CN104447770A - Asenapine compound - Google Patents

Asenapine compound Download PDF

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Publication number
CN104447770A
CN104447770A CN201310413290.8A CN201310413290A CN104447770A CN 104447770 A CN104447770 A CN 104447770A CN 201310413290 A CN201310413290 A CN 201310413290A CN 104447770 A CN104447770 A CN 104447770A
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CN
China
Prior art keywords
toxilic acid
acid asenapine
compound
asenapine
preparation
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CN201310413290.8A
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Chinese (zh)
Inventor
严洁
李轩
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Tianjin Hankang Pharmaceutical Biotechnology Co Ltd
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Tianjin Hankang Pharmaceutical Biotechnology Co Ltd
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Priority to CN201310413290.8A priority Critical patent/CN104447770A/en
Publication of CN104447770A publication Critical patent/CN104447770A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/43—Separation; Purification; Stabilisation; Use of additives by change of the physical state, e.g. crystallisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
    • C07C57/13—Dicarboxylic acids
    • C07C57/145—Maleic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

Belonging to the medical technology field, the invention in particular relates to a maleic acid asenapine compound and a preparation method thereof. The invention also relates to application of compositions containing the maleic acid asenapine compound in preparation of drugs treating antipsychotic drugs.

Description

Asenapine compound
Technical field
The invention belongs to medical art, be specifically related to toxilic acid asenapine compound and preparation method thereof.
Background technology
Schizophrenia (schizophrenia) is the mental disorder that a kind of common cause of disease is not illustrated completely.A lot of disease, in person between twenty and fifty, often has the obstacle of the aspects such as consciousness, thinking, emotion and behavior, generally unconscious and disturbance of intelligence.At present drug main clinically will be divided into two large classes: generation antipsychotics and two generation antipsychotics, the price of generation antipsychotics is lower, but the cognitive function of patient can not be improved, and the ratio causing the extrapyramidal symptoms and tardive dyskinesia is higher, not good enough to the remission effect of positive symptom, thus reduce the compliance of patient medication.S-generation antipsychotics, they have higher 5-hydroxytryptamine receptor blocking effect, claim Dopamine HCL-5-HT receptor antagonist (SDAs), have more selectivity to the effect comparison striatum systemic effect of mesolimbic system.This kind of medicine, because clinical effect spectrum is wide, it is less or not obvious to cause EPS ratio, will have more wide application prospect at field of psychiatry from now on.
Bipolar affective disorder generally refers to existing manic or hypomania, has again a class mood disorder of paralepsy.During maniac access, show as mood elevation, speech increases, activity increases; The symptom such as depressed, slowness of thinking, movable minimizing is then there is during paralepsy.Also can there is the psychotic symptoms such as illusion, vain hope or tonus symptom in the person of being in a bad way in outbreak peak period.Bipolar affective disorder is generally in the ictal course of disease, manic and the normal iterative cycles of depression or alternately occur, but also can exist in a mixed manner, the reasonable time in that each outbreak symptom often continuing, (maniac access continues more than 1 week, paralepsy continues more than 2 weeks), and detrimentally affect is produced to the daily life of patient and social function etc.The clinical mainstream medicine be used for the treatment of mainly mood stabilizers lithium salts and Sodium Valproate, for the unconspicuous patient of relief of symptoms, can add with other class medicines, candidate's mood stabilizers such as tic medicine as anti-in other, antipsychotics.
Schizophrenia and bipolar affective disorder are the pernicious mental disorderes having a strong impact on human normal life, are a kind of multifactorial diseases.Although at present still not bery clear and definite to the understanding of its cause of disease, the effect that the susceptible quality of individual mind and the undesirable element of outside social environment develop the generation of disease know together by everybody.It is susceptible quality or outside undesirable element all can cause disease generation by inherent biological factor acting in conjunction.
Toxilic acid asenapine Sublingual tablet is as a kind of novel s-generation antipsychotics, its receptor affinity is higher, side effect is less, and as a kind of novel sublingual tablet formulation, patient can be solved significantly and mismatch the problem of taking medicine, increase the compliance of patient, easy administration, onset is rapid.
But, toxilic acid asenapine treatment schizophrenia and the precise mechanism of bipolar affective disorder not fully aware of yet, may with dopamine D 2with serotonin 2A(5-HT 2A) antagonistic action relevant.Toxilic acid asenapine and multiple Dopamine HCL, serotonin, norepinephrine (NE) acceptor and histamine receptor sub-types have high affinity, also have avidity to N-methyl-D-aspartate (NMDA) and alpha-amino group-3-hydroxy-5-methyl base-4-isoxazole propionic acid (NMPA) acceptor.And as a kind of newtype drug, may be used for treatment schizophrenia and the assisting therapy as bipolar affective disorder, because its receptor-selective is higher, some two generation antipsychotics untoward reaction such as body weight increase, the untoward reactions such as metabolism disorder occur less in the pharmacology test of toxilic acid asenapine.And as a kind of new formulation of Sublingual tablet, putting into the mouth several seconds dissolves, and can improve the compliance of patient consumes, reducing the event of stealing medicine Tibetan medicine and occur, is also a kind of selection newly for there being the patient of dysphagia and dysmasesis.
My company researchist is through experiment repeatedly, filter out optimum pharmaceutical adjunct, the basis that cost reduces also assures that quality, not only there is the curative effect suitable with import drugs, reasonable price simultaneously, especially be applicable to the patient needing long-term prescription, while meeting the need of market, also benefit extensive patients.
Toxilic acid asenapine Sublingual tablet is researched and developed by ORGANON SUB MERCK company, and in August, 2009 goes on the market in the U.S., trade(brand)name: SAPHRIS ?, specification is 5mg and 10mg, clinically for the acute treatment of the manic of schizophrenia and bipolar affective disorder and mixing outbreak.The same year is multinational listing in Europe, only for the manic of bipolar affective disorder and the acute treatment mixing outbreak.
Toxilic acid asenapine
Chemical name: (3aR, 12bR)-trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydrochysene-1H-dibenzo [2,3:6,7] oxa-also [4,5-c] pyrroles (2Z)-(E)-butenedioic acid hydrogen ester (1:1)
Fraction: C 17h 16clNO C 4h 4o 4;
Molecular weight: 401.84;
Structural formula:
Pharmacology type: toxilic acid asenapine can potent blocking 5-hydroxytryptamine and Dopamine Receptors, and having maximum effectiveness to 5-hydroxytryptamine receptor, also have stronger antagonistic activity to alpha-adrenergic receptor, is minimum to the avidity of M-ChR.Suppose that the drug effect of toxilic acid asenapine is pass through dopamine D at least partly 2and 5-HT 2Athe antagonistic action of acceptor mediates jointly, so to other acceptors (as 5-HT 2C, 5-HT 6, 5-HT 7, 5-HT 1A, 5-HT 1B, D 3with α-2-adrenergic receptor) effect also may be relevant with its clinical efficacy.The antagonistic action of α-1-adrenoceptor seems with toxilic acid asenapine to cardiovascular effect, as postural hypotension is relevant with the reflex bradycardia of neural mediation.Histamine H 1the antagonistic action of acceptor seems relevant with the sedative effect of toxilic acid asenapine.
Mechanism of action: the mechanism of action of toxilic acid asenapine, the same as other medicines effective in schizophrenia with bipolar affective disorder is unknown.The curative effect of toxilic acid asenapine in schizophrenia is mainly by antagonises D to have investigator to think 2and 5-HT 2Aacceptor and onset.
Indication:
schizophrenia
Toxilic acid asenapine is applicable to schizoid treatment.
bipolar affective disorder
Single therapy: toxilic acid asenapine be applicable to Bipolar I Disorder manic or mixing outbreak acute treatment.
Assisting therapy: toxilic acid asenapine is applicable to the adjuvant therapy medicaments as lithium or valproate is acute treatment that is manic with Bipolar I Disorder or mixing outbreak.
In research process, repeat the method for prior art, the toxilic acid asenapine impurity number obtained is more, and total impurities is higher, and optical purity is low.The toxilic acid asenapine that the present invention obtains, the advantage had: chemical purity is high, maximum contaminant is less than 1 ‰, and optical purity is high; Good stability, especially to wet good stability.
Summary of the invention
One object of the present invention, discloses a kind of toxilic acid asenapine compound.
Another object of the present invention, discloses the preparation method of toxilic acid asenapine compound crystal form.
Another object of the present invention, discloses the pharmaceutical composition comprising toxilic acid asenapine compound.
The invention also discloses the application of toxilic acid asenapine compound in the medicine manufacturing treatment schizophrenia and bipolar affective disorder.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of toxilic acid asenapine compound (shown in formula I),
（Ⅰ）
Karl_Fischer method (Karl Fischer method) a kind ofly measures in all kinds of chemical processes of moisture in material, and, method the most accurately the most single-minded to water, has been listed in the standard method of moisture determination in many materials, especially organic compound, reliable results.Through 6 batches of mensuration, its moisture is less than 1 ‰:
Batch Moisture (‰) Batch Moisture (‰)
1 0.25 4 0.26
2 0.30 5 0.28
3 0.25 6 0.23
This toxilic acid asenapine compound crystal, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ) and D value as follows,
Peak number 2 θ angle (°) measured values D() measured value I/I 0
1 10.620 15.6325 92
2 15.940 11.9140 37
3 16.560 9.5474 5
4 18.480 9.3208 4
5 19.720 7.6318 22
6 20.560 6.2833 2
7 21.280 5.8491 3
8 23.450 5.7084 45
9 25.780 4.1659 4
10 26.940 3.9645 7
11 30.760 3.7982 2
12 32.340 3.2341 3
13 33.740 2.6142 4
14 35.120 2.3417 2
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Another object of the present invention, discloses the preparation method of toxilic acid asenapine compound crystal,
Specifically comprise the following steps:
1) toxilic acid asenapine adds in 2-3 times of (weight or measurement (WM) ratio) methyl alcohol, and stir 40 minutes, filter, filtrate is cooled to 5 DEG C-10 DEG C, for subsequent use;
2) mixed solution of toxilic acid asenapine 6-9 times acetonitrile-acetone=5:5 is cooled to 5 DEG C-10 DEG C, adds above-mentioned stock solution, insulation 15-20 hour, crystallization, filter, drying obtains.
Chemical purity is up to 99.9%, and maximum contaminant is less than 1 ‰, and optical purity is up to more than 99.9%ee.
In above-mentioned preparation method, toxilic acid asenapine moisture is low, good stability, can ensure the quality of pharmaceutical preparation.
The chemical structure of toxilic acid asenapine used, through determination of elemental analysis, proves that chemical structure is correct.
Another object of the present invention, provides the composition comprising the toxilic acid asenapine compound that toxilic acid asenapine compound crystal and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is 1% ~ 30%(weight of composition).
stability test
The stability of contriver to crystal formation of the present invention is studied, and investigation condition is high temperature (60 DEG C ± 2 DEG C), strong illumination (4500Lx ± 500lx), and high humidity (92.5%, RH) inspection target is outward appearance, content and related substance.
Result: from 0-15 days under high light, high temperature, super-humid conditions, outward appearance, related substance, content do not change, and illustrate that chemical stability is good, are applicable to manufacture and the standing storage of pharmaceutical preparation.
At 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in toxilic acid asenapine compound crystal:
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), water tariff collection is constant, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
Toxilic acid asenapine purity 98.3% (HPLC normalization method) used in the present invention, optical purity 99.1%ee, its chemical structure, through determination of elemental analysis, proves that chemical structure is correct.
embodiment 1
In the 400ml reaction flask that stirring, thermometer, condenser are housed, add 60 grams of toxilic acid asenapines and 180 ml methanol, stir 40 minutes, filter, filtrate is cooled to 8 DEG C, for subsequent use.
The mixed solution of 480ml acetonitrile-acetone=5:5 is cooled to 8 DEG C, adds above-mentioned stock solution under stirring, be incubated 15 hours, crystallization, filter, drying obtains white crystals 53.3 grams.Purity 99.9% (HPLC normalization method), optical purity 99.96%ee (chirality HPLC).
X-ray diffraction mensuration is carried out to this crystallization.INSTRUMENT MODEL and condition determination: Rigaku D/max 2500 type diffractometer; CuKa 40Kv 100mA; 2 θ sweep limit: 0-50 °.Result is as follows:
Peak number 2 θ angle (°) measured values D() measured value I/I 0
1 10.620 15.6325 92
2 15.940 11.9140 37
3 16.560 9.5474 5
4 18.480 9.3208 4
5 19.720 7.6318 22
6 20.560 6.2833 2
7 21.280 5.8491 3
8 23.450 5.7084 45
9 25.780 4.1659 4
10 26.940 3.9645 7
11 30.760 3.7982 2
12 32.340 3.2341 3
13 33.740 2.6142 4
14 35.120 2.3417 2
embodiment 2
Tablet containing toxilic acid asenapine compound
Prescription: toxilic acid asenapine compound 20 grams, 100 grams, N.F,USP MANNITOL, lactose 140 grams, 50 grams, calcium carbonate, Magnesium Stearate 5 grams, 8% ethyl cellulose solution is appropriate, makes 1000.
Technique: get toxilic acid asenapine compound, N.F,USP MANNITOL, lactose, calcium carbonate mixes; Add suitable amount of adhesive 8% ethyl cellulose solution softwood, 20 eye mesh screens are granulated, 40 DEG C ± 2 DEG C oven dry, whole grain, and mix Magnesium Stearate outside adding and mix, compressing tablet, to obtain final product.

Claims (5)

1. the compound of toxilic acid asenapine shown in formula I,
（Ⅰ）
The crystal of described toxilic acid asenapine compound, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle and D value,
Peak number 2 θ angle (°) measured values D() measured value I/I 0 1 10.620 15.6325 92 2 15.940 11.9140 37 3 16.560 9.5474 5 4 18.480 9.3208 4 5 19.720 7.6318 22 6 20.560 6.2833 2 7 21.280 5.8491 3 8 23.450 5.7084 45 9 25.780 4.1659 4 10 26.940 3.9645 7 11 30.760 3.7982 2 12 32.340 3.2341 3 13 33.740 2.6142 4 14 35.120 2.3417 2
The error of 2 θ diffraction angle is ± 0.2.
2. the preparation method of toxilic acid asenapine compound crystal described in claim 1, comprises the steps:
1) toxilic acid asenapine adds in 2-3 times of (weight or measurement (WM) ratio) methyl alcohol, and stir 40 minutes, filter, filtrate is cooled to 5 DEG C-10 DEG C, for subsequent use;
2) mixed solution of toxilic acid asenapine 6-9 times acetonitrile-acetone=5:5 is cooled to 5 DEG C-10 DEG C, adds above-mentioned stock solution, insulation 15-20 hour, crystallization, filter, drying obtains.
3. the composition of toxilic acid asenapine compound that forms of toxilic acid asenapine compound crystal and one or more pharmaceutically acceptable carriers according to claim 1.
4. composition according to claim 3, is characterized in that said composition is for the preparation of solid preparation.
5. toxilic acid asenapine according to claim 1 is manufacturing the application in the psychotolytic medicine for the treatment of.
CN201310413290.8A 2013-09-12 2013-09-12 Asenapine compound Withdrawn CN104447770A (en)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10898449B2 (en) 2016-12-20 2021-01-26 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US10980753B2 (en) 2016-12-20 2021-04-20 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine
US11337932B2 (en) 2016-12-20 2022-05-24 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and polysiloxane or polyisobutylene
US11033512B2 (en) 2017-06-26 2021-06-15 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine and silicone acrylic hybrid polymer
US11648213B2 (en) 2018-06-20 2023-05-16 Lts Lohmann Therapie-Systeme Ag Transdermal therapeutic system containing asenapine

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Application publication date: 20150325