CN1131035C - Method for treating cognitive dysfunction - Google Patents

Abstract

The present invention provides a method for treating cognitive dysfunction, comprising taking an effective dose of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.

Description

Approaches to treating cognitive dysfunction

The present invention provides a method for the treatment of Identify dysfunctions.

Alzheimer's disease is a condition of mental decline clinically characterized by a progressive decline in memory, recognition, reasoning and judgment. Eventually, comprehensive disorders develop to include all aspects of the brain's higher cortical functions. The decline begins and the patient may appear absent-minded. In addition to reduced recognition function, impairments in speech, motor activity, and sensory abilities may all be present. The usual personality qualities may become more prominent, even exaggerated. The initial emotional changes may be mainly heightened arousal, with periodic periods of anger and violence. Patients typically show impaired thinking and confusion. As the condition worsens, it generally develops into an uncontrollable commotion. Alzheimer's disease has so far proven incurable.

Treatment with palliative agents to reduce symptoms of recognition dysfunction during disease progression, such as palliative agents, can improve the quality of life of Alzheimer's disease patients and caregivers. This treatment can reduce or delay symptoms from becoming severe enough to require hospitalization or special care. Therefore, such palliative treatment is required not only for health economic purposes but also to improve quality of life when recognition dysfunction occurs.

Although cholinergic neurons decline, a hallmark of Alzheimer's disease, post-synaptic muscarinic receptors persist in the forebrain and hippocampus. Therefore, muscarinic cholinergic agonists are useful in treating Alzheimer's disease and improving cognitive dysfunction caused by Alzheimer's disease.

Surprisingly, according to the present invention, the applicant has found that the compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1, 5] Benzodiazepines can be used in the treatment of cognitive dysfunction, especially Alzheimer's disease. The compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine is a known compound, in the U.S. It is described in Patent No. 5,229,382. This patent is incorporated by reference.

The patent-pending invention provides a method of treating cognitive dysfunction comprising administering to a patient in need thereof an effective amount of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno [2,3-b][1,5]benzodiazepines.

In addition, the present invention provides a method for palliative treatment of cognitive dysfunction comprising administering to a patient in need of such treatment an effective amount of 2-methyl-4-(4-methyl-1-piperazinyl)-10H - Thieno[2,3-b][1,5]benzodiazepines. The 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine on Alzheimer's Palliative treatment of the disease is particularly useful.

The chemical formula of compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine is as follows, or its Acid addition salts. The free base of formula (I) is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine

The substantially pure anhydrous The crystals (Form I) have a typical X-ray powder diffraction pattern, essentially as follows, obtained using a Sieman's D5000 diffractometer equipped with a copper radiation source, d representing the interplanar spacing:

d I/I ₁

                                                         

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

Typical X- The ray diffraction powder pattern is basically as follows. This was obtained using a Sieman's D5000 diffractometer equipped with a copper radiation source, where d represents the interplanar spacing:

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

The X-ray powder diffraction patterns listed here were obtained using copper K at a wavelength of 1.541A. The interplanar spacing values for row "d" are in Angstroms. The data in the "I/I ₁ " row are typical relative intensity values. The detector used was a Kevex silicon lithium solid state detector.

By "substantially pure" is meant that the anhydrous Form I contains less than 5% of Form II. Preferably, however, less than 2% of Form II is present. Even more preferably, "substantially pure" should contain <0.5% of the non-Form I polymorph.

By "substantially pure" is meant that the anhydrous Form I contains <5% Form II, and preferably <2% Form II. It is further required that, preferably, "substantially pure" should contain <0.5% of other related substances. When the Form I polymorph is used as a pharmaceutical ingredient in a preparation, "substantially pure" shall mean containing about <15% of the Form II polymorph; preferably, when the Form I polymorph is processed as a pharmaceutical When formulated into a preparation, "substantially pure" shall mean containing about <10% of the Form II polymorph; preferably, when substantially pure material is processed into a preparation, "substantially pure" shall mean containing about <5% % Form II polymorph.

The term "2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine", if not specified otherwise is a chemical solvate or polymorph, it refers to technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1, 5] Benzodiazepines. A typical technical grade of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine contains About <5% undesired related substances, and possibly a mixed polymorph. Such technical grades of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine usually contain less About 1% of undesired related substances.

The term "crude" refers to the 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine band There are undesired polymorphs and/or greater than about 5% undesired related species. This crude grade of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine may contain less Less than about 1% of undesired related substances.

The term "mammal" as used herein refers to the higher vertebrate mammals. The term "mammal" includes, but is not limited to, humans. The term "treatment" as used herein includes prevention of the onset of symptoms of Alzheimer's disease, amelioration or elimination of symptoms once they have occurred.

The term 'palliative treatment' here refers to the alleviation of symptoms of cognitive dysfunction, rather than the cure of the disease. Symptoms of cognitive dysfunction include progressive decline in memory, recognition, reasoning and judgment, and higher cortical function; decreased motivation, Severe mental laxity, excessive talking, high motor activity and oversensitivity; exaggerated or exaggerated original personality characteristics, increased excitement, irritability or even violent behavior, uncontrollable agitation and confusion; but not These symptoms are limited. The method of the present invention is particularly applicable to confusion and sensory disturbance in the treatment of cognitive dysfunction symptoms. And, the method of the present invention is particularly expected to be used for the treatment of exaggerating the characteristics of the original personality, hyperactivity, irritability, violent behavior and symptoms such as uncontrollable agitation.

The term "cognitive dysfunction" refers to a patient's dysfunction in sensory, reasoning, and memory abilities, as well as in the ability to acquire knowledge. This dysfunction may be related to Alzheimer's disease, AIDS, and other central nervous system symptoms that cause the dysfunction.

The results of pharmacological studies show that 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine has Alkaline cholinergic receptor activity. The compound is active on dopamine D-1 and D-2 receptors at 3H-SCH233390 [Billard et al., life Sciences 35: 1885 (1984)] and 3HSpiperone [Seeman et al., Nature 216: 717 (1976)], respectively This is indicated by the half-inhibitory concentration IC50 < 1 μM in the binding assay. Also, the anhydrous Form I compound is active at the serotonin-2 receptor and at the serotonin 1C receptor. The complex pharmacological profile of this compound provides an agent for the treatment of cognitive dysfunction.

Animal experiments and clinical observations show that 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine There is a complex profile of muscarinic receptor subtypes. For example, rats exposed to overdoses of this compound were surprisingly found to have severe salivation. Also, clinical studies have shown pupillary constriction, rather than the expected pupillary dilation.

For the method of the present invention, the compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, Either in the free base form or in the form of its acid addition salt. Preferred acid addition salts are the pharmaceutically acceptable, non-toxic addition salts prepared with appropriate acids, such as certain inorganic acids, such as hydrochloric, hydrobromic, nitric, sulfuric or phosphoric acids; organic acids such as organic carboxyl Acids such as glycolic acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, tartaric acid, citric acid or lactic acid; or organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, 2-Hydroxyethanesulfonic acid, p-toluenesulfonic acid or naphthalene-2-sulfonic acid.

Compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine can be prepared as follows, which The process includes:

或(a) N-methylpiperazine is reacted with a compound of formula (II), wherein Q is a leaving group that can be split

or

(b) the compound of chemical formula (III) is subjected to ring-closing reaction

For these reaction processes, appropriate reaction conditions and appropriate Q values can be easily selected.

For example, in reaction (a), the group Q can be amino, or mono- or di-alkyl substituted amino (each alkyl substituent contains 1-4 carbon atoms), hydroxyl, thiol, or alkoxy , an alkylthio or alkylsulfonyl group (appropriately containing 1 to 4 carbon atoms, eg methoxy or methylthio), or a halogen atom, especially a chlorine atom. Preferably, Q is amino ( _-NH2 ), hydroxy or thiol, with amino being most preferred. The reaction is preferably carried out at a temperature in the range of 50-200°C.

当Q是羟基、或硫羟基时，化学式(II)的中间体，可能以它们酰胺和硫代酰胺形式存在：或 When Q is amino, the intermediate of formula (II) may also exist in the form of imino:

When Q is a hydroxyl group or a thiol group, the intermediates of the formula (II) may exist in their amide and thioamide forms: or

The amidine of chemical formula (II) (Q is -NH ₂ ) can exist in the form of salt, for example inorganic acid salt, as hydrochloride, and can be in organic solvent, as in anisole, toluene, dimethylformamide , Or in dimethyl sulfoxide, react with N-methylpiperazine, the suitable temperature range of the reaction is 100-150 ℃.

Amidines can be prepared by condensation of thiophenes of the following formula with o-halonitrobenzenes,

The reaction is carried out in the presence of a base, for example, in the presence of sodium hydride, while in a solvent such as tetrahydrofuran, or a tetrahydrofuran solution of n-butyllithium, or a dimethyl sulfoxide solution of potassium carbonate or lithium hydroxide, or aqueous hydrogen Dimethyl sulfoxide solution of sodium oxide; or condensation reaction with tetraalkylammonium salt in two-phase system to form nitronitrile with the following chemical formula:

For example, using tin chloride and hydrogen chloride, the nitronitrile formed is simultaneously reduced and ring-closed to an amidine of formula (II) in aqueous ethanol, or alternatively, reduction with hydrogen and palladium/carbon or ammonium polysulfide, followed by Acid-catalyzed ring formation. The intermediate of formula (IIa) may be isolated with ammonium chloride (NH ₄ Cl) or ammonium acetate (NH ₄ OAc).

When Q is hydroxyl, reaction (a) is best carried out in the presence of titanium tetrachloride, which has the ability to react with N-methylpiperazine to form metal amine complexes. It is also possible to use other metal chlorides, such as zirconium, hafnium or vanadium chlorides. The reaction can be carried out in the presence of a reagent which binds the acid, such as a tertiary amine, eg triethylamine.

Alternatively, the reaction is performed using an excess of N-methylpiperazine as the acid binding reagent. Suitable organic solvents such as toluene or chlorobenzene can be used as the reaction medium, but anisole is particularly suitable, at least as a co-solvent, from the point of view of its ability to form soluble complexes with _TiCl4 .

The suitable temperature range for the reaction is 80-120°C. If necessary, the temperature can be increased, for example to 200°C, to speed up the reaction.

Intermediate amides of formula (II) (Q is -OH) can be prepared by mediation of the corresponding amidine (Q is -NH ₂ ) with a base, or derivatized by compounds of the formula, In the chemical formula, R is an alkyl group, preferably a C _1-4 alkyl group, which can be ring-closed using, for example, sodium methylsulfinylmethanide in a suitable solvent, such as dimethyl sulfoxide. Another way to prepare amides is by ring closure of an amino acid using, for example, dicyclohexylcarbodiimide (DCC) in a suitable solvent, such as tetrahydrofuran. Such amino acids are prepared, for example, by alkaline hydrolysis of the above-mentioned esters with sodium hydroxide in ethanol.

Thioamides of formula (II) (Q is -SH), iminothioethers, iminoethers or iminohalogens, or other derivatives specifically mentioned above containing active Q reactive groups, tend to be more readily N-methylpiperazine reacts, and the reaction does not require the presence of TiCl ₄ , but the reaction temperature and solvent conditions are the same.

Thioamides of formula (II) (Q is -SH) can be prepared by reacting a solution of the corresponding amide in an anhydrous basic solvent, such as pyridine, with phosphorus pentasulfide. Similarly, amides can be converted into iminosulfides, iminoethers, or iminohalogens, or other derivatives containing active Q reactive groups, by treating with usual reagents, for example, when converting into iminochloro, use Phosphorus pentachloride treatment.

In the intermediate compound of chemical formula (II), when Q is a leaving group that can be separated, especially when Q is -NH ₂ , -OH or -SH, and when Q is -NH ₂ salts, the compound is a novel compound , become the further content of the present invention.

Regarding the above reaction (b), using, for example, titanium tetrachloride as a catalyst; anisole as a solvent, the compound of formula (III) can be ring-closed in the range of 100-250°C, such as 150-200°C.

化学式(IV)中的R是烷基，优选地是C_1-4烷基，加热到30-120℃之间，例如约100℃，在适当溶剂中，例如苯甲醚，并采用TiCl₄为催化剂。The intermediate compound of chemical formula (III) is preferably directly prepared without isolation by reacting a compound of chemical formula (IV) with N-methylpiperazine,

R in the chemical formula (IV) is an alkyl group, preferably a C _1-4 alkyl group, heated to between 30-120° C., such as about 100° C., in a suitable solvent, such as anisole, and using _TiCl as catalyst.

Compounds of formula (IV) can be prepared from the corresponding nitro compounds of formula (V).

In the compound of chemical formula (V), R is allyl, such as C _1-4 alkyl, which is novel and becomes a further content of the present invention.

If convenient, this nitro compound can be converted to the amine of formula (IV) without isolation prior to reaction with N-methylpiperazine. Intermediate compounds of formula (V) can be prepared by condensation reaction of thiophene of formula (VI) with o-halonitrobenzene, preferably o-fluoro or o-chloronitrobenzene. The condensation reaction is carried out in the presence of a base, such as (a) sodium hydride in a solvent such as tetrahydrofuran at a temperature of -20°C to 30°C, or (b) anhydrous potassium carbonate or lithium hydroxide in In a solvent such as dimethylsulfoxide, the temperature range is 90-120°C. Compounds of formula (V) can be converted into compounds of formula (IV) by reduction reactions, such as catalytic reduction, using hydrogen and palladium on carbon, or chemical reduction, using tin chloride and hydrogen chloride in aqueous ethanol, or polysulfide ammonium, or tin in aqueous ammonium chloride solution.

It will be appreciated that the compounds of formula (I) can be isolated as such, or converted into acid addition salts using conventional methods.

Yamamura, HI and Snyder, SH introduced in Proc.Nat.Acad.Sci.USA, 71 , 1725 (1974), in ³ H-QNB binding test, the IC ₅₀ of this compound is less than 1mM, and this shows, it has poisonous mushroom Alkali-cholinergic activity. Alzheimer's disease appears to be caused by the degeneration of up to 90% of the muscarinic cholinergic neurons in the basal layer of the nucleus, which is part of the anonymity, and these neurons project into the anterior cortical layer and hippocampus , has a general stimulating effect on the recognition function of the forebrain and hippocampus. Cholinergic neurons declined, but post-synaptic muscarinic receptors persisted in the forebrain and hippocampus. Thus, muscarinic cholinergic agonists could be used to treat Alzheimer's disease.

2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b ][1,5]Safety and efficacy of benzodiazepines. The patients were all 65 years of age or older. The patients were randomly divided into medication groups, namely taking 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine group and the placebo group. The BEHAVE-AD, BPRS, and CGI ratio scales familiar to and available to the skilled artisan were used to measure the changes in the patient's pre- and post-dose behavioral performance. The results showed that 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine was effective in the treatment of cognitive dysfunction The resulting abnormal behavior is useful.

The 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine compound is effective in a wide range of doses, The actual dosage will depend on the condition being treated. For example a daily dosage for the treatment of an adult is from 0.25-50 mg, preferably 1-30 mg, most preferably 1-20 mg. Although it can be taken in several divided doses, once a day is usually effective. For the treatment of cognitive dysfunction, a suitable daily dosage range is 1-30 mg, preferably 1-20 mg'. Radiolabeled 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine can be detected in saliva Detection, therefore, of the compound can be monitored and evaluated in the patient.

A preferred formulation of this invention is an oral solid dosage form comprising about 1-20 mg or 1-10 mg of the active, anhydrous form I of 2-methyl-4-(4-methyl-1-piperazinyl)-10H - an effective dose of thieno[2,3-b][1,5]benzodiazepine as active ingredient.

More preferably, the solid oral preparation is packaged in packaging materials to avoid light and moisture. For example, suitable packaging materials include, light yellow, high-density polyethylene bottles, light yellow glass bottles, and containers made of other light-resistant materials. More preferably, a desiccant packet is placed in the packaging container. Containers may be sealed with aluminum foil to provide needed protection and maintain product stability.

The compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, usually administered orally or by injection, For this purpose, they usually take the form of pharmaceutical compositions.

The pharmaceutical composition comprises 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine as an active ingredient and Related pharmaceutical carriers. Conventional methods of preparing pharmaceutical compositions can be used to prepare the compositions of the present invention. For example, the active ingredient is usually mixed with a carrier, or diluted with a carrier, or wrapped in a carrier, which may be a capsule, sachet, paper or other form of container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material, which acts as a carrier, excipient or medium for the active ingredient. The active ingredient may be adsorbed onto solid granular containers, for example onto sachets. The following are some examples of suitable carriers: lactose, glucose, sucrose, sorbose, mannitol, starch, acacia, calcium phosphate, tragacanth, gelatin, syrup, methylcellulose, methyl- and propyl- Parabens, talc, magnesium stearate or mineral oil. The compositions of the present invention may, if desired, be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient. For example, U.S. Patent Nos. 5,079,018, 5,039,540, 4,305, 5024,758,598 and 4,371,516, which describe a rapid release formulation, are incorporated herein by reference. Most preferably such formulations comprise 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine , Water, Hydrolyzed Gelatin and Mannitol.

Depending on the method of administration, this composition for the treatment of central nervous system diseases can be prepared in various dosage forms: tablets, capsules, injections for parenteral administration, colloids or suspensions for transdermal administration, slow absorption, oral administration Suspension or elixir, or suppository. Preferably, the pharmaceutical composition is presented in unit dosage form, each unit dosage containing 0.25-100 mg, more usually 1-30 mg of active ingredient. When sustained release formulations are desired, unit doses may contain 0.25-200 mg of active ingredient. The preferred formulation of the present invention is capsules or tablets, each capsule or tablet contains 0.25-75 mg or 1-30 mg of active ingredient mixed together with a pharmaceutical carrier. More preferred preparations are injections, the unit dosage form of which contains 0.25-30 mg or 1-30 mg of the active ingredient in admixture with a pharmaceutically acceptable diluent.

The materials used in the present invention can be bought, and can also be prepared by various methods, and these methods are mastered by ordinary skilled persons. 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine compounds can be obtained according to Chakrabarti in U.S. Patent No. 5,229,382 ('382), which is hereby incorporated by reference. It is most desirable to prepare a fast-dissolving formulation comprising substantially pure Form I of the crystalline compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b ][1,5]Benzodiazepines. This substantially pure Form I crystalline compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5][benzo ] diazepines, which can be prepared according to the techniques described in the Preparations section below.

In the mixing step, common agitation methods such as stirring, shaking and the like can be used. The so-called "preparation of a crystalline product from a mixture" refers to crystallization from a mixture of the above-mentioned compound and a solvent. Also, the artisan knows that the crystallization process may include seeding, cooling, scraping the walls of the reaction vessel glass, and other common techniques.

Compound identification methods include, for example, X-ray powder pattern analysis, thermogravimetric analysis, differential scanning calorimetry, titration analysis for water, and nuclear magnetic resonance analysis ( ¹ H-NMR) for organic solvent content.

The following examples are provided to illustrate the present invention, but not to limit the scope of the patent application of the present invention.

Preparation 1

Compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine, crystalline form II

Suspend 10 g of crude 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine sample in two (100) g in methyl chloride, stirred at ambient temperature (20-25°C) for 1 hour. The slurry was vacuum filtered, and the filtrate was recovered. The filtrate was stirred in an ice bath, allowed to cool to 0-5°C, and the solvent was evaporated slowly under a stream of nitrogen to obtain a thick paste. About 3/4 of the solvent was evaporated. A certain amount of pre-cooled dichloromethane (30 g, 0-5° C.) was mixed into the thick paste, and the obtained slurry was vacuum-filtered, and the precipitate was air-dried on a funnel. After the solid was removed, it was further dried in a vacuum oven at 50°C for 30 minutes. Isolated: 4.8 g _, X-ray powder identification: Form II+ _CH2Cl2 solvate.

The resulting solid was isolated and dried in a vacuum oven at 50°C under nitrogen flow for a further 30 hours. Isolated: 4.5 g, X-ray powder identification: Form II (Form II above).

Preparation 2

Crystalline Form I of the compound 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.

Ethyl acetate of saturated technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine Ester solution with 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine seeded as Form I Contact the crystalline form II of the zine and stir at about 25°C for about 5 hours. The reaction product was isolated by vacuum filtration and dried under ambient conditions. Yield: 0.25 g. X-ray powder analysis indicated that the product was anhydrous 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzo Diazepine Form I Compound.

Preparation 3

Technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.

Intermediate 1

Add the following materials to a suitable three-neck bottle:

Dimethyl sulfoxide (analytical grade): 6 volumes

Intermediate 1: 75g

N-methylpiperazine (reagent grade): 6 equivalents

Intermediate 1 can be prepared by a skilled person using known methods. How to prepare intermediate I is disclosed, for example, in the '382 patent.

A nitrogen sparge line was placed under the reaction liquid surface to drive off the ammonia gas generated during the reaction. The reactants were heated to 120°C and maintained until the reaction was complete. The progress of the reaction was monitored by HPLC. Until the unreacted intermediate I is less than or equal to 5%. After the reaction was complete, the mixture was slowly cooled to 20°C (about 2 hours). Transfer each reaction mixture to an appropriate three necked round bottom flask placed on a water bath. With stirring, 10 volumes of reagent grade methanol were added to the solution and stirred at 20°C for 30 minutes. During 30 minutes, 3 volumes of water were slowly added. The reaction slurry was cooled to 0-5°C and stirred for 30 minutes. The product was filtered off and the wet cake was washed with cold methanol. The wet cake was vacuum dried overnight at 45°C. This product was identified as technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine .

Yield: 76.7%: Recovery rate (Potency): 98.1%

Basically, the procedure of Preparation 3 described above was repeated, and the yield was 81%, and the recovery rate (Potency): 101.1%.

Preparation 4

Technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.

Intermediate 1 (above) was suspended in DMSO (dimethylsulfoxide, 3, 2 vol) and toluene (4.5 vol). Part of the solvent (~0.65 vol) was distilled off at 120-125°C. The mixture was cooled to 110°C, N-methylpiperazine (NMP, 4.2 equivalents) was added, and the mixture was heated to reflux (120-125°C). The reaction mixture was distilled to dryness and another portion of solvent (ca. 1 vol) was removed. Vigorous reflux is required to drive off the ammonia generated in the reaction and promote the completion of the reaction (about 7 hours). The product was isolated by slowly adding water (12.75 vol) to the cooled (10°C) reaction solution. The product was filtered off and washed with cold water (2 vol). 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine crude product was dried under vacuum at 60°C . The crude product was recrystallized from hot toluene (5 volumes) to give technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b] [1,5] Benzodiazepines. After drying under vacuum at 50°C, the technical grade product was recrystallized from ethyl acetate (10 vol)/toluene (0.62 vol)/methanol (3.1 vol) to give 2-methyl-4-(4- Methanol solvate of methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine. The methanol solvate was converted to anhydrous technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][ 1,5] Benzodiazepines.

Preparation 5

Preparation of Form I from Acetone

Suspend 3.0 g of technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine in acetone Medium (30g). The mixture was stirred, heated to about 60°C, and held at 60°C for about 30 minutes. The mixture was then cooled to 25°C. The product was separated by vacuum filtration. The product was identified as 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine by X-ray powder analysis Zax, Form I. Yield: 0.8g.

Preparation 6

Preparation of Form I using tetrahydrofuran

Suspend 8.0 g of technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine in tetrahydrofuran (25g). The mixture was stirred and heated to about 60°C and maintained at this temperature at about 30°C. Then cool to about 25°C. The product was isolated by vacuum filtration. Using X-ray powder analysis, the product was identified as 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzobis Azepine, Form I. Yield: 1.3g.

Preparation 7

Preparation of Form I Using Ethyl Acetate

Suspend 270 g of technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine in acetic acid in ethyl ester (2.7 L). The mixture was heated to about 76°C and maintained at this temperature for about 30 minutes. It was then cooled to about 25°C. Vacuum filtration separates the product. Using X-ray powder analysis, the product was identified as 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzobis Azepine, Form I. 197g.

Preparation 8

Preparation of Form I from tert-butanol

Suspend 1.0 g of technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine in in tert-butanol (30 g). The mixture was stirred, heated to about 60°C, and maintained at this temperature for about 30 minutes. The mixture was cooled to 25°C. The product was filtered off in vacuo. The product was identified as Form I 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] by X-ray powder analysis Benzodiazepines. Yield 0.3g.

Preparation 9

Conversion of syrupy Form II to Form I in toluene

A sample of 0.5 g of technical grade 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine and 0.5 g sample of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine in form II, suspended in In toluene (5ml), this toluene was treated with 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine Miscellaneous presaturation. The mixture was stirred at ambient temperature for about 22 hours in a sealed reactor. The product was filtered off in vacuo and dried in vacuo at 45°C. The product was identified as Form I 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5] by X-ray powder analysis Benzodiazepines.

Example 1

Take a part of hydroxypropyl cellulose and dissolve it in pure water to form a solution for granulation. The remaining superfine hydroxypropyl cellulose (total amount is 4.0% of final tablet weight) and 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2 ,3-b][1,5]benzodiazepine (1.18% W/W), lactose (79.32%, W/W) and part of Crospovidone (5%, W/W) were mixed in a high shear Granulate in a variable granulator. The individual ingredients are ensured to be sieved and dry blended in a granulator before being added. This mixture was then granulated in a high shear granulator together with the hydroxypropyl cellulose solution. The granules were wet sieved using standard methods. The wet granules are then dried on a fluid bed dryer and sieved. This material was then added to the rolling bin mixer.

A running powder consisting of microcrystalline cellulose (granule) (10%, W/W), magnesium stearate (0.5% W/W) and the remainder of Crospovidone, was added to the sieved granulation process. This mixture is blended and compressed with appropriate tools on a tablet compression machine. Prepainted

Hydroxypropylmethylcellulose (10% W/W) was mixed with pure water to form a solution. The tablet core is divided into approximately equal parts and sprayed with hydroxypropyl methylcellulose solution. Operation is carried out in perforated spray pans.

Smear core

Color Mixture White (Hydroxypropylmethylcellulose, Polyethylene Glycol, Polysorbate 80 and Titanium Dioxide) is mixed with purified water to make a coating suspension. The precoated tablet cores were divided into approximately equal portions and sprayed with the coating suspension described above. Operation is carried out in a perforated coating pan.

Coated tablets are lightly coated with carnauba wax and stamped with appropriate identifying marks.

Example 2

Essentially repeating the procedure described in Example 1, using the following ingredients, delicate tablets were prepared, each containing 1, 2.5, 5, 7.5 and 10 mg of 2-methyl-4-(4-methyl-1- Piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine:

Each tablet contains 1 mg 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine ingredient name Dosage (mg/tablet) Active ingredient: 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine 1.0 Other Ingredients Lactose Hydroxypropyl Cellulose Crospovidone Microcrystalline Cellulose Magnesium Stearate Pre-coated Hydroxypropyl Methyl Cellulose Color Mixture White Polished Carnauba Wax Marker Edible Blue Ink 67.433.404.258.500.421.703.47 trace trace

Each tablet contains 2.5 mg 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine ingredient name Dosage (mg/tablet) Active ingredient: 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine 2.5 Other Ingredients Lactose Hydroxypropyl Cellulose Crospovidone Microcrystalline Cellulose Magnesium Stearate Pre-coated Hydroxypropyl Methyl Cellulose Color Mixture White Polished Carnauba Wax Marker Edible Blue Ink 102.155.206.5013.000.652.605.30 Trace Trace

Each tablet contains 5.0 mg 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine ingredient name Dosage (mg/tablet) Active ingredient: 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine 5.00 Other Ingredients Lactose Hydroxypropyl Cellulose Crospovidone Microcrystalline Cellulose Magnesium Stearate Pre-coated Hydroxypropyl Methyl Cellulose Color Mixture White Polished Carnauba Wax Marker Edible Blue Ink 156.008.0010.0020.001.004.008.16 trace trace

Each tablet contains 7.5 mg 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine ingredient name Dosage (mg/tablet) Active ingredient: 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine 7.50 Other Ingredients Lactose Hydroxypropyl Cellulose Crospovidone Microcrystalline Cellulose Magnesium Stearate Pre-coated Hydroxypropyl Methyl Cellulose Color Mixture White Polished Carnauba Wax Marker Edible Blue Ink 234.0012.0015.0030.001.506.0012.24 trace trace

Each tablet contains 10mg 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine ingredient name Dosage (mg/tablet) Active ingredient: 2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine 10.00 Other Ingredients Lactose Hydroxypropyl Cellulose Crospovidone Microcrystalline Cellulose Magnesium Stearate Pre-coated Hydroxypropyl Methyl Cellulose Color Mixture White Polished Carnauba Wax Marker Edible Blue Ink 312.0016.0020.0040.002.008.0016.32 trace trace

Example 4

                                                                     

A powder formulation is prepared by mixing the active ingredient with silicone starch and filling it into hard-shell gelatin capsules.

Each 300mg capsule contains:

Compound of the present invention 30.0mg

Silicone 2.9mg

Flowable starch 267.1mg

Example 5

Tablets

The active ingredient is mixed with appropriate diluents, lubricants, disintegrants and binders to granulate and compress into tablets.

Compound of the present invention 10.0mg

Magnesium stearate 0.9mg

Microcrystalline Cellulose 75.0mg

Polyvinylpyrrolidone (Povidone) 15.0mg

Compressible starch 204.1 mg

Example 6

Aqueous Injection

First make a freeze-dried product, add an appropriate sterile diluent to dissolve (total volume 10ml) before use, and then obtain an aqueous injection of the active substance.

The compound of the present invention is mixed with mannitol, and the pH is adjusted to 5-5.5 with N hydrochloric acid and/or N sodium hydroxide.

Compound of the present invention 20.0mg

Mannitol 20.0mg

N hydrochloric acid and/or N sodium hydroxide to adjust the pH to 5-5.5.

Example 7

Controlled-release intramuscular injection formulation

Suspend the microparticles of the active ingredient in the oily excipient to make a controlled-release sterile intramuscular injection.

Compound of the present invention 50.0mg

Aluminum stearate 0.04mg

Sesame oil 2ml

Example 8

                                                                                                                   

The active ingredient is mixed with silicone starch and starch and filled into hard-shell gelatin capsules. Each 300mg capsule contains:

Compound of the present invention 2.5mg

Flowable starch (with 0.96% silicone 220) 222.5mg

Flowable starch 75.0mg

Example 9

2-Methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine granules

Mix mannitol with hydroxymethylpropylcellulose in a high shear mixer; with 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3 -b] Granulation of an aqueous suspension of [1,5]benzodiazepine and polysorbate 20; wet sieving and subsequent drying on a fluid bed drier. After dry sieving, they are blended and packed. 1a 250mg sachet ingredients Benzene and two-nitrogen miscellaneous ingredients other ingredients. Glycolic alcohol 234.97 hydroxylopyl methyl cellulose 3 CPS 12.50 Polyglysis 20 0.0281B 750mg small medicine bag ingredient Mg/small pill active ingredient 2-methyl-4- (4 4- (4 4- (4 4- (4 4- (4 4- (4 4- (4 4- (4 4- (4 4- (4 -Nethel-1-0 750 azinyl) -10H-噻 噻 〔[2, 3-B] [1, 5] benzene and two nitrogen mixed ingredients ingredients ingredients 704.93 hydroxyl methyl cellulose 37.49 Polymorrhrinal ester 20 0.081c 1000mg of small pill component Mg/small pill active ingredients 2-methyl-4- (4-methyl-1-哌 1000zinel) -10H-pneumatopatopais and [2,3-B 〕 [1, 5] Benzene and two nitrogen mixed ingredients, other ingredients, glycotol 939.90 hydroxylopyl methyl cellulose 3 CPS 49.99 Polyolsol 20 0.11

If it is desired to prepare these particles in suspension or solution, acidic media are most preferred.

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.