIYING HE XINHUA LIU KELIANG TO: ZHONG BOHUA ZHENG JIANQUAN LI MEIYING HE XINHUA LIU KELIANG SHI WEIGUO ZHANG ZHENQING XIE JIANWEI

C14 Grant of patent or utility model
GR01 Patent grant
IP01 Partial invalidation of patent right

Commission number: 4W106781

Conclusion of examination: On the basis of items 1-12 of the rights claim submitted by the patentee on 10 August 2018, patent No. 208178611.X is maintained valid.

Decision date of declaring invalidation: 20180905

Decision number of declaring invalidation: 37051

Denomination of invention: Optical isomer of penehyclidine and medicinal composition and application thereof

Granted publication date: 20130424

Patentee: INSTITUTE OF PHARMACOLOGY AND TOXICOLOGY ACADEMY OF MILITARY MEDICAL SCIENCES PLA CHINA|YUNNAN GREEN-FIELD BIOLOGICAL AND MEDICINAL Co.,Ltd.

IP01 Partial invalidation of patent right