CN101830896B - Organic acid salt of optical isomer of penehyclidine - Google Patents
Organic acid salt of optical isomer of penehyclidine Download PDFInfo
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- CN101830896B CN101830896B CN 200910119525 CN200910119525A CN101830896B CN 101830896 B CN101830896 B CN 101830896B CN 200910119525 CN200910119525 CN 200910119525 CN 200910119525 A CN200910119525 A CN 200910119525A CN 101830896 B CN101830896 B CN 101830896B
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Abstract
The invention relates to organic acid salt of an optical isomer of penehyclidine, in particular to a compound of a formula I or the crystals, solvate or prodrug of the compound, wherein n and HX are defined in the description. The invention also relates to a method for preparing the compound of the formula I or the crystals, solvate or prodrug of the compound, application thereof in the preparation of medicaments, a method for treating diseases by using the same and a drug composition containing the same. The organic acid salt of the optical isomer of penehyclidine has the characteristics of high stability.
Description
Technical field
The present invention relates to the organic acid salt of optical isomer of penehyclidine, be specifically related to (3R, the organic acid salt of 2 ' R)-amyl ethyl quin ether or its crystal type, solvate or prodrug.The invention still further relates to that (their pharmaceutical applications uses their treatment disease or the method for the state of an illness and pharmaceutical compositions that comprises them for 3R, the preparation method of the organic acid salt of 2 ' R)-amyl ethyl quin ether or its crystal type, solvate or prodrug.
Background technology
Penequine hydrochloride [English name: Penehyclidine Hydrochloride; Chemical name: 3-(2 '-hydroxyl-2 '-cyclopentyl-2 '-phenyl ethoxy) quinuclidine hydrochloride], its structure is shown below:
Penequine hydrochloride
Amyl ethyl quin ether belongs to ethyl cyclic hydrocarbon amido ether compounds, it 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.), clinical successfully for aspects such as treatment organophosphate poisonings, 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 the anti-nerve poison effect with Isodose level with instrument medicine QNB (3-Quinuclidine benziate), 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 very important 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 and/or prevent chronic obstructive pulmonary disease; By suppressing the respiratory tract glandular secretion, effectively alleviate 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 the front premedicate of inhalation anesthesia.Therefore develop the focus that medicine has become each large pharmaceuticals new drug research of the world from the m receptor antagonist.But non-selective m receptor antagonist can produce the side effects such as dry, tachycardia, constipation, uroschesis, mydriasis and central nervous system symptom; In even same tissue, the different subtype of m receptor has different pharmacological properties.At respiratory tract, M
2The function of acceptor and M
1And M
3The function of acceptor is completely contradicted.Therefore, be the key that determines the anticholinergic agent application prospect to the selectivity of the m receptor of different subtype.The inventor finds, and amyl ethyl quin ether and salt thereof for example hydrochloride can be used as effective as selective m receptor antagonist, particularly can be used as selectivity M
3Receptor antagonist.The inventor it has also been found that, amyl ethyl quin ether and salt thereof for example hydrochloride can be as the medicine that treats and/or prevents chronic obstructive pulmonary disease, treat and/or prevent the medicine of flu and/or the medicine of preanesthetic medication.Can predict, other acid salt of amyl ethyl quin ether also will have above-mentioned purposes as selectivity m receptor antagonist and be used for the clinical purposes such as tuberculosis, flu, anesthesia treatment such as inorganic acid salt such as phosphoric acid salt and organic acid salt.
Contain two chiral centres in the molecular structure of Penequine hydrochloride, so have four optical isomers.Preliminary study shows, the active isomer of Penequine hydrochloride cholinolytic effect is (3R, 2 ' R)-configuration.With regard to regard to rat brain m receptor avidity, the strongest (3R, the effect of 2 ' R)-isomer is than the most weak (3S, 2 ' S)-more than 1000 times of isomery height (Niu, W.Z.et al.Arch.Iht.Pharmacodyn Ther.1990,304,64.).Therefore, (3R, 2 ' R)-isomer are the cholinolytic active isomer of amyl ethyl quin ether.
Existing published (3R, the salt of 2 ' R)-amyl ethyl quin ether is hydrochloride, but the inventor is the unexpected (3R that finds, the hydrochloride solution of 2 ' R)-amyl ethyl quin ether is to thermally labile, at preparation (3R, in the process of the hydrochloride of 2 ' R)-amyl ethyl quin ether and to (3R in the process of 2 ' R)-amyl ethyl quin ether hydrochloride solution autoclaving sterilization, racemization occurs easily.The inventor finds that also (3R, the aqueous solution of the vitriol of 2 ' R)-amyl ethyl quin ether, hydrobromate etc. also exists heat-labile deficiency.Investigator of the present invention is through intensive research discovery, and (3R, the organic acid salt of 2 ' R)-amyl ethyl quin ether are to thermally-stabilised, and the process that is conducive to the medicine preparation is processed, and favourable for amyl ethyl quin ether is used for pharmaceutical composition.Therefore, the inventor is accomplished the present invention based on above discovery.
Summary of the invention
Technical problem to be solved by this invention is to provide a kind of stable amyl ethyl quin ether active optical isomer.The present invention finds (3R, there is heat-labile problem in the inorganic acid salts such as the hydrochloride of 2 ' R)-amyl ethyl quin ether and vitriol, hydrobromate, and the inventor is surprisingly found out that, (3R, the organic acid salt of 2 ' R)-amyl ethyl quin ether is to thermally-stabilised.The inventor is accomplished the present invention based on this discovery.
One aspect of the present invention provides with following formula I compound or its crystal type, solvate or prodrug:
Wherein,
N is selected from 1,2/3,1/2 or 1/3; With
HX represents the acceptable organic acid of pharmacy.
Formula I compound of the present invention be 3-(2 '-hydroxyl-2 '-cyclopentyl-2 '-phenyl ethoxy) organic acid salt of quinuclidine, can be referred to as (3R, 2 ' R)-amyl ethyl quin ether organic acid salt at this paper.
Formula I compound described according to the first aspect present invention any one or its crystal type, solvate or prodrug, wherein said n is selected from 1 or 1/2.
Formula I compound described according to the first aspect present invention any one or its crystal type, solvate or prodrug, wherein said organic acid is selected from:
Citric acid, fumaric acid, tartrate, succsinic acid, toxilic acid, oxysuccinic acid,
Formic acid, acetic acid, propionic acid, propanedioic acid, butyric acid, caproic acid, enanthic acid,
Oxalic acid, Whitfield's ointment, xitix, lactic acid, hexanodioic acid,
Gluconic acid, tosic acid, phenylformic acid, Lalgine, aspartic acid, Phenylsulfonic acid, dextrocamphoric acid, camphorsulfonic acid, didextrose acid, and
Nicotinic acid, 2-naphthene sulfonic acid, palmitinic acid, pectic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), L-glutamic acid.
Formula I compound described according to the first aspect present invention any one or its crystal type, solvate or prodrug, wherein said organic acid is selected from: citric acid, fumaric acid, tartrate, succsinic acid, toxilic acid, oxysuccinic acid.
Formula I compound described according to the first aspect present invention any one or its crystal type, solvate or prodrug, wherein said organic acid is selected from: citric acid, fumaric acid, tartrate, toxilic acid.
Formula I compound described according to the first aspect present invention any one or its crystal type, solvate or prodrug, wherein said organic acid is selected from:
Formic acid, acetic acid, propionic acid, propanedioic acid, butyric acid, caproic acid, enanthic acid,
Oxalic acid, Whitfield's ointment, xitix, lactic acid, hexanodioic acid,
Gluconic acid, tosic acid, phenylformic acid, Lalgine, aspartic acid, Phenylsulfonic acid, dextrocamphoric acid, camphorsulfonic acid, didextrose acid, and
Nicotinic acid, 2-naphthene sulfonic acid, palmitinic acid, pectic acid, 3-phenylpropionic acid, picric acid, PIVALIC ACID CRUDE (25), L-glutamic acid.
Formula I compound described according to the first aspect present invention any one or its crystal type, solvate or prodrug, it is selected from:
1) formula I
1Shown (3R, 2 ' R)-amyl ethyl quin ether fumarate:
2) formula I
2Shown (3R, 2 ' R)-amyl ethyl quin ether hemifumarate:
3) formula I
3Shown (3R, 2 ' R)-amyl ethyl quin ether maleate:
4) formula I
4Shown (3R, 2 ' R)-amyl ethyl quin ether L-TARTARIC ACID salt:
5) formula I
5Shown (3R, 2 ' R)-amyl ethyl quin ether citrate:
Or its crystal type, solvate or prodrug.
According to formula I compound or its crystal type, solvate or the prodrug of first aspect present invention, it is formula I
1Shown (3R, 2 ' R)-amyl ethyl quin ether fumarate is characterized in that:
A) use Cu-K α radiation, with the powder x-ray diffraction collection of illustrative plates that 2 θ angles represent, have at least three and be selected from the absorption peak that is about following position: 8.96,9.46,12.12,15.14,17.32,17.96,18.76,19.74,20.80,22.08,22.40,23.12,24.82 and 26.36; And/or
B) its DSC endothermic transition point is about 178.6 ℃.
According to formula I compound or its crystal type, solvate or the prodrug of first aspect present invention, it is formula I
1Shown (3R, 2 ' R)-amyl ethyl quin ether fumarate is characterized in that:
A) use Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates that represents with 2 θ angles, have at least three and be selected from the absorption peak that is about following position: 8.96,9.46,12.12,15.14,17.32,17.96,19.74,20.80,23.12 and 26.36; And/or
B) its DSC endothermic transition point is about 178.6 ℃.
According to formula I compound or its crystal type, solvate or the prodrug of first aspect present invention, it is formula I
1Shown (3R, 2 ' R)-amyl ethyl quin ether fumarate, it is characterized in that: use Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates that represents with 2 θ angles, at about 8.96,9.46,12.12,15.14,17.32,17.96,19.74,20.80,23.12 and 26.36 places, absorption peak is arranged.
According to formula I compound or its crystal type, solvate or the prodrug of first aspect present invention, it is formula I
1Shown (3R, 2 ' R)-amyl ethyl quin ether fumarate, it is characterized in that: use Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates that represents with 2 θ angles has absorption peak at about 8.96,9.46,12.12,15.14,17.32,17.96,18.76,19.74,20.80,22.08,22.40,23.12,24.82 and 26.36 places.
According to formula I compound or its crystal type, solvate or the prodrug of first aspect present invention, it is formula I
2Shown (3R, 2 ' R)-amyl ethyl quin ether hemifumarate, it is characterized in that: use Cu-K α radiation, with the powder x-ray diffraction collection of illustrative plates that 2 θ angles represent, have at least three and be selected from the absorption peak that is about following position: 8.92,9.40,12.12,15.10,17.30,17.88,19.68,20.72,20.86,22.44,24.66 and 29.92.
According to formula I compound or its crystal type, solvate or the prodrug of first aspect present invention, it is formula I
2Shown (3R, 2 ' R)-amyl ethyl quin ether hemifumarate, it is characterized in that: use Cu-K α radiation, with the powder x-ray diffraction collection of illustrative plates that 2 θ angles represent, have at least three and be selected from the absorption peak that is about following position: 8.92,9.40,12.12,15.10,17.88 and 19.68.
According to formula I compound or its crystal type, solvate or the prodrug of first aspect present invention, it is formula I
2It is shown that (3R, 2 ' R)-amyl ethyl quin ether hemifumarate is characterized in that: use Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates that represents with 2 θ angles has absorption peak at about 8.92,9.40,12.12,15.10,17.88 and 19.68 places.
According to formula I compound or its crystal type, solvate or the prodrug of first aspect present invention, it is formula I
2Shown (3R, 2 ' R)-amyl ethyl quin ether hemifumarate, it is characterized in that: use Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates that represents with 2 θ angles has absorption peak at about 8.92,9.40,12.12,15.10,17.30,17.88,19.68,20.72,20.86,22.44,24.66 and 29.92 places.
According to formula I compound or its crystal type, solvate or the prodrug of first aspect present invention, it is the pure form of basic optical.Further, according to formula I compound or its crystal type, solvate or the prodrug 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 formula I compound or its crystal type, solvate or the prodrug of first aspect present invention, it can be used as the therapeutical agent of organophosphate poisoning.
According to formula I compound or its crystal type, solvate or the prodrug of first aspect present invention, its useful as selective m receptor antagonist, preferred useful as selective M3 receptor antagonist.
According to formula I compound or its crystal type, solvate or the prodrug of first aspect present invention, it can be used as the medicine that treats and/or prevents chronic obstructive pulmonary disease, treats and/or prevents the medicine of flu and/or the medicine of preanesthetic medication.
Second aspect present invention provides the preparation method of the described formula I compound of first aspect present invention any one or its crystal type, solvate or prodrug, and it comprises the following steps:
I) make (R)-amygdalic acid
Carry out aldol reaction with special valeral; [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 the lactone compound of formula II
Iii) making cyclopentanone and step I i) the formula II lactone compound of gained carries out the Michael addition reaction, and products therefrom obtains the oxyacetic acid compound of formula VI through dehydration, deprotection, hydrogenation
[can add synthesis in the Michael addition reaction, preferably use two (trimethylsilyl) Lithamide]
Iv) make step I ii) reduction of the formula VI oxyacetic acid compound of gained, obtain the dihydroxyl compound of formula VII
Then with to toluene sulphur chlorine react, obtain and the tosic acid monoester compound;
V) making step I v) monoester compound of gained is through Intra-molecular condensation, obtains (R)-1-phenyl of formula IX-1-cyclopentyl-1,2-oxyethane
Vi) make (R)-1-phenyl-1-cyclopentyl-1,2-oxyethane and 3-(R)-quinine cyclol
Reaction obtains optical isomer formula X compound
With
Vii) make formula X compound and organic acid HX react salify in solvent, obtain formula I compound
Wherein, the definition of n, XH is with the described formula I compound of first aspect present invention any one.
Method described according to second aspect present invention, wherein said formula X compound and organic acid HX react with the ratio of calculated amount to obtain corresponding salt, for example, if formula X compound and fumaric acid salify, formula X compound can be 1: 1 or 1: 1/2 with the molar equivalent ratio of organic acid HX; Again for example, if formula X compound and Citric Acid salify, formula X compound can be 1: 1 or 1: 2/3 or 1: 1/3 with the molar equivalent ratio of organic acid HX.
Three aspects: of the present invention provides the pharmaceutical applications of the described compound of first aspect present invention any one or its crystal type, solvate or prodrug.Specifically, three aspects: of the present invention provides the described compound of first aspect present invention any one or its crystal type, solvate or prodrug preparing as the purposes in the medicine of acute organophosphorus pesticide poisoning agent.Three aspects: of the present invention also provides the described compound of first aspect present invention any one or its crystal type, solvate or prodrug preparing as selectivity m receptor antagonist, preferably as the purposes in the medicine of selectivity M3 receptor antagonist.Three aspects: of the present invention also provides the described compound of first aspect present invention any one or its crystal type, solvate or prodrug preparing as the purposes in the medicine that treats and/or prevents the medicine of chronic obstructive pulmonary disease, the medicine that treats and/or prevents flu and/or preanesthetic medication.
The present invention four aspects provide the described compound of use first aspect present invention any one or its crystal type, solvate or prodrugs therapy and/or prophylactic method.Specifically, the present invention four aspects provide the method for the treatment of organophosphate poisoning, and it comprises the described compound of first aspect present invention any one or its crystal type, solvate or prodrug to experimenter's administering therapeutic that needs are arranged and/or prevention significant quantity.The present invention four aspects also provide and have treated and/or prevented and selectivity m receptor selectivity M particularly
1Receptor related disease or the method for the state of an illness, it comprises the described compound of first aspect present invention any one or its crystal type, solvate or prodrug as selectivity m receptor antagonist to experimenter's administering therapeutic that needs are arranged and/or prevention significant quantity.The present invention four aspects also provide the method that treats and/or prevents chronic obstructive pulmonary disease, flu and/or the front associated conditions of anesthesia, and it comprises the described compound of first aspect present invention any one or its crystal type, solvate or prodrug to experimenter's administering therapeutic that needs are arranged and/or prevention significant quantity.
Fifth aspect present invention provides a kind of pharmaceutical composition, it comprises the described compound of one or more first aspect present invention any one or its crystal type, solvate or the prodrug that treat and/or prevent significant quantity as 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 that treats and/or prevents chronic obstructive pulmonary disease, treats and/or prevents the medicine of flu and/or the medicine of preanesthetic medication.
The described pharmaceutical composition of above-mentioned according to fifth aspect present invention or following any one, it is tablet, capsule, injection, sprays, aerosol, nasal drop or powder inhalation.
The described pharmaceutical composition of above-mentioned according to fifth aspect present invention or following any one wherein comprises 0.005 to 100mg the described compound of first aspect present invention any one or its crystal type, solvate or prodrug as activeconstituents in per unit dosage.Preferably, the described pharmaceutical composition of above-mentioned according to fifth aspect present invention or following any one wherein comprises 0.05 to 10mg the described compound of invention first aspect any one or its crystal type, solvate or prodrug as activeconstituents in per unit dosage.
The below is further described term involved in the present invention and the features and advantages of the present invention.
As described herein, what the n in formula I compound represented is, the organic acid that represents with HX in the salt that formula I represents and formula
Free alkali feasible or possible in conjunction with equivalence ratio in theory between the two.For example when this free alkali and acetic acid (monoprotic acid) formation salt, this n can be 1 usually; For example when this free alkali and fumaric acid (diprotic acid) form salt, this n can be 1 or 1/2 usually again.
As described herein, what the HX in formula I compound represented is the described various possible organic acids of first aspect present invention, and this organic acid can be for example formic acid, diprotic acid tartrate, triprotic acid Citric Acid for example for example of monoprotic acid.
As being used for this paper, term " pharmacy is acceptable " typically refers to and can be used on pharmacopedics or medically available, although 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 medical science.Specifically, for example, the described organic acid of " pharmacy is acceptable " expression that relates in phrase " the acceptable organic acid of pharmacy " is that pharmacy can be used, comprise and to be directly used in clinical organic acid, although also comprise to be directly used in clinically, can be used as the organic acid that pharmaceutical raw material uses.To rear a kind of situation, for example, although related organic acid can not be directly used in clinical and can not form the formula I compound that is directly used in clinical patients, but this organic acid can with a kind of stable salt of formula X compound formation, provide stable useful operation steps in order to make in preparation formula X compound and final formula I compound.And for example, as being used for this paper, term " pharmaceutically acceptable carrier or vehicle " refers to the pharmaceutical excipient that the preparation industrial circle is commonly used, for example at Luo Mingsheng, etc. pharmaceutical necessities is complete works of, and Sichuan science tech publishing house is enumerated in 1995.
Formula I 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 the acceptable solvent of pharmacy such as water, ethanol etc.
With powder x-ray diffraction figure profiling the compounds of this invention formula I for example
1It is shown that (3R, related " approximately " during the crystallization of 2 ' R)-amyl ethyl quin ether fumarate, and related " approximately " of other situation have the implication of the margin of error of well known to a person skilled in the art.
Term used herein " treatment " and " prevention " have its general implication, and typically refer to related disease or the state of an illness are produced prevent, alleviate, the reactions such as treatment, healing, alleviation.
As being used for this paper, " significant quantity " that treats and/or prevents has its general implication, and typically refer to related disease or the state of an illness are produced effectively prevent, alleviate, the dosage of the formula I compound of the present invention of the reactions such as treatment, healing, alleviation.
As being used for this paper, term " basic optical is pure " refers to that optical isomer compound shown in formula I of the present invention is basically pure on optical purity, so that its optical purity is greater than 90%, be that optical isomer shown in formula I accounts for raw material weight percentage in batches more than 90%, be preferably greater than 95%, be preferably greater than 98%, be preferably greater than 99%, be preferably greater than 99.5%.
M receptor has this area implication the most widely, and typically refers to M
1Acceptor, M
2Acceptor, M
3Acceptor, M
4Acceptor, M
5Acceptor refers to M in the present invention especially
3Acceptor.
Term used herein " composition " means to comprise 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.Pharmaceutical composition of the present invention can be with single a kind of formula I compound or its crystal type, solvate or prodrug as unique activeconstituents, also can with arbitrary proportion two or more formula I compound or its crystal type, solvate or prodrug as activeconstituents.In addition, can also contain at least a other activeconstituents in drug regimen of the present invention, for example can also contain the pyraloxime methyl-chloride (PAM-CL) that treats and/or prevents significant quantity in pharmaceutical composition of the present invention, in order to form compound preparation for clinical using with the compounds of this invention.In the situation that above-mentioned use pyraloxime methyl-chloride (PAM-CL), the consumption of pyraloxime methyl-chloride (PAM-CL) with and can easily determine according to the various factors such as the concrete state of an illness according to the clinician with the proportioning of formula I compound of the present invention or its crystal type, solvate or prodrug.
According to pharmaceutical composition of the present invention, it can be such as 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 aseptic or water type injection 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 art technology people knowledge existing according to it or can prepares with reference to being correlated with textbook or reference book.
Although the amount of the activeconstituents that comprises 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) refers to one group of clinical disease take substantially irreversible CAO as feature.The main pathophysiological mechanism of COPD bronchial obstruction comprises the mucous membrane hypersecretion of being controlled by vagus nerve and is increased by the bronchial smooth muscle tension force that cholinergic mechanism is brought out.Anticholinergic drug has the effect of bronchiectatic activity, secretion inhibition and reduction vagal tone, and pulmonary function, exercise tolerance, the quality of life 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 lacking effective preventive means and antiviral, primary treatment method to flu is symptomatic treatment, namely suppresses runny nose, suppresses cough or remove nasal congestion to alleviate cold symptoms by shrink medicine with antihistamine drug inhibition, antitussive medicine or peripheral blood vessel.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 andsafety of intranasal ipratropium bromide in common colds.Arandomized, double-blind, placebo-controlled trial.Ann Intern Med1996; 125:89-97.).
As described herein, term " preanesthetic medication " refers to 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 the front premedicate of inhalation anesthesia.
One aspect of the present invention relates to and contains formula I compound or its crystal type, solvate or prodrug as the pharmaceutical composition of 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 are conducive to active compound is processed into the preparation that can pharmaceutically use.Suitable dosage 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 formula I compound or its crystal type, solvate or prodrug and treat and/or prevent the medicinal use of medicine, common cold treatment and/or prophylactic agent, preanesthetic medication etc. as chronic obstructive pulmonary disease as the pharmaceutical composition of activeconstituents.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.
Comprise powder, sprays, ointment and inhalation for the local dosage form that gives the compounds of this invention.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 pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response for concrete patient, composition and administering mode.The dosage level fibrous root is selected according to severity and the patient's condition and the medical history to be treated and/or the prevention patient of the activity of particular compound, route of administration, the patient's condition that treats and/or prevents.But the way of this area is, the dosage of compound increases dosage, until obtain required effect gradually from lower than for obtaining required treating and/or preventing the level that effect requires.
When being used for above-mentioned treat and/or prevent or when other treatment and/or prevention, a kind of the compounds of this invention that treats and/or prevents significant quantity can be used with pure form, perhaps uses with the acceptable crystal type of pharmacy, solvate, ester or prodrug forms (in the situation that having 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 compounds of this invention that word " treats and/or prevents significant quantity " refers to be applicable to the reasonable effect of any therapeutic treatment/risk than the compound of the q.s for the treatment of 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 effective dose that treats and/or prevents is decided according to many factors, and described factor comprises the severity of the obstacle that treats and/or prevents and this obstacle; The activity of the particular compound that adopts; The concrete composition that adopts; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound that adopts, route of administration and excretion rate; Treat and/or prevent the time length; The medicine that is used in combination with the particular compound that adopts or uses simultaneously; And the known similar factor of medical field.For example, the way of this area is, the dosage of compound increases dosage, until obtain required effect gradually from lower than for obtaining required treating and/or preventing the level that effect requires.
The dosage that gives people's formula I compound of the present invention or its crystal type, solvate or prodrug can be approximately 0.0005 to the about scope of 1000mg/ time, and more preferably dosage can be approximately 0.005 to the about scope of 100mg/ time; Be administered once every day or repeatedly.If necessary, 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 consist of per daily dose.Can determine 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 with the administration frequency of formula I compound of the present invention or its crystal type, solvate or prodrug, for example give every day 1 time, 2 times, 3 times, 4 times, 5 inferior, perhaps every 2 days once, every 3 days once, every 1 week once, every 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, 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 tolerate with one or more nontoxic physiology or acceptable thinner, carrier, auxiliary material or vehicle (this paper is referred to as thinner with them) together be mixed with composition, for transmit in parenteral injection, nose, with solid or liquid form oral administration, rectum or topical etc.
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, such as parabens, trichloro-butyl alcohol, phenol, Sorbic Acid etc. can guarantee to prevent the effect of microorganism.Also expectation comprises isotonic agent, such as 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.
Also can contain suspension agent except the active ingredient beyond the region of objective existence in suspensoid, such as 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 be by realizing with the crystal of 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 oily vehicle and realize.
The injectable depot formulations form can prepare by the microcapsule matrix that forms medicine in biodegradable polymer such as polylactide-PGA (polylactide-polyglycolide).Can according to the character of medicine with ratio with the concrete polymkeric substance that adopts of polymkeric substance, drug releasing rate be controlled.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 or sterilize by the disinfectant that mixes the aseptic solid composite form with bacterial filter, and described solids composition can be dissolved or dispersed in sterilized water or other sterile injectable medium before use.
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 Si Liaodengji dicalcium phosphate feed grade and/or following material with the medicine of at least a inertia 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, calcium carbonate, potato or tapioca (flour), Lalgine, some silicate and sodium carbonate; 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.In the situation that capsule, tablet and pill also can comprise buffer reagent in described formulation.
The solids composition of similar type uses such as lactose and high molecular weight polyethylene glycol etc. of vehicle, also can be used as the weighting material in soft capsule and hard capsule.
The solid dosage of tablet, dragee (dragees), capsule, pill and granule can prepare together 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 containing the active ingredient beyond the region of objective existence, for example water or other solvents, solubilizing agent and emulsifying agent be ethanol for example, Virahol, ethyl-carbonate, ethyl acetate, benzylalcohol, peruscabin, propylene glycol, 1, the 3-butyleneglycol, dimethyl formamide, oils (Oleum Gossypii semen particularly, peanut oil, Semen Maydis oil, germ oil, sweet oil, Viscotrol C and sesame oil), glycerine, tetrahydrofurfuryl alcohol (tetrahydrofurfuryl alcohol), the fatty acid ester of polyoxyethylene glycol and sorbitan and their mixture.
Oral compositions also can comprise auxiliary material except 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 mix to prepare with the compounds of this invention and suitable non-irritating excipient or carrier, they are at room temperature 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 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 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.
Formula I compound of the present invention or its crystal type, solvate or prodrug preferably can synthesize with reference to following route:
Can be take (R)-amygdalic acid as chiral template, with trifluoromethanesulfonic acid (TfOH) as catalyzer, under 30～35 ℃, at first hydroxyl in the amygdalic acid molecule 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)-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 ℃, add synthesis (preferably to use two (trimethylsilyl) Lithamide, LHMDS), obtain adduct III; Compound III obtains (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy acetic acid (VI) after dehydration, deprotection, hydrogenation; VI uses LiAlH in tetrahydrofuran (THF)
4Reduction obtains dihydroxyl compound VII.Make VII and Tosyl chloride be condensed into tosic acid monoesters compound, 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); Make IX under the sodium hydride effect, with 3-(R)-quinine cyclol reaction, obtain (3R, 2 ' R)-amyl ethyl quin ether (X).Then make (3R, 2 ' R)-amyl ethyl quin ether and corresponding organic acid are at suitable solvent (for example, but be not limited to, dehydrated alcohol) salify in, namely obtain the organic acid salt shown in corresponding formula I of the present invention, this organic acid salt can obtain with suitable crystal type or solvate, also can randomly with the further esterification of the organic acid salt of gained, for example form the prodrug of ester structure by the structural hydroxyl of amyl ethyl quin ether and carboxylic acid.
Although 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.
Description of drawings
Fig. 1 is Compound I
1Powder x-ray diffraction collection of illustrative plates, X-coordinate are 2 θ angles (2-Theta (°)), ordinate zou is the intensity (intensity (CPS)) of absorption peak.
Fig. 2 is Compound I
1The DSC scintigram, X-coordinate is temperature (Temperature (℃)), ordinate zou is heat content (Heat Flow Endo Up (mW)).Peak as shown in FIG., its area (Area)=314.107mJ, Delta H=116.336J/g, peak (Peak)=178.565 ℃, initial (Onset)=176.054, peak ℃.
Fig. 3 is Compound I
1Infrared spectrogram, X-coordinate is wave number (Wavenumber (cm
-1)), ordinate zou is transmittance (Transmittance[%]).
Fig. 4 is Compound I
2Powder x-ray diffraction collection of illustrative plates, X-coordinate are the absorption peak with the powder x-ray diffraction collection of illustrative plates of 2 θ angles (degree) (2Theta[deg.]) expression, and ordinate zou is the intensity (intensity[counts]) of absorption peak.
Embodiment
Further illustrate the present invention below by specific embodiment, still, should be understood to, these embodiment are only used for the use that specifically describes more in detail, and should not be construed as for limiting in any form the present invention.
The present invention carries out generality and/or concrete description to the material and the test method that use in test.Although for to realize that many materials and working method that the object of the invention is used 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, material therefor of the present invention and working method are well known in the art.
1.1,(2R, 5R)-2-tertiary butyl-5-phenyl-1, the preparation of 3-diox-4-ketone (II)
R-MA 20g (0.13mol) is added in the 200mL Skellysolve A, then add special valeral 21.2mL (content 80%, 0.16mol is available from Fluka company), then add trifluoromethanesulfonic acid 0.5mL, 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, underpressure distillation, remove Skellysolve A, filter, 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)
(2S with 10g (45mmol), 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 (trimethylsilyl) Lithamide (solution in tetrahydrofuran (THF), 1.0M).Stir the lower cyclopentanone 65mmol that drips, will react and stir 2 hours, the dropping saturated sodium hydrogen phosphate solution of 15mL and 200mL saturated ammonium chloride solution.Separate organic layer, the water layer ethyl acetate extraction.The organic layer that merges is dry, distillation, desolventizing obtains (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)-2-tertiary butyl-5-phenyl-5-(cyclopentyl-1-hydroxyl)-1,3-diox-4-ketone (III) is dissolved in 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, dry, distillation, desolventizing obtains (2R, 5R)-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,The preparation of (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy acetic acid (VI)
With (2R, 5R)-2-tertiary butyl of 2.34g (8.18mmol)-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 1N HCl acidifying, then use ethyl acetate extraction, and drying, distillation, desolventizing obtains (R)-α-phenyl-α-cyclopentenyl-Alpha-hydroxy acetic acid (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 of 1.16g (5.3mmol)-α-cyclopentenyl-Alpha-hydroxy acetic acid (V) is dissolved in 50mL methyl alcohol, adds the 10%Pd/C of 0.2g, use H under 1atm
2Reduced 8 hours.Filter, underpressure distillation, desolventizing obtains (R)-α-phenyl-α-cyclopentyl-Alpha-hydroxy acetic acid (VI) 1.08g, yield 93%.[α]
D 20=+2.5 ° (MeOH, c=3), fusing point: 118-119 ℃.
1.5,(R) synthesizing of-α-phenyl-α-cyclopentyl-Alpha-hydroxy ethyl p-toluenesulfonate (VIII)
At N
2Under protection, will contain (R)-α-phenyl of 2.2g (0.01mol)-α-cyclopentyl-10mL anhydrous THF solution of Alpha-hydroxy acetic acid (VI) and slowly be added drop-wise to and contain LiAlH
4In 20mL anhydrous THF solution (0.02mol), slowly be warming up to backflow under stirring, reaction 3h.Cooling, carefully drip the saturated NaHCO of 2mL
3Solution, then drip the NaOH solution of the 2N of 10mL.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, desolventizing, 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 the 100mL of drying there-necked flask, add the CH of (R)-α-phenyl of 1.89g-α-cyclopentyl-Alpha-hydroxy ethanol (VII) and 50mL drying
2Cl
2, be cooled to 0 ℃, add Tosyl chloride 3.42g (18mmol).Stir the lower triethylamine 2.43g (24mmol) of dropping.Dropwise, stir 2h under 0 ℃, the mixed liquid of reaction slightly is yellow.Then carefully add saturated NaHCO
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)-1-phenyl-1-cyclopentyl-1, the preparation of 2-oxyethane (IX)
In the 50mL of drying there-necked flask, add (R)-α-phenyl of 1.0g-α-cyclopentyl-Alpha-hydroxy ethyl p-toluenesulfonate (VIII) and 20mL anhydrous methanol.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)。
Under nitrogen protection; the NaH of 0.6g (15mmol) is placed in dry there-necked flask, adds the anhydrous DMSO of 10mL, after 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 drip 20mL water.Use ether extraction, wash with water, then with 10% hydrochloric acid soln washing ether layer, merge water; With the hydrochloric acid extraction liquid of 40% NaOH alkalization gained, use extracted with diethyl ether, use anhydrous sodium sulfate drying, to distill, desolventizing obtains the colourless liquid of X, 2.84g, yield 65%, [α]
D 20=+8.26 ° (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)。
With fumaric acid 0.6g (5mmol) and (3R, 2 ' R)-amyl ethyl quin ether 1.58g (5mmol) joins in the 14ml dehydrated alcohol, and reflux is until solid all dissolves, filtered while hot, Slow cooling is separated out column crystallization, filters, dry, obtain the 1.90g title compound, fusing point 170-172 ℃, yield 86.9%.Ultimate analysis: theoretical value C:66.80%, H:7.71%, N:3.25%;
Observed value: C:66.67%, H:7.72%, N:3.28%.
Embodiment 4,(3R, 2 ' R)-amyl ethyl quin ether hemifumarate (I
2) preparation
After fumaric acid 0.3g (2.5mmol) is dissolved in 4ml acetone, be added drop-wise to that (3R, 2 ' R)-amyl ethyl quin ether 1.58g (5mmol) is dissolved in the solution of 10ml acetone.Add completely, system clarification was stirred after 5 minutes, had solid to separate out.Continue to stir 2 hours, filter, obtaining title compound is white powder, drying, the 1.75g that weighs, yield 93.1%, fusing point 140-142 ℃.Ultimate analysis: theoretical value C:70.75%, H:8.37%, N:3.75%; Observed value: C:70.56%, H:8.53%, N:3.95%.
With toxilic acid 0.3g (2.5mmol) with (3R, 2 ' R)-amyl ethyl quin ether 0.79g (2.5mmol) joins in 12ml acetone.Add completely, system clarification was stirred after 5 minutes, had solid to separate out.Continue to stir 2 hours, filter, obtaining title compound is white powder, drying, the 1.05g that weighs, yield 96.33%.Ultimate analysis: theoretical value C:66.80%, H:7.71%, N:3.25%; Observed value: C:66.56%, H:7.73%, N:3.35%.
Embodiment 6,(3R, 2 ' R)-amyl ethyl quin ether-L-TARTARIC ACID salt (I
4) preparation
With L-TARTARIC ACID 0.375g (2.5mmol) with (3R, 2 ' R)-amyl ethyl quin ether 0.79g (2.5mmol) join in 60 ℃ of dehydrated alcohol 7ml.Add completely, system clarification was stirred after 5 minutes, naturally lowered the temperature, and had solid to separate out.Continue to stir 2 hours, filter, obtaining title compound is white powder, drying, the 0.96g that weighs, yield 82.4%.Ultimate analysis: theoretical value C:61.92%, H:7.58%, N:3.01%; Observed value: C:61.82%, H:7.55%, N:3.11%.
Embodiment 7,(3R, 2 ' R)-amyl ethyl quin ether citrate (I
5) preparation
With Citric Acid 0.48g (2.5mmol) with (3R, 2 ' R)-amyl ethyl quin ether 0.79g (2.5mmol) join in the dehydrated alcohol 7ml of 65 ℃.Add completely, system clarification was stirred after 10 minutes, naturally lowered the temperature, and had solid to separate out.Continue to stir 2 hours, filter, obtain white powder, drying, the 1.12g that weighs, yield 88.19%.Ultimate analysis: theoretical value C:61.52%, H:7.35%, N:2.76%; Observed value: C:61.56%, H:7.29%, N:2.69%.
With (3R, 2 ' R)-amyl ethyl quin ether 1.0g dissolve with anhydrous diethyl ether, drip hydrogenchloride-diethyl ether solution, separate out white solid; Filter, with acetone recrystallization, obtain (3R, 2 ' R)-amyl ethyl quin ether hydrochloride 0.85g, fusing point 160-162 ℃.
Utilize stably express M
1To M
5The Chinese hamster ovary celI of receptor subtype prepares membranin, with [
3H]-N-epoxytropine tropate (NMS) in conjunction with experiment, measures the IC of target compound competitive inhibitory effect for being at war with property of aglucon
50, compare its avidity to the different subtype m receptor, its experiment the results are shown in Table shown in 1.
Table 1: target compound
Competitive binding experiment result (IC to the different subtype m receptor
50, M)
| Receptor subtype | M 1 | M 2 | M 3 | M 4 | M 5 |
| Compounds X | 3.6×10 -8 | 7.4×10 -7 | 1.9×10 -9 | 8.3×10 -8 | 9.2×10 -8 |
| Compound I 1 | 4.4×10 -8 | 9.8×10 -7 | 2.5×10 -9 | 9.0×10 -8 | 10.1×10 -8 |
| Compound I 2 | 4.1×10 -8 | 9.5×10 -7 | 2.7×10 -9 | 8.6×10 -8 | 9.8×10 -8 |
From the table result as seen, (3R, the organic acid salt of 2 ' R)-amyl ethyl quin ether and its free alkali have essentially identical biologic activity in the present invention.
1), analytical procedure:
Chromatographic condition and system suitability test octadecylsilane chemically bonded silica are weighting agent; Take methyl alcohol: 0.05M sodium-acetate-acetum (pH=5)=9: 1 is as moving phase; The detection wavelength is 220nm, flow velocity 1ml/min.Number of theoretical plate is by (3R, 2 ' R)-amyl ethyl quin ether calculates and is not less than 3000.
2), stability testing method
Get the testing compound sample, be mixed with the aqueous solution of 0.5mg/ml as storing solution, the accurate storing solution 1.0ml that draws puts the 25ml volumetric flask, adds moving phase to scale, product solution in contrast after shaking up.
Get the testing compound sample, be mixed with the aqueous solution of 0.5mg/ml, in 100 ℃ of water-baths, heating is 2 hours, and is cooling; The accurate 1.0ml that draws puts the 25ml volumetric flask, adds moving phase to scale, shakes up rear as need testing solution.
Get trial-product, each 20 μ l of reference substance solution, inject respectively high performance liquid chromatograph and measure, with the content of external standard method by target compound in the calculated by peak area trial-product.3), the stability test result result is as shown in table 2:
With Compound I
1, I
2, I
3, I
4, I
5, and (test-results sees Table 2 for 3R, the sample that 2 ' R)-amyl ethyl quin ether hydrochloride is investigated as stability test.
Table 2:(3R, the stability test result of the aqueous solution of 2 ' R)-amyl ethyl quin ether salt
| Compound | I 1 | I 2 | I 3 | I 4 | I 5 | Hydrochloride |
| Residue content (%) | 101.3 | 99.7 | 100.9 | 98.6 | 99.2 | 85.5 |
From table 2 result as seen, (3R, the organic acid salt of 2 ' R)-amyl ethyl quin ether be after solution stability testing is processed, and its stability is obviously than height of hydrochloride.
(3R, the crystal type of the organic acid salt of 2 ' R)-amyl ethyl quin ether characterizes to of the present invention to adopt X-ray diffraction method, dsc (DSC) and Infrared spectroscopy.
1, specimen:
(3R, 2 ' R)-amyl ethyl quin ether fumarate (I that embodiment 3 makes
1),
(3R, 2 ' R)-amyl ethyl quin ether hemifumarate (I that embodiment 4 makes
2).
2, the test condition of powder x-ray diffraction method and method
Instrument: DMAX-2500 powder x-ray diffraction instrument,
Method: using Cu-K α radiation, is the 200-300 order with the testing sample porphyrize, scanning angle scope 3.0-60.0 degree, and sweep velocity is 0.15 degree/second counting.
3, the test condition of dsc and method
Instrument model: TGA-7,
Experimental technique: it is 10.00 ℃/min that heat-up rate is set, and heats up, and observes and note down the interior dq/dt of 20.00 ℃ of-300.00 ℃ of temperature ranges changing.
4, the test condition of Infrared spectroscopy and method
Instrument: German Brooker Tensor 27 detector RT-DLaTGS,
Experimental technique: pressing potassium bromide troche, resolving power 4, wave number 400-4000, scanning times 32.
5, test result
Compound I
1And Compound I
2Powder x-ray diffraction collection of illustrative plates, DSC scintigram and infrared spectrogram respectively referring to Fig. 1,2,3 and 4.
According to Fig. 1, formula I
1Shown (3R, 2 ' R)-amyl ethyl quin ether fumarate, at about 8.96,9.46,12.12,15.14,17.32,17.96,18.76,19.74,20.80,22.08,22.40,23.12,24.82 and 26.36 places, absorption peak is arranged, particularly at about 8.96,9.46,12.12,15.14,17.32,17.96,19.74,20.80,23.12 and 26.36 places, absorption peak is arranged.I
12 θ values and the relative kurtosis (I/I at powder x-ray diffraction peak
0, the ratio of absorption peak area and base peak and maximum absorption peak area) concrete outcome see Table 3.
According to Fig. 4, formula I
2Shown (3R, 2 ' R)-amyl ethyl quin ether hemifumarate, at about 8.92,9.40,12.12,15.10,17.30,17.88,19.68,20.72,20.86,22.44,24.66 and 29.92 places, absorption peak is arranged, particularly at about 8.92,9.40,12.12,15.10,17.88 and 19.68 places, absorption peak is arranged.I
22 θ values and the relative kurtosis (I/I at powder x-ray diffraction peak
0, the ratio of absorption peak area and base peak and maximum absorption peak area) concrete outcome see Table 4.
Table 3:I
1The powder x-ray diffraction data
| Peak number | 2θ(°) | I/I 0(％) |
| 1 | 8.959 | 16.6 |
| 2 | 9.459 | 12.1 |
| 4 | 12.121 | 20.2 |
| 6 | 15.140 | 13.9 |
| 9 | 17.319 | 19.2 |
| 10 | 17.960 | 100 |
| 11 | 18.760 | 11.6 |
| 12 | 19.740 | 16.1 |
| 13 | 20.800 | 20.5 |
| 14 | 22.079 | 14.3 |
| 15 | 22.400 | 19.7 |
| 16 | 23.119 | 15.4 |
| 18 | 24.821 | 18.1 |
| 20 | 26.360 | 24.3 |
Table 4:I
2The powder x-ray diffraction data
| Peak number | 2θ(°) | I/I 0(％) |
| 2 | 8.920 | 55 |
| 3 | 9.400 | 25 |
| 5 | 12.12 | 31 |
| 7 | 15.100 | 34 |
| 10 | 17.300 | 21 |
| 11 | 17.880 | 100 |
| 14 | 19.680 | 17 |
| 15 | 20.720 | 28 |
| 16 | 20.860 | 25 |
| 18 | 22.440 | 18 |
| 21 | 24.660 | 18 |
| 28 | 29.920 | 16 |
Claims (7)
1. compound, it is selected from:
1) formula I
1Shown (3R, 2 ' R)-amyl ethyl quin ether fumarate:
2) formula I
2Shown (3R, 2 ' R)-amyl ethyl quin ether hemifumarate:
3) formula I
3Shown (3R, 2 ' R)-amyl ethyl quin ether maleate:
4) formula I
4Shown (3R, 2 ' R)-amyl ethyl quin ether L-TARTARIC ACID salt:
5) formula I
5Shown (3R, 2 ' R)-amyl ethyl quin ether citrate:
2. the compound of claim 1, it is formula I
1Shown (3R, 2 ' R)-amyl ethyl quin ether fumarate is characterized in that:
A) use Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates that represents with 2 θ angles has absorption peak at about 8.96,9.46,12.12,15.14,17.32,17.96,19.74,20.80,23.12 and 26.36 places; And/or
B) its DSC endothermic transition point is about 178.6 ℃.
3. the compound of claim 1, it is formula I
2It is shown that (3R, 2 ' R)-amyl ethyl quin ether hemifumarate is characterized in that: use Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates that represents with 2 θ angles has absorption peak at about 8.92,9.40,12.12,15.10,17.88 and 19.68 places.
4. the preparation method of the described compound of claim 1, it comprises the following steps:
I) make (R)-amygdalic acid
Carry out aldol reaction with special valeral;
Ii) make step I) in hydroxyl and carboxyl in the hemiacetal molecule that forms carry out intramolecular condensation, obtain the lactone compound of formula II
Iii) making cyclopentanone and step I i) the formula II lactone compound of gained carries out the Michael addition reaction, and products therefrom obtains the oxyacetic acid compound of formula VI through dehydration, deprotection, hydrogenation
Iv) make step I ii) reduction of the formula VI oxyacetic acid compound of gained, obtain the dihydroxyl compound of formula VII
Then with to toluene sulphur chlorine react, obtain and the tosic acid monoester compound;
V) making step I v) monoester compound of gained is through Intra-molecular condensation, obtains (R)-1-phenyl of formula IX-1-cyclopentyl-1,2-oxyethane
Vi) make (R)-1-phenyl-1-cyclopentyl-1,2-oxyethane and 3-(R)-quinine cyclol
Reaction obtains optical isomer formula X compound
With
Vii) make formula X compound and organic acid HX react salify in solvent, obtain formula I compound
Wherein, formula I compound is compound claimed in claim 1.
5. the described compound of claims 1 to 3 any one is preparing as the purposes in the medicine of selectivity m receptor antagonist.
6. the purposes of claim 5, it is that described compound is preparing as the purposes in the medicine of acute organophosphorus pesticide poisoning agent, preparing as the purposes in the medicine that treats and/or prevents chronic obstructive pulmonary disease,, perhaps preparing as the purposes in the medicine of preanesthetic medication as the purposes in the medicine that treats and/or prevents flu in preparation.
7. pharmaceutical composition, it comprises the described compound of one or more claims 1 to 3 any one that treats and/or prevents significant quantity, and pharmaceutically acceptable carrier or vehicle.
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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 |
| 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 |
| CN102850345A (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 | Quaternary ammonium salt and its pharmaceutical composition and its use |
| CN104297354B (en) * | 2013-07-16 | 2016-07-06 | 重庆市康乾医药有限公司 | The detection method of impurity in a kind of high effective liquid chromatography for measuring amyl ethyl quin ether hydrochloride |
| CN104072345B (en) * | 2014-06-20 | 2016-06-01 | 成都力思特药物研究有限公司 | A kind of method being applicable to prepare 1-cyclopentyl-2-methoxyl group-1-phenylethyl alcohol |
| CN111689956B (en) * | 2019-03-14 | 2021-12-24 | 银谷制药有限责任公司 | Resolution method of quinine compound containing quaternary ammonium group |
| CN110003198B (en) * | 2019-04-22 | 2021-09-21 | 上海旭东海普药业有限公司 | Purification method of penehyclidine |
| CN115397823A (en) * | 2020-04-26 | 2022-11-25 | 北京硕佰医药科技有限责任公司 | M receptor antagonist crystal, preparation method and application thereof |
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| WO2004016590A1 (en) * | 2002-08-16 | 2004-02-26 | Chengdu List Pharmaceutical Co.,Ltd | The salts of the quinuclidine derivatives and the preparation and applications thereof |
| CN1568984A (en) * | 2003-07-21 | 2005-01-26 | 北京小伙伴医药生物技术有限公司 | Spray and aerosol for treating respiratory system disease and its preparing process |
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| CN1568984A (en) * | 2003-07-21 | 2005-01-26 | 北京小伙伴医药生物技术有限公司 | Spray and aerosol for treating respiratory system disease and its preparing process |
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