CN1131035C - Method for treating cognitive dysfunction - Google Patents
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- CN1131035C CN1131035C CN95197876A CN95197876A CN1131035C CN 1131035 C CN1131035 C CN 1131035C CN 95197876 A CN95197876 A CN 95197876A CN 95197876 A CN95197876 A CN 95197876A CN 1131035 C CN1131035 C CN 1131035C
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Abstract
The present invention provides a method for treating cognitive dysfunction, which comprises 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno [2, 3-b] [1, 5] benzodiazepine taken in effective dosage.
Description
The invention provides a method, treat cognitive dysfunction with 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine .
Alzheimer is a kind of disease of brains decline, and its feature that shows clinically is that the gradual of memory, discernment, reasoning and judgment weakens.At last, comprehensive obstacle develops into the various aspects that comprise the senior cortex hormone function of brain.The decline beginning, patient may show as absent-minded.Except recognition function reduces, speak, the obstacle of aspects such as motor activity, sensory capacity all may show to some extent.Individual character at ordinary times, it is more outstanding to become, even wave has been overstated.Initial emotion changes, and may mainly be erethism, and periodically angry and violent behavior occurs.Patient generally shows ability of thinking and weakens and confuse.Along with increasing the weight of of the state of an illness, generally develop into uncontrollable disturbance.Up to the present, Alzheimer has proved incurable disease.
To alleviate the symptom of cognitive dysfunction in the pathogenic process, can improve person with Alzheimer's disease and caregiver's quality of life with the alleviating medicine treatment as alleviating medicine.This treatment can alleviate or delay symptom and develop into and need to be in hospital or the order of severity of special nurse.Therefore, when cognitive dysfunction occurred, not only for the healthy economy purpose, and in order to improve the quality of living, the treatment of this alleviating medicine all needed.
Though cholinergic neuron has failed, the characteristics of Alzheimer are that processus aboralis can still exist in forebrain and Hippocampus by M-ChR.Therefore, the muscarine cholinergic agonist is useful in treatment Alzheimer and improvement by the cognitive dysfunction due to the Alzheimer.
Surprisingly, according to the present invention, the applicant finds that chemical compound 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine can be used for the treatment of cognitive dysfunction, especially Alzheimer.Chemical compound 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine is a known compound, in U.S. Patent No. 5,229, is described in 382.This patent is classified reference as.
The invention that this applies for a patent provides a method for the treatment of the recognition function obstacle, comprises that the patient to the needs treatment takes 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] the benzodiazepine of effective dose.
In addition, the invention provides a method of taking stopgap measures and treating, comprise that the patient to this treatment of needs takes the 2-methyl-4-of effective dose (4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine at cognitive dysfunction.This 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine is useful especially to the treatment that takes stopgap measures of Alzheimer.
Chemical compound 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine chemical formula is as follows, or its acid-addition salts.The free alkali of chemical formula (I) is 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine
Chemical compound 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] the pure basically anhydrous crystal (form I) of benzodiazepine has typical X-ray powder diffraction pattern shape, substantially as follows, this is to utilize the Sieman ' s D5000 diffractometer that is equipped with the copper radiation source to obtain, and d represents interplanar distance:
d I/I
1
10.2689 100.00
8.577 7.96
7.4721 1.41
7.125 6.50
6.1459 3.12
6.071 5.12
5.4849 0.52
5.2181 6.86
5.1251 2.47
4.9874 7.41
4.7665 4.03
4.7158 6.80
4.4787 14.72
4.3307 1.48
4.2294 23.19
4.141 11.28
3.9873 9.01
3.7206 14.04
3.5645 2.27
3.5366 4.85
3.3828 3.47
3.2516 1.25
3.134 0.81
3.0848 0.45
3.0638 1.34
3.0111 3.51
2.8739 0.79
2.8102 1.47
2.7217 0.20
2.6432 1.26
2.6007 0.77
The typical X-ray diffraction coatings of the form II of chemical compound 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine are as follows substantially.This is to utilize the Sieman ' s D5000 diffractometer that is equipped with the copper radiation source to obtain, and d represents interplanar distance:
d I/I
1
9.9463 100.00
8.5579 15.18
8.2445 1.96
6.8862 14.73
6.3787 4.25
6.2439 5.21
5.5895 1.10
5.3055 0.95
4.9815 6.14
4.8333 68.37
4.7255 21.88
4.6286 3.82
4.533 17.83
4.4624 5.02
4.2915 9.19
4.2346 18.88
4.0855 17.29
3.8254 6.49
3.7489 10.64
3.6983 14.65
3.5817 3.04
3.5064 9.23
3.3392 4.67
3.2806 1.96
3.2138 2.52
3.1118 4.81
3.0507 1.96
2.948 2.40
2.8172 2.89
2.7589 2.27
2.6597 1.86
2.6336 1.10
2.5956 1.73
Here the X-ray powder diffraction pattern of listing utilizes wavelength 1.541A copper K to obtain.The unit of the interplanar distance value of " d " row is a dust." I/I
1" row data are typical relative intensity values.Used detector is a Kevex silicon lithium solid-state detector.
So-called " pure basically " implication is meant to contain among the anhydrous form I to be less than 5% form II.Be less than 2% form II and preferably contain.Good again, " pure basically " should be to contain＜polymorph of 0.5% non-form I.
So-called " pure substantially " implication is meant among the anhydrous form I to contain＜5% form II, and preferably contains＜2% form II.Further requirement, good again, " pure basically " should be to contain＜other related substance of 0.5%.When the polymorph of form I was formed preparation as ingredient, " pure substantially " should be meant the form II polymorph that contains approximately＜15%; Preferably, when form I polymorph was processed into preparation as medicine, " pure substantially " should be meant the form II polymorph that contains approximately＜10%; Best, when pure substantially material was processed into preparation, " pure substantially " was meant the form II polymorph that contains approximately＜5%.
Term " 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2; 3-b] [1; 5] benzodiazepine ", be chemical solution thinner thing or polymorph if not otherwise specified, then be meant 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2 of technical grade, 3-b] [1,5] benzodiazepine .2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] the benzodiazepine of typical technical grade includes undesirable related substance approximately＜5%, and may be a mixing polymorph.2-methyl-the 4-of technical grade (4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine comprises usually and is less than about 1% undesirable related substances like this.
Term " thick " be meant 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine have undesirable polymorph and (or) undesirable related substances greater than about 5%.2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] the benzodiazepine of this thick level may contain and be less than about 1% undesirable related substances.
The term here " mammal " is meant higher vertebrate mammals.Term " mammal " comprises the mankind, but is not limited to the mankind.The term here " treatment " comprises the prevention that the Alzheimer symptom is occurred, in case symptom occurs, then can improve or eliminate these symptoms.
The term here ' treatment that takes stopgap measures " is meant the symptom that can relax cognitive dysfunction, rather than effects a radical cure this disease.The cognitive dysfunction symptom comprises that memory, identification ability, reasoning and judgement and the gradual of senior cortical layer function weaken; Enthusiasm reduces, and serious rhembasmus is spoken too much, motor hyperactivity and excessive responsive; Amplify or the unrestrained characteristics of having overstated original individual character erethism, irritability even generation violent behavior, the exciting and fascination of losing control of; But be not limited to these symptoms.Method of the present invention is specially adapted to treat fascination and the sensory disorder in the cognitive dysfunction symptom.And method of the present invention wishes to be used for the treatment of symptoms such as the characteristics that wave is overstated original individual character, erethism, irritability, violent behavior and uncontrollable excitement especially.
Term " cognitive dysfunction " is meant the patient aspect sensation, reasoning and memory ability, and the malfunction aspect the ability of acquire knowledge.This malfunction may with the Alzheimer that causes malfunction, acquired immune deficiency syndrome (AIDS) and other central nervous system's symptoms etc. are relevant.
The pharmaceutical research result shows that 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine has the mAChR activity.This chemical compound is active on dopamine D-1 and D-2 receptor, respectively at 3H-SCH233390[Billard etc., life Sciences 35:1885 (1984)] and 3HSpiperone[Seeman etc., Nature 216:717 (1976)] in conjunction with the check in, 503nhibiting concentration IC50＜1 μ M has just shown this point.And anhydrous form I chemical compound is on 5-hydroxy tryptamine-2 receptor and be active on the 5-hydroxy tryptamine 1C receptor.The complicated pharmacological profile of this chemical compound provides a kind of medicament for the treatment of cognitive dysfunction.
Experiment and clinical observation show that 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine has the M-ChR paratype profile of a complexity in the animal body.For example, rat is exposed in this chemical compound of overtreatment, being surprised to find it has serious sialorrhea phenomenon.And clinical research shows pupil contraction, rather than the platycoria of expection.
For method of the present invention, chemical compound 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine both can be a free alkali form, also can be the form of its acid-addition salts.Acid-addition salts is pharmaceutically useful, the nontoxic addition salts that gets with suitable processed with acid preferably, as some mineral acids, and for example hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid or phosphoric acid; Organic acid such as organic carboxylic acid, glycolic for example, maleic acid, hydroxy-maleic acid, fumaroyl, malic acid, tartaric acid, citric acid or lactic acid; Perhaps organic sulfonic acid, for example methanesulfonic acid, ethyl sulfonic acid, 2-ethylenehydrinsulfonic acid, right-toluenesulfonic acid or naphthalene-2-sulfonic acid.
Chemical compound 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine can be as following method preparation, and its process comprises:
(a) with the chemical compound reaction of the same chemical formula of N methyl piperazine (II), wherein Q can divide the leaving group that splits
Or
(b) chemical compound with chemical formula (III) carries out ring-closure reaction
For these courses of reaction, appropriate reaction conditions and suitable Q-value can be easily selected.
For example; in reaction (a); group Q can be amino or amino (each alkyl substituent contains 1-4 carbon atom), hydroxyl, the thiol of list or dialkyl group replacement; perhaps alkoxyl, alkylthio group or alkyl sulfonyl group (suitably contain 1-4 carbon atom; for example methoxyl group or methyl mercapto), perhaps halogen atom chlorine atom especially.Preferably, Q is amino (NH
2), hydroxyl or thiol and amino is most preferred.Be reflected at and carry out in the 50-200 ℃ of temperature range better.
When Q was amino, the intermediate of chemical formula (II) also may exist with the imino group form:
When Q was hydroxyl or thiol, the intermediate of chemical formula (II) may exist with their amide and thioamides form:
Or
(Q is-NH the amidine of chemical formula (II)
2) can exist with the form of salt, inorganic acid salt for example, example hydrochloric acid salt, and can be in organic solvent, as at methyl phenyl ethers anisole, toluene, dimethyl formamide, or in the dimethyl sulfoxide, with the N methyl piperazine reaction, the preference temperature scope of reaction is 100-150 ℃.
Amidine can prepare by the thiophene and the neighbour-halogenated nitrobenzene condensation reaction of following chemical formula,
Reaction is under the alkali existence condition, for example when sodium hydride exists, simultaneously in as tetrahydrofuran solvent, the perhaps dimethyl sulfoxide solution of the dimethyl sulfoxide solution of the tetrahydrofuran solution of n-BuLi or potassium carbonate or Lithium hydrate or aqueous NaOH; Perhaps in two-phase system, carry out condensation reaction, form the following nitro nitrile of chemical formula with tetraalkylammonium salt:
For example utilize stannic chloride and hydrogen chloride, in aquiferous ethanol, make the nitro nitrile of formation be reduced the amidine that becomes chemical formula (II) with closed loop simultaneously, perhaps change a way, use the reduction of hydrogen and palladium/carbon or ammonium polysulfide, follow the acid catalysis ring formation.The intermediate of chemical formula (IIa) may be used ammonium chloride (NH
4Cl) or ammonium acetate (NH
4OAc) separate.
When Q was hydroxyl, reaction (a) is preferably under the titanium tetrachloride existence condition to be carried out, and titanium tetrachloride has the ability to form the metal amine complex with the N methyl piperazine reaction.Also may use other metal chloride, as the chloride of zirconium, hafnium or vanadium.Reaction can be carried out under the reagent existence condition of combined acid, as tertiary amine, and triethylamine for example.
Other method utilizes excessive N-methyl piperazine to react as the reagent of combined acid.Suitable organic solvent such as toluene or chlorobenzene can be used as reaction medium, but methyl phenyl ethers anisole is suitable especially, from its energy and TiCl
4Form the soluble complex angle and see that it can be used as cosolvent at least.
The suitable temperature range of reacting is 80-120 ℃, if necessary, improves temperature, and for example to 200 ℃, but accelerated reaction is carried out.
Chemical formula (II) (Q is-OH) midbody acid amide, and can being situated between by alkali, (Q is-NH corresponding amidine
2) prepare, perhaps derive by the chemical compound of following chemical formula,
R is an alkyl in the chemical formula, preferably C
1-4Alkyl utilizes for example methylsulfinyl methanation sodium (sodium methylsulfinylmethanide), in appropriate solvent, in dimethyl sulfoxide, makes it closed loop.The other way of preparation amide, be for example utilize dicyclohexyl carbodiimide (DCC) in appropriate solvent as a seed amino acid closed loop is made.This amino acid whose preparation example is come the above-mentioned esters of basic hydrolysis with the sodium hydroxide in the ethanol in this way.
The thioamides of chemical formula (II) (Q is-SH), the imido thioether, imido ether or imido halogen, or top other derivant that contains active Q reactive group of mentioning especially, they tend to be easier to the N methyl piperazine reaction, and the carrying out of reaction do not need TiCl
4Exist, but reaction temperature is identical with solvent condition.
The thioamides of chemical formula (II) (Q is-SH) preparation, can be by in anhydrous basic solvent, and be used for realization as the solution and the Phosphoric sulfide of corresponding amide in the pyridine.Similar situation, amide can be transformed into imido thioether, imino-ethers or imido halogen, perhaps contain other derivant of active Q reactive group, and method is to handle with common reagent, when for example being transformed into imido chlorine, handles with phosphorus pentachloride.
When Q was the leaving group that can separate in the midbody compound of chemical formula (II), especially Q was-NH
2,-OH or-during SH, and as Q be-NH
2The salt time-like, chemical compound is a compounds, becomes further content of the present invention.
About top reaction (b), adopt, for example, titanium tetrachloride is made catalyst; Methyl phenyl ethers anisole is made solvent, in 100-250 ℃ of scope, and for example 150-200 ℃, can be with the chemical compound ring closure of chemical formula (III).
The intermediate compound of chemical formula (III) preferably need not separate and directly preparation, and method is with the chemical compound of chemical formula (IV) and N methyl piperazine reaction,
R in the chemical formula (IV) is an alkyl, preferably C
1-4Alkyl is heated between 30-120 ℃, and for example about 100 ℃, in appropriate solvent, for example methyl phenyl ethers anisole, and employing TiCl
4Be catalyst.
The chemical compound of chemical formula (IV) can prepare from the corresponding nitro compound of chemical formula V.
In the chemical compound of chemistry formula V, R is a pi-allyl, for example C
1-4Alkyl is novel, becomes further content of the present invention.
If talk about easily, this nitro compound can convert the amine of chemical formula (IV) to before reacting with N methyl piperazine, need not to separate.The midbody compound of chemistry formula V can be by with the thiophene and the neighbour-halogenated nitrobenzene of chemical formula (VI), and preferably neighbour-fluorine or neighbour-chloronitrobenzene carry out condensation reaction and prepare.
Condensation reaction is to carry out under the alkali existence condition, and (a) sodium hydride for example is in a kind of solvent, for example in the oxolane, temperature is-20 ℃-30 ℃, perhaps (b) Anhydrous potassium carbonate or Lithium hydrate, in a kind of solvent, for example in the dimethyl sulfoxine, temperature range is 90-120 ℃.By reduction reaction, the chemical compound of chemical formula V can be transformed into the chemical compound of chemical formula (IV), for example catalytic reduction, adopt hydrogen and palladium/carbon, or electronation, the aquiferous ethanol solution of employing stannic chloride and hydrogen chloride, perhaps ammonium polysulfide, or stannum is in aqueous ammonium chloride solution.
The chemical compound itself that will be appreciated that chemical formula (I) can be separated, and perhaps adopts conventional method that it is transformed into acid-addition salts.
Yamamura, HI and Snyder, SH be at Proc.Nat.Acad.Sci.USA,
71, 1725 (1974) middle introductions,
3H-QNB in conjunction with the check in, the IC of this chemical compound
50Less than 1mM, this shows that it has muscarine-cholinergic activity.Alzheimer seemingly degenerates to many 90% and causes owing to the muscarine cholinergic nerve of nuclear in the basal layer is former, this nuclear basal layer is the part of substantia innominata, these neurons reach frontal cortex layer and Hippocampus, for the identification function of forebrain and Hippocampus general stimulation are arranged.Failed though cholinergic nerve is former, the processus aboralis in forebrain and Hippocampus can still exist by M-ChR.Therefore, the cholinergic agonist of muscarine can be used to treat Alzheimer.
Two the region between the heart and the diaphragm multi-center clinical trials that 237 examples suffer from the gerontal patient of cognitive dysfunction have been tested disease safety and the effectiveness of 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine .These patient's age are all at 65 years old or over-65s.Patient is divided into the medication group at random, promptly takes 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine group and takes placebo group.Adopt the technical staff to be familiar with, and getable BEHAVE-AD, the ratio scale of BPRS and CGI is measured the variation that patient's behavior successively of taking medicine shows.The result shows that 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine is useful in the caused behavior performance of treatment cognitive dysfunction unusually.
The effective dosage ranges of 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine chemical compound is very wide, and actual taking dose will depend on the symptom of treatment.For example treatment adult every day dosage from 0.25-50mg, 1-30mg preferably, selecting excellent most is 1-20mg.Take several times though can divide, normally effective once a day.The treatment cognitive dysfunction, suitable dosage range every day is 1-30mg, preferably 1-20mg '.Radiolabeled 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine can be detected in saliva, and therefore, this chemical compound is can be monitored in the patient body, and assesses.
The preferred formulation of this invention is oral solid dosage forms, 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2 that comprises the activity of about 1-20mg or 1-10mg, anhydrous form I, 3-b] [1,5] benzodiazepine is as the effective dose of active component.
More preferably this solid orally ingestible is packaged in lucifuge protection against the tide in the packaging material.For example, suitable packaging material comprise, and are flaxen, in the highdensity polyethylene bottle, and in the flaxen vial, and in the container of making by other lucifuge material.Preferred, be to put a desiccant parcel in the packing container.Container may be used foil sealing, and the protection that needs is provided, and keeps the stability of product.
Chemical compound 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine , normally oral or injection for adapting to this purpose, is adopted the form of pharmaceutical composition usually.
Pharmaceutical composition comprises 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine as active component and relevant pharmaceutical carrier.The conventional method of pharmaceutical compositions can be used for preparing compositions of the present invention.For example, active component mixes with carrier usually, or dilutes with carrier, or is wrapped in the carrier, and the carrier of packaging medicine may be a capsule, sachet, the container of the scraps of paper or other form.When carrier was used as diluent, it may be solid, semisolid or fluent material, and they are as carrier, excipient or the medium of active component.Active component can be adsorbed onto on the solid particulate container, for example is adsorbed onto on the little sachet.Be some examples of suitable carrier below: lactose, glucose, sucrose, sorbose, mannitol, starch, Radix Acaciae senegalis, calcium phosphate, Tragacanth, animal glue, syrup, methylcellulose, methyl-and propyl group-hydroxyl-benzoate, Talcum, magnesium stearate or mineral oil.If necessary, compositions of the present invention can be made a kind of preparation, so as patient can be fast after taking, continue or delay release of active ingredients.For example, United States Patent(USP) Nos. 5,079 in 018,5,039,540 4,305,5024,758,598 and 4,371,516, has been introduced a kind of preparation of rapid release, classifies reference here as.This class preparation most preferably comprises 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine , water, gelatin hydrolysate and mannitol.
Depend on administrated method, the compositions of this treatment central nervous system disease can be made into various dosage forms: tablet, capsule, injection are for the intestinal medicine for external use, and colloid or suspension are so that transdermal administration absorbs suspension for oral use or elixir, perhaps suppository lentamente.Preferably, pharmaceutical composition is made unit dosage form, and each unit dose comprises 0.25-100mg, more generally be the 1-30mg active component.When the needs extended release preparation, unit dose can comprise the 0.25-200mg active component.Preferred formulation of the present invention is capsule or tablet, and each capsule or tablet comprise 0.25-75mg or 1-30mg active component and pharmaceutical carrier and mix.Preferred preparation is an injection, and its unit dosage form is that the active component and the medicinal diluent that comprise 0.25-30mg or 1-30mg mix.
Used material among the present invention can have been bought, also can prepare by the whole bag of tricks, and these methods, those skilled in the art grasp.2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine chemical compound can be according to Chakrabarti in U.S. Patent No. 5,229, and the method that 382 (' 382) are introduced prepares, and this patent is classified reference here as.Wish most a kind of dissolution formulation of preparation, it is comprising crystalline compounds 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno [2,3-b] [1,5] benzodiazepine of pure basically form I.Crystalline compounds 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) (benzo) diaza of this pure basically form I can prepare according to the technology that following preparation part is introduced.
In a blended step, can adopt common agitating method, as the method that stirs, vibrates and so on.So-called " from mixture, preparing crystallized product ", be meant that crystallization is separated out from the mixture of above-mentioned chemical compound and solvent.And the technologist knows that crystallization process may comprise puts into crystal seed, and reaction vessel glass wall and other ordinary skill are scraped in cooling.
The discrimination method of chemical compound comprises, for example, the analysis of X-ray powder figure, thermogravimetric analysis, the differential scanning calorimetric analysis method, titrimetry is surveyed water, and the nuclear magnetic resonance spectroscopy method (
1H-NMR) survey organic solvent content.
Below some examples be in order to provide to explanation of the present invention, rather than the scope of restriction patent application of the present invention.
Preparation 1
The crystal form II of chemical compound 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine
With the thick 2-methyl-4-of 10g (4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine sample, be suspended in (100) g in the dichloromethane, (20-25 ℃) stirred 1 hour at ambient temperature.The slurry vacuum filtration reclaims filtrate.Stir filtrate in ice bath, make it to be cooled to 0-5 ℃, evaporating solvent slowly in nitrogen current obtains heavy-gravity paste.Boil off about 3/4 solvent.The a certain amount of cold dichloromethane (30g, 0-5 ℃) that gives is sneaked in the thick paste, and the slurry vacuum filtration that obtains is deposited on the funnel air-dry.After solid takes off, in 50 ℃ of vacuum tanks, further dry 30 minutes.Separation obtains: 4.8g, the X-ray powder is identified: form II+CH
2Cl
2Solvate.
Separate the solid that obtains, in 50 ℃ of vacuum tanks, in the nitrogen current, dry 30 hours again.Separation obtains: 4.5g, the X-ray powder is identified: form II (above-mentioned form II).
Preparation 2
The crystal form I of chemical compound 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine .
With saturated technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) ethyl acetate solution of benzodiazepine , with 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2 as form I crystal seed, 3-b) (1,5) benzodiazepine crystal form II contact was about 25 ℃ of stir abouts 5 hours.By vacuum filtration, reaction product isolated, and dry under environmental condition.Productive rate: 0.25g.The X-ray powder the analysis showed that product is anhydrous 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine form I chemical compound.
Preparation 3
2-methyl-the 4-of technical grade (4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine .
Intermediate 1
Material beneath is joined in the suitable there-necked flask:
Dimethyl sulfoxine (analytical pure): 6 volumes
Intermediate 1:75g
N methyl piperazine (SILVER REAGENT): 6 equivalents
Intermediate 1 can be prepared with known method by those skilled in the art.For example, in ' 382 patents, disclose how to prepare intermediate compound I.
The nitrogen jet pipeline is placed under the reaction liquid level, to drive away the ammonia that produces in the reaction.Reactant is heated to 120 ℃, and is maintained to the reaction end.Carrying out with the HPLC monitoring reaction.The intermediate compound I of reacting up to the end is less than or equals till 5%.After reaction was finished, mixture slowly was cooled to 20 ℃ (needing 2 hours approximately).Each reactant mixture is transferred to flask at the bottom of the three mouthfuls of suitable gardens that place in the water-bath.Under stirring state, in solution, add the reagent-grade methanol of 10 volumes, under 20 ℃, stirred 30 minutes.During 30 minutes, add the water of 3 volumes lentamente.The slurry of reaction is cooled to 0-5 ℃, and stirred 30 minutes.Leach product, with the wet filter cake of cold methanol washing.This wet cake is spent the night at 45 ℃ of following vacuum dryings.2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) the benzodiazepine of this product through being accredited as technical grade.
Yield: 76.7%: the response rate (Potency): 98.1%
Basically according to the program of above-described preparation 3, repeat yield 81%, the response rate (Potency): 101.1%.
Preparation 4
Technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine .
Intermediate 1 (above-mentioned) is suspended in DMSO (dimethyl sulfoxine, 3,2 volumes) and the toluene (4.5 volumes).In the time of 120-125 ℃, boil off partial solvent (～0.65 volume).Mixture is cooled to 110 ℃, adds N methyl piperazine (NMP, 4.2 equivalents), (120-125 ℃) again refluxes mixture heated.Reactant mixture is distilled to dried, removes another part solvent (about 1 volume).Need to reflux tempestuously, drive away the ammonia that produces in the reaction, promote reaction to finish (about 7 hours).By slowly adding water (12.75 volume) in the reaction solution of chilled (10 ℃), separated product.Leach product, with cold water washing (2 volumes).2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-thick product of 10H-thieno (2,3-b) (1,5) benzodiazepine is at 60 ℃ of following vacuum dryings.With recrystallization in the toluene (5 volume) of crude product self-heating, obtain 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) the benzodiazepine of technical grade.After 50 ℃ of following vacuum dryings, the product of this technical grade is recrystallization in ethyl acetate (10 volumes)/toluene (0.62 volume)/methanol (3.1 volumes), obtain 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) the methanol solvate thing of (1,5) benzodiazepine .The methanol solvate thing becomes anhydrous technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine by dry converting under greater than 50 ℃ of temperature.
Preparation 5
Preparation form I in acetone
3.0g technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine is suspended in (30g) in the acetone.Stir the mixture, be heated to about 60 ℃, and remain on 60 ℃ about 30 minutes.Mixture is cooled to 25 ℃ then.Vacuum filtration is told product.Product is analyzed by the X-ray powder, is accredited as 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine , form I.Yield: 0.8g.
Preparation 6
Utilize oxolane to prepare form I
8.0g technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine is suspended in the oxolane (25g).Stir the mixture and be heated to about 60 ℃, and under this temperature, keep about 30 ℃.Be cooled to about 25 ℃ then.The isolated by vacuum filtration product.Utilize the analysis of X-ray powder, identify that this product is 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine , form I.Yield: 1.3g.
Preparation 7
Utilize ethyl acetate to prepare form I
Technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine of 270g is suspended in (2.7 liters) in the ethyl acetate.Mixture heated arrives about 76 ℃, and keeps this temperature about 30 minutes.Then it is cooled to about 25 ℃.Vacuum filtration is told product.Utilize the analysis of X-ray powder, identify that this product is 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine , form I.197g。
Preparation 8
Preparation form I in uncle-butanols
2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) the benzodiazepine of 1.0g technical grade is suspended in (30g) in uncle-butanols.Stir the mixture, be heated to about 60 ℃, and keep this temperature about 30 minutes.Mixture is cooled to 25 ℃.Vacuum filtration goes out product.Analyze by the X-ray powder, identify that this product is 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine of form I.Yield 0.3g.
Preparation 9
In toluene, pulpous state form II is transformed into form I
With 0.5g technical grade 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2 of benzodiazepine sample and 0.5g form II, 3-b) (1,5) benzodiazepine sample is suspended in (5ml) in the toluene, and oneself uses 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2 this toluene, 3-b) (1,5) benzodiazepine presaturation.Mixture the sealing reactor in, at ambient temperature, stir about 22 hours.Vacuum leaches product, and under 45 ℃, vacuum drying.Analyze by the X-ray powder, identify that this product is 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine of form I.
Example one
Get a part of hydroxypropyl cellulose and be dissolved in the pure water, form the solution of a granulation.All the other superfine hydroxypropyl celluloses (total amount for finally make tablet weight 4.0%) with 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2; 3-b) (1; 5) benzodiazepine (1.18%W/W), lactose (79.32%; W/W) and portion C rospovidone (5%; W/W) mix, in the granulator of a high shear, granulate.Each composition all will be guaranteed to sieve before adding, and did in granulator and mix.Then with this mixture with hydroxypropyl cellulose solution, in high shear granulator, granulate.Adopt standard method, with the granule wet sieving.Then, wet granular is dry on fluidized bed dryer again, and screening.Then, again this material is added in the rolling hopper blender.
(10%, W/W), the powder that is moving that the remainder of magnesium stearate (0.5%W/W) and Crospovidone is formed adds in the pelletization of screening by microcrystalline Cellulose (granule).This mixture is mixed, on the tablet compressor, carries out tabletting with proper implements.Precoating
Hydroxypropyl emthylcellulose (10%W/W) is mixed with pure water, form a solution.Label is divided into about moiety, sprays with Gonak.Operation is to carry out in the spraying dish of perforation.
Be coated with label
White mixture (Color Mixture White) (hydroxypropyl emthylcellulose, Polyethylene Glycol, polysorbate 80 and titanium dioxide) is mixed with pure water, make and be coated with the stain suspension.The label of precoating is divided into approximately equalised part, sprays with the above-mentioned stain suspension that is coated with.Operation is to carry out being coated with in the stain dish of perforation.
The tablet that was coated with applies a little with Brazil wax, and stamps suitable discriminating labelling.
Example two
Basically repeat in the example 1 operating process described, utilize following ingredients, make exquisite tablet, every contains 1,2.5,5,7.5 and 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine of 10mg respectively:
Every contains 1mg2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine
| The composition title | Consumption (mg/ sheet) |
| Active component: 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine | 1.0 |
| Other composition lactose hydroxypropyl cellulose Crospovidone microcrystalline cellulose magnesium stearate precoating hydroxypropyl methylcellulose is coated with the blue ink of stain white mixture (Color Mixture White) polishing Brazil wax marking note edible | 67.43 3.40 4.25 8.50 0.42 1.70 3.47 trace traces |
Every contains 2.5mg2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine
| The composition title | Consumption (mg/ sheet) |
| Active component: 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine | 2.5 |
| Other composition lactose hydroxypropyl cellulose Crospovidone microcrystalline cellulose magnesium stearate precoating hydroxypropyl methylcellulose is coated with the blue ink of stain white mixture (Color Mixture White) polishing Brazil wax marking note edible | 102.15 5.20 6.50 13.00 0.65 2.60 5.30 trace traces |
Every contains 5.0mg2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine
| The composition title | Consumption (mg/ sheet) |
| Active component: 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine | 5.00 |
| Other composition lactose hydroxypropyl cellulose Crospovidone microcrystalline cellulose magnesium stearate precoating hydroxypropyl methylcellulose is coated with the blue ink of stain white mixture (Color Mixture White) polishing Brazil wax marking note edible | 156.00 8.00 10.00 20.00 1.00 4.00 8.16 trace traces |
Every contains 7.5mg2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine
| The composition title | Consumption (mg/ sheet) |
| Active component: 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine | 7.50 |
| Other composition lactose hydroxypropyl cellulose Crospovidone microcrystalline cellulose magnesium stearate precoating hydroxypropyl methylcellulose is coated with the blue ink of stain white mixture (Color Mixture White) polishing Brazil wax marking note edible | 234.00 12.00 15.00 30.00 1.50 6.00 12.24 trace traces |
Every contains 10mg2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine
| The composition title | Consumption (mg/ sheet) |
| Active component: 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine | 10.00 |
| Other composition lactose hydroxypropyl cellulose Crospovidone microcrystalline cellulose magnesium stearate precoating hydroxypropyl methylcellulose is coated with the blue ink of stain white mixture (Color Mixture White) polishing Brazil wax marking note edible | 312.00 16.00 20.00 40.00 2.00 8.00 16.32 trace traces |
Example 4
Powder formulation
Active component is mixed with silicones starch, and put in the duricrust gelatine capsule, promptly make powder formulation.
The capsule of every 300mg contains:
Chemical compound 30.0mg of the present invention
Silicones 2.9mg
But flow starch 267.1mg
Example 5
Tablet
With active component and suitable dilution agent, lubricant, disintegrating agent and binding agent mixing granulation and tabletting.
Chemical compound 10.0mg of the present invention
Magnesium stearate 0.9mg
Microcrystalline Cellulose 75.0mg
Polyvinyl pyrrolidone (Povidone) 15.0mg
Compressible starch 204.1mg
Example 6
Aqueous injectable
Make the lyophilization product earlier, before the use, add suitable sterile diluent dissolving (cumulative volume 10ml), can make the aqueous injectable of active substance.
The compounds of this invention is mixed with mannitol, and regulate pH to 5-5.5 with N hydrochloric acid and/or N sodium hydroxide.
The compounds of this invention 20.0mg
Mannitol 20.0mg
N hydrochloric acid and/or N sodium hydroxide transfer pH to 5-5.5.
Example 7
The intramuscular injectable formulations of controllable release
The particle suspension of effective ingredient in the oily excipient, is promptly made the aseptic intramuscular dose of controllable release.
Chemical compound 50.0mg of the present invention
Aluminium stearate 0.04mg
Oleum sesami 2ml
Example 8
Capsule preparations
Active component is mixed with silicones starch and starch, and in the duricrust gelatine capsule of packing into.Every 300mg capsule contains:
The compounds of this invention 2.5mg
But flow starch (containing 0.96% silicones 220) 222.5mg
But flow starch 75.0mg
Example 9
2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine granule
Mannitol is mixed in high-shear mixer with hydroxymethyl-propyl cellulose; Granulate with the water slurry of 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine and polysorbate20; Wet sieving, and then dry on the thermopnore exsiccator.Behind the dry sieving, remix, packing then.1a 250mg deck ingredient m g/ deck active component 2-methyl-4-(4-methyl isophthalic acid-piperazine 250 piperazine bases)-10H-thieno (2,3-b) (1,5) other composition mannitol 234.97 hydroxypropyl emthylcelluloses of benzodiazepine 3 cps 12.50 polysorbate20 0.0281b 750mg deck ingredient m g/ deck active component 2-methyl-4-(4-methyl isophthalic acid-piperazine 750 piperazine bases)-10H-thienos (2,3-b) (1,5) other composition mannitol 704.93 hydroxypropyl emthylcelluloses of benzodiazepine 3 cps 37.49 polysorbate20 0.081c 1000mg deck ingredient m g/ deck active component 2-methyl-4-(4-methyl isophthalic acid-piperazine 1000 piperazine bases)-10H-thienos (2,3-b) other composition mannitol 939.90 hydroxypropyl emthylcelluloses of (1,5) benzodiazepine 3 cps 49.99 polysorbate20s 0.11
If wish these granules are made suspension or solution, most preferably use acid medium.
Claims (15)
1. 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine or its medicinal salts application in the pharmaceutical composition of preparation treatment mammal cognitive dysfunction.
2. claim 1 is used, and cognitive dysfunction wherein is an Alzheimer.
3. claim 1 is used, 2-methyl-4-wherein (4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine is pure form I basically, utilize Sieman ' s D5000 diffractometer, can obtain typical X-ray powder diffraction pattern, as follows substantially, d represents interplanar distance:
d
10.2689
8.577
7.4721
7.125
6.1459
6.071
5.4849
5.2181
5.1251
4.9874
4.7665
4.7158
4.4787
4.3307
4.2294
4.141
3.9873
3.7206
3.5645
3.5366
3.3828
3.2516
3.134
3.0848
3.0638
3.0111
2.8739
2.8102
2.7217
2.6432
2.6007
4. the application of claim 3, cognitive dysfunction wherein is an Alzheimer.
5. 2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2,3-b) (1,5) benzodiazepine or its medicinal salts application in preparation takes stopgap measures the medicine for the treatment of the mammal cognitive dysfunction.
6. the application of claim 5, cognitive dysfunction wherein is an Alzheimer.
7. the application of claim 5, cognitive dysfunction wherein is relevant with the HIV disease.
8. the application of claim 6, the symptom for the treatment of of wherein taking stopgap measures comprises that the gradual of memory, discernment, reasoning and judgment and senior cortex hormone function weakens, initiative reduces, excessive is absent-minded, speaks, the obstacle of aspects such as motor activity, sensory capacity, and individual character at ordinary times becomes more outstanding, irritability, erethism, rage, violent behavior, illusion etc. takes place in the excitement of losing control of.
9. the application of claim 8, the symptom for the treatment of of wherein taking stopgap measures comprises that initiative reduces, excessive is absent-minded, the obstacle of aspects such as motor activity and sensory capacity in a minute,, individual character originally becomes more outstanding, irritability, erethism, rage, generation violence and the excitement of losing control of.
10. the application of claim 9, the symptom for the treatment of of wherein taking stopgap measures comprises excessively giving prominence to of personal characteristics, the excited excitement of crossing Sheng, rage, generation violence and losing control of.
11. the application of claim 5,2-methyl-4-(4-methyl isophthalic acid-piperazinyl)-10H-thieno (2 wherein, 3-b) (1,5) benzodiazepine is pure form I substantially, utilize Sieman ' s D5000 diffractometer, it is as follows substantially to obtain typical X-ray powder diffraction pattern, and d is an interplanar distance here
d
10.2689
8.577
7.4721
7.125
6.1459
6.071
5.4849
5.2181
5.1251
4.9874
4.7665
4.7158
4.4787
4.3307
4.2294
4.141
3.9873
3.7206
3.5645
3.5366
3.3828
3.2516
3.134
3.0848
3.0638
3.0111
2.8739
2.8102
2.7217
2.6432
2.6007
12. the application of claim 11, wherein the sort of cognitive dysfunction is an Alzheimer.
13. the application of claim 11, wherein cognitive dysfunction is relevant with the HIV disease.
14. the application of claim 11, the symptom of the treatment that wherein takes stopgap measures comprises that initiative reduces, and excessive is absent-minded, speaks, the obstacle of aspects such as motor activity and sensory capacity, and is furious, violence takes place, uncontrollable excitement and illusion takes place.
15. the application of claim 5, wherein effective dose is about 1-20mg every day.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN95197876A CN1131035C (en) | 1995-05-30 | 1995-05-30 | Method for treating cognitive dysfunction |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN95197876A CN1131035C (en) | 1995-05-30 | 1995-05-30 | Method for treating cognitive dysfunction |
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| CN1185108A CN1185108A (en) | 1998-06-17 |
| CN1131035C true CN1131035C (en) | 2003-12-17 |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0454436A1 (en) * | 1990-04-25 | 1991-10-30 | Lilly Industries Limited | Pharmaceutical compounds |
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|---|---|---|---|---|
| EP0454436A1 (en) * | 1990-04-25 | 1991-10-30 | Lilly Industries Limited | Pharmaceutical compounds |
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