CN101830896A - Organic acid salt of optical isomer of penehyclidine - Google Patents
Organic acid salt of optical isomer of penehyclidine Download PDFInfo
- Publication number
- CN101830896A CN101830896A CN200910119525A CN200910119525A CN101830896A CN 101830896 A CN101830896 A CN 101830896A CN 200910119525 A CN200910119525 A CN 200910119525A CN 200910119525 A CN200910119525 A CN 200910119525A CN 101830896 A CN101830896 A CN 101830896A
- Authority
- CN
- China
- Prior art keywords
- acid
- formula
- compound
- solvate
- prodrug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Images
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.), 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 and/or prevent 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.The inventor finds that 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 also finds, 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 for example inorganic acid salt such as phosphoric acid salt and organic acid salt also will have above-mentioned as selectivity m receptor antagonist purposes and be used for clinical purposes such as tuberculosis, flu, anesthesia treatment.
Contain two chiral centres in the molecular structure of Penequine hydrochloride, so have four optical isomers.Preliminary study shows that 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 most weak more than 1000 times of (3S, 2 ' the S)-isomery height (Niu, W.Z.et al.Arch.Iht.Pharmacodyn Ther.1990,304,64.) of effect ratio of 2 ' R)-isomer.Therefore, (3R, 2 ' R)-isomer are the cholinolytic active isomer of amyl ethyl quin ether.
Now disclosed (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 takes place 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 discovering, (3R, the organic acid salt of 2 ' R)-amyl ethyl quin ether are to thermally-stabilised, and the process that helps medication preparation is handled, 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 provides a kind of stable amyl ethyl quin ether active optical isomer.The present invention finds that (3R, there is heat-labile problem in 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 abbreviate (3R, 2 ' R)-amyl ethyl quin ether organic acid salt as at this paper.
According to first aspect present invention each described formula I compound or its crystal type, solvate or prodrug, wherein said n is selected from 1 or 1/2.
According to first aspect present invention each described formula I compound 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, acetate, 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.
According to first aspect present invention each described formula I compound 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.
According to first aspect present invention each described formula I compound or its crystal type, solvate or prodrug, wherein said organic acid is selected from: citric acid, fumaric acid, tartrate, toxilic acid.
According to first aspect present invention each described formula I compound or its crystal type, solvate or prodrug, wherein said organic acid is selected from:
Formic acid, acetate, 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.
According to first aspect present invention each described formula I compound 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-tartrate:
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 are represented, 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, with the powder x-ray diffraction collection of illustrative plates that 2 θ angles are represented, 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 is characterized in that: use Cu-K α radiation, the powder x-ray diffraction collection of illustrative plates of representing 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, powder x-ray diffraction collection of illustrative plates so that 2 θ angles are represented 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 are represented, 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 are represented, 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 so that 2 θ angles are represented 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, powder x-ray diffraction collection of illustrative plates so that 2 θ angles are represented 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 each described formula I compound of first aspect present invention or its crystal type, solvate or prodrug, and it may further comprise the 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 metallic lithium reagent in the Michael addition reaction, preferably use two (front three is silica-based) Lithamide]
Iv) make the ii) formula VI oxyacetic acid compound reduction of gained of step I, obtain the dihydroxyl compound of formula VII
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 of formula IX, 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 in solvent, react salify, obtain formula I compound
Wherein, the definition of n, XH is with each described formula I compound of first aspect present invention.
According to the described method of 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, then 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, then formula X compound can be 1: 1 or 1: 2/3 or 1: 1/3 with the molar equivalent ratio of organic acid HX.
The present invention three aspects provide the pharmaceutical applications of each described compound of first aspect present invention or its crystal type, solvate or prodrug.Specifically, the present invention three aspects provide each described compound of first aspect present invention or its crystal type, solvate or prodrug preparing as the purposes in the medicine of organophosphate poisoning therapeutical agent.The present invention three aspects also provide each described compound of first aspect present invention or its crystal type, solvate or prodrug preparing as selectivity m receptor antagonist, preferably as selectivity M
3Purposes in the medicine of receptor antagonist.The present invention three aspects also provide each described compound of first aspect present invention 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 each described compound of use first aspect present invention or its crystal type, solvate or prodrugs therapy and/or prophylactic method.Specifically, the present invention four aspects provide the method for treatment organophosphate poisoning, and it comprises each described compound of first aspect present invention 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
1The receptor related disease or the method for the state of an illness, it comprises each described compound of first aspect present invention 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 preceding associated conditions of anesthesia, and it comprises each described compound of first aspect present invention 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 as each described compound of one or more first aspect present invention that treat and/or prevent significant quantity of activeconstituents or its crystal type, solvate or prodrug 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.
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 0.005 to 100mg each described compound of first aspect present invention or its crystal type, solvate or prodrug in the per unit dosage as activeconstituents.Preferably, according to above-mentioned or following each the described pharmaceutical composition of fifth aspect present invention, wherein comprise 0.05 to 10mg each described compound of invention first aspect or its crystal type, solvate or prodrug in the per unit dosage as activeconstituents.
Below term involved in the present invention and the features and advantages of the present invention are further described.
As described herein, what the n in the formula I compound represented is organic acid of representing with HX in the salt that formula I represents and formula
Free alkali feasible between the two or possible in theory in conjunction with equivalence ratio.For example when this free alkali and acetate (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 the 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, a triprotic acid Citric Acid for example for example of monoprotic acid.
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.Specifically, for example, the described organic acid of " pharmacy is acceptable " expression that relates in the phrase " the acceptable organic acid of pharmacy " is the pharmacy available, comprise and to be directly used in clinical organic acid, though also comprise to be directly used in clinically, can be used as the organic acid that pharmaceutical raw material uses.To a kind of situation in back, for example, though 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 so that make in preparation formula X compound and final formula I compound.And for example, as be used for this paper, term " pharmaceutically acceptable carrier or vehicle " is meant the pharmaceutical excipient that the preparation industrial circle is commonly used, and for example at Luo Mingsheng, etc. pharmaceutical necessities complete works, 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 pharmacy acceptable solvent 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 " pact " during the crystallization of 2 ' R)-amyl ethyl quin ether fumarate, and related " pact " 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 produced prevent, alleviate, reactions such as treatment, healing, alleviation.
As be 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 produced effectively prevent, alleviate, the dosage of the formula I compound of the present invention of reactions such as treatment, healing, alleviation.
As be used for this paper, term " basic optical is pure " is meant that optical isomer compound shown in the formula I of the present invention is purified basically on optical purity, so that its optical purity is greater than 90%, be that optical isomer shown in the 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 is meant M in the present invention especially
3Acceptor.
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.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 the drug regimen of the present invention, can also contain the pyraloxime methyl-chloride (PAM-CL) that treats and/or prevents 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 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 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 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 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 intranasal ipratropium bromide in common colds.A randomized, double-blind, placebo-controlled trial.Ann Intern Med1996; 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 gelsemium 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 formula I compound or its crystal type, solvate or the prodrug pharmaceutical composition 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 formula I compound or its crystal type, solvate or prodrug treat and/or prevent medicine, common cold treatment and/or prophylactic agent, preanesthetic medication etc. as chronic obstructive pulmonary disease as the pharmaceutical composition of activeconstituents medicinal use.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.
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 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 that the dosage of compound increases dosage gradually from being lower than for obtaining the required level that effect requires that treats and/or prevents, up to obtaining required effect.
When being used for above-mentioned treating and/or preventing or other treatment and/or when 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 (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 that word " treats and/or prevents 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 effective dose that treats and/or prevents is decided according to multiple factor, and described factor comprises the severity of the obstacle that treated and/or prevented 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; Treat and/or prevent the 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 required level that effect requires that treats and/or prevents, up to obtaining required effect.
The formula I compound of the present invention of administration of human or the dosage of its crystal type, solvate or prodrug can be in about 0.0005 to about 1000mg/ time scopes, and more preferably dosage can be about 0.005 to about 100mg/ 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.Use the administration frequency of formula I compound of the present invention or its crystal type, solvate or prodrug to 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, 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.
Formula I compound of the present invention or its crystal type, solvate or prodrug preferably can synthesize with reference to following route:
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), hydroxyl in the hemiacetal molecule that forms carries out intramolecular condensation with carboxyl again, reacts 5～10 hours, and stereoselectivity obtains interior ester products (2R, 5R)-and 2-tertiary butyl-5-phenyl-1,3-two
Alkane-4-ketone (II), the 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.Make VII and Tosyl chloride be condensed into tosic acid mono-esterification thing,, obtain optical purity at the synthetic key intermediate (R) more than 98%-1-phenyl-1-cyclopentyl-1,2-oxyethane (IX) through intramolecular ring closure reaction; Make IX under the sodium hydride effect,, obtain (3R, 2 ' R)-amyl ethyl quin ether (X) with 3-(R)-quinine cyclol reaction.Make (3R then, 2 ' R)-amyl ethyl quin ether and corresponding organic acid are in appropriate solvent (for example, but be not limited to, dehydrated alcohol) salify in, promptly obtain the organic acid salt shown in the corresponding formula I of the present invention, this organic acid salt can obtain with suitable crystal type or solvate, also can for example form the prodrug of ester structure by structural hydroxyl of amyl ethyl quin ether and carboxylic acid randomly with the further esterification of the organic acid salt of gained.
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.
Description of drawings
Fig. 1 is a 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 a 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 a Compound I
1Infrared spectrogram, X-coordinate is wave number (Wavenumber (cm
-1)), ordinate zou is transmittance (Transmittance[%]).
Fig. 4 is a 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 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.
1.1,(2R, 5R)-2-tertiary butyl-5-phenyl-1,3-two
The preparation of alkane-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-two
Alkane-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)-1,3-two
The preparation of alkane-4-ketone (III)
With 10g (45mmol) (2S, 5S)-2-tertiary butyl-5-phenyl-1,3-two
Alkane-4-ketone (II) is dissolved in the 70mL dry tetrahydrofuran, is cooled to-78 ℃, and two (front three is silica-based) Lithamide of adding 60mL (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-two
Alkane-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)-1,3-two
The preparation of alkane-4-ketone (IV)
With 3.6g (10mmol) (2S, 5R)-2-tertiary butyl-5-phenyl-5-(cyclopentyl-1-hydroxyl)-1,3-two
Alkane-4-ketone (III) is dissolved in the 70mL dry tetrahydrofuran solution, is cooled to 0 ℃, adds 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, and distillation removes and desolvates, obtain (2R, 5R)-2-tertiary butyl-5-phenyl-5-(1-cyclopentenyl)-1,3-two
Alkane-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-two
Alkane-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%.
(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 Tosyl chloride 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)。
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 the colourless liquid of X, 2.84g, and yield 65%,
(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 all dissolved until solid, filtered while hot, slowly column crystallization is separated out in cooling, 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.Interpolation finishes, and the 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 the 12ml acetone.Interpolation finishes, and the 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-tartrate (I
4) preparation
With L-tartrate 0.375g (2.5mmol) with (3R, 2 ' R)-amyl ethyl quin ether 0.79g (2.5mmol) join among 60 ℃ of dehydrated alcohol 7ml.Interpolation finishes, and the system clarification was stirred after 5 minutes, and cooling has solid to separate out naturally.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 among 65 ℃ the dehydrated alcohol 7ml.Interpolation finishes, and the system clarification was stirred after 10 minutes, and cooling has solid to separate out naturally.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,, obtain (3R, 2 ' R)-amyl ethyl quin ether hydrochloride 0.85g, fusing point 160-162 ℃ with acetone recrystallization.
Embodiment 9,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-methyl scopolamine (NMS) for being at war with property of aglucon in conjunction with experiment, measure the IC of target compound 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: 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 the 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; With methyl alcohol: 0.05M sodium-acetate-acetum (pH=5)=9: 1 is a 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, the aqueous solution that is mixed with 0.5mg/ml is as storing solution, and 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, heating is 2 hours in 100 ℃ of water-baths, cooling; The accurate 1.0ml that draws puts the 25ml volumetric flask, adds moving phase to scale, shakes up the back as need testing solution.
Get trial-product, each 20 μ l of reference substance solution, inject high performance liquid chromatograph respectively and measure, with the content of external standard method by target compound in the calculated by peak area trial-product.The result is as shown in table 2:
3), stability test result
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 handled, 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 a counting 0.15 degree/second.
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 absorption peak is arranged at about 8.96,9.46,12.12,15.14,17.32,17.96,19.74,20.80,23.12 and 26.36 places.I
1The 2 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 absorption peak is arranged at about 8.92,9.40,12.12,15.10,17.88 and 19.68 places.I
2The 2 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 |
| Peak number | ??2θ(°) | ??I/I 0(％) |
| ??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 (10)
1. 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.
2. the formula I compound of claim 1 or its crystal type, solvate or prodrug, wherein said n is selected from 1 or 1/2.
3. the formula I compound of claim 1 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, acetate, 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.
4. the formula I compound of claim 3 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.
5. the formula I compound of claim 1 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-tartrate:
5) formula I
5Shown (3R, 2 ' R)-amyl ethyl quin ether citrate:
Or its crystal type, solvate or prodrug.
6. 1 formula I compound or its crystal type, solvate or the prodrug of claim, 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 are represented, 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 ℃.
7. 1 formula I compound or its crystal type, solvate or the prodrug of claim, 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 are represented, 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.
8. the preparation method of each described formula I compound of claim 1 to 7 or its crystal type, solvate or prodrug, it may further comprise the 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 the ii) formula VI oxyacetic acid compound reduction of gained of step I, obtain the dihydroxyl compound of formula VII
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 of formula IX, 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 in solvent, react salify, obtain formula I compound
Wherein, the definition of n, XH is with claim 1.
9. each described formula I compound of claim 1 to 7 or its crystal type, solvate or prodrug are preparing as the purposes in the medicine of organophosphate poisoning therapeutical agent, preparing as the purposes in the medicine of selectivity m receptor antagonist, and 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.
10. pharmaceutical composition, it comprises each described formula I compound of one or more claims 1 to 7 or its crystal type, solvate or prodrug and optional pharmaceutically acceptable carrier or the vehicle that treats and/or prevents significant quantity.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910119525 CN101830896B (en) | 2009-03-12 | 2009-03-12 | Organic acid salt of optical isomer of penehyclidine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200910119525 CN101830896B (en) | 2009-03-12 | 2009-03-12 | Organic acid salt of optical isomer of penehyclidine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101830896A true CN101830896A (en) | 2010-09-15 |
| CN101830896B CN101830896B (en) | 2013-05-15 |
Family
ID=42715132
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200910119525 Expired - Fee Related CN101830896B (en) | 2009-03-12 | 2009-03-12 | Organic acid salt of optical isomer of penehyclidine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101830896B (en) |
Cited By (8)
| 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 |
| 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 |
| CN104072345A (en) * | 2014-06-20 | 2014-10-01 | 成都力思特药物研究有限公司 | Method applicable to preparation of 1-cyclopentyl-2-methoxy-1-phenyl ethanol |
| CN104297354A (en) * | 2013-07-16 | 2015-01-21 | 重庆市康乾医药有限公司 | Detection method for determining impurities in penehyclidine hydrochloride through high performance liquid chromatography (HPLC) |
| CN110003198A (en) * | 2019-04-22 | 2019-07-12 | 上海旭东海普药业有限公司 | The purification process of amyl ethyl quin ether |
| CN111689956A (en) * | 2019-03-14 | 2020-09-22 | 银谷制药有限责任公司 | Resolution method of quinine compound containing quaternary ammonium group |
| WO2021218833A1 (en) * | 2020-04-26 | 2021-11-04 | 北京硕佰医药科技有限责任公司 | Crystal of m receptor antagonist as well as preparation method therefor and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2009
- 2009-03-12 CN CN 200910119525 patent/CN101830896B/en not_active Expired - Fee Related
Cited By (12)
| 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 |
| 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 |
| CN104297354A (en) * | 2013-07-16 | 2015-01-21 | 重庆市康乾医药有限公司 | Detection method for determining impurities in penehyclidine hydrochloride through high performance liquid chromatography (HPLC) |
| 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 |
| CN104072345A (en) * | 2014-06-20 | 2014-10-01 | 成都力思特药物研究有限公司 | Method applicable to preparation of 1-cyclopentyl-2-methoxy-1-phenyl ethanol |
| 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 |
| CN111689956A (en) * | 2019-03-14 | 2020-09-22 | 银谷制药有限责任公司 | Resolution method of quinine compound containing quaternary ammonium group |
| 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 |
| CN110003198A (en) * | 2019-04-22 | 2019-07-12 | 上海旭东海普药业有限公司 | The purification process of amyl ethyl quin ether |
| WO2021218833A1 (en) * | 2020-04-26 | 2021-11-04 | 北京硕佰医药科技有限责任公司 | Crystal of m receptor antagonist as well as preparation method therefor and application thereof |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101830896B (en) | 2013-05-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101830896B (en) | Organic acid salt of optical isomer of penehyclidine | |
| CN102485721B (en) | 2，3-benzodiazine ketone compound replaced and uses thereof | |
| CN1104430C (en) | Angiogenesis inhibiting pyridazinamines | |
| TW200413331A (en) | Small molecule PI 3-kinase inhibitors and methods of their use | |
| CN101495186A (en) | Inhibitors of undecaprenyl pyrophosphate synthase | |
| CN102089290A (en) | Triazole derivatives useful for the treatment of diseases | |
| TW201028142A (en) | Heterobicyclic sphingosine 1-phosphate analogs | |
| JP6929857B2 (en) | 6,7,8,9-Tetrahydro-5H-pyrido [2,3-d] azepine dopamine D3 ligand | |
| CN100345840C (en) | Stable hydrate of a muscarinic receptor antagonist | |
| CN101735213B (en) | Optical isomer of penehyclidine and medicinal composition and application thereof | |
| CN101573332A (en) | Arylsulfonyl pyrrolidines as 5-HT6 inhibitors | |
| CN102050755A (en) | Novel agomelatine crystal forms and preparation methods of agomelatine crystal forms | |
| CN102070631A (en) | Quaternary ammonium salt of penehyclidine optical isomer, medicinal composition and medical application thereof | |
| CN102459177A (en) | 2,5-disubstituted arylsulfonamide ccr3 antagonists | |
| CN1219930A (en) | Benzoxazinone dopamine D4 receptor antagonists | |
| CN102459178A (en) | 2,5-disubstituted arylsulfonamide ccr3 antagonists | |
| CN101460484A (en) | 6-methoxy-8-[4-(1-(5-fluoro)-quinolin-8-yl-piperidin-4-yl)-piperazin-1-yl]-quinoline hydrochloric acid salts | |
| CN101361741B (en) | New anti-tumor use of iso-oxazoline derivates | |
| CN103319402B (en) | Diphenyl thiourea derivatives, preparation method and applications thereof | |
| CN102653522B (en) | Diphenyl thiourea compounds of ω-carboxyl substituted and its production and use | |
| CN101066980A (en) | Crystalline tenofovir fumarate and its medicine prepn | |
| CN102459210A (en) | Arylsulfonamide ccr3 antagonists | |
| BRPI0713107A2 (en) | 6-Methoxy-8- [4- (1- (5-fluoro) -quinolin-8-yl-piperidin-4-yl) -piperazin-1-yl] -quinoline siccinate salts, and crystalline forms thereof | |
| CN102803247A (en) | Novel fumarate salts of a histamine H3 receptor antagonist | |
| CN101717364B (en) | Paradoximes as HIV reverse transcriptase inhibitor as well as preparation method and purpose thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20130515 Termination date: 20200312 |
|
| CF01 | Termination of patent right due to non-payment of annual fee |