KR100366895B1 - Method for Treating Cognitive Dysfunction - Google Patents

Abstract

A cognitive impairment comprising administering an effective amount of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine It provides a method for treating.

Description

Pharmaceutical composition for treating cognitive impairment {Method for Treating Cognitive Dysfunction}

The present invention provides a method of using 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine to treat cognitive impairment. to provide.

Alzheimer's disease is a degenerative brain disorder characterized by a gradual loss of memory, cognition, reason and judgment clinically. Eventually, an overall defect develops across all higher cortical functions. Creativity is reduced and the patient may fall into distraction (mental spawning). In addition to the reduced cognitive function, special disorders in language, motility and perception can be identified. Normal personality traits may be exaggerated or satire. Early emotional changes have periods of anger and violence and can be dominated by responsiveness. Frequently, patients exhibit a diminished thought process and delusions. As the disease progresses, mental disorders often develop out of control. To date, Alzheimer's disease has been known to be incurable.

Palliative treatment to alleviate symptoms of cognitive dysfunction of a disease process such as Alzheimer's disease can improve quality of life for both patients and their caregivers. Such treatment can minimize or delay the appearance of symptoms requiring hospitalization or treatment of the organ. Therefore, such treatment is desirable for both health economic purposes and quality of life improvement when cognitive dysfunction is manifested.

In addition, Alzheimer's disease is characterized by the presence of muscarinic receptors at the posterior nerve junction in the forebrain and hippocampus, even if cholinergic neurons degenerate. Thus, muscarinic cholinergic agonists are useful for treating Alzheimer's disease and improving cognitive impairment in patients suffering from Alzheimer's disease.

Surprisingly, according to the present invention, Applicants have found that compound 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine is impaired in recognition, It has been found to be useful in treating Alzheimer's disease. Compound 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine is known and is incorporated herein by reference in its entirety. US Pat. No. 5,229,382.

The present invention provides an effective amount of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] to patients in need of treatment for cognitive impairment. Provided is a method of treating the disease, comprising administering benzodiazepines.

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

2-Methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine compound consists of the following formula (I) or acid addition salts thereof. The free base of formula (I) is 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine.

Substantially pure crystalline anhydrous Form I 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine (form I) is copper Measurements using a Sieman's D5000 diffractometer equipped with a radiation source have in fact typical X-ray powder diffraction patterns as shown in the table below.

2-Methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine (form II) of Form II is a mannose equipped with a copper radiation source. Measurements using a D5000 diffractometer have a typical X-ray powder diffraction pattern substantially as shown in the table below.

The X-ray powder diffraction pattern disclosed herein was obtained using copper K having a wavelength of 1.54 lA. In the items marked "d", the interlayer spacing is in Angstroms. Typical relative intensities are indicated by the item "I / I ₁ ". The detector was a Kevex silicon lithium solid state detector.

As used herein, the term "substantially pure" means anhydrous Form I with less than 5% of Form II mixed, most preferably less than 2% of Form II. Even more preferably, the term "substantially pure" means that the non-form I polymorph is less than 0.5%.

As used herein, the term "substantially pure" means anhydrous Form I with less than about 5% of Form II mixed, more preferably less than about 2% of Form II. Even more preferably the term "substantially pure" means that the mixed material is less than 0.5%. When formulating a Form I polymorph as a pharmaceutical composition, the term "substantially pure" means that less than about 15% of the Form II polymorph is included, and more preferably the Form I polymorph is formulated as a medicament. When formulated, it means less than about 10% of the Form II polymorph, and particularly preferably when formulating substantially pure material, less than about 5% of the Form II polymorph.

As used herein, the term "2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine" is specifically a solvate or polymorph. When is not specified, it means industrial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine. Typically, industrial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine contains less than about 5% of unwanted substances And mixed polymorphs. Such industrial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepines often contain less than about 1% of unwanted substances. .

The term “crude” typically refers to 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2 mixed with unwanted polymorphs and / or at least about 5% of unwanted materials. , 3-b] [1,5] benzodiazepine. This crude grade 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine contains less than about 1% of unwanted substances can do.

As used herein, the term "mammal" refers to the mammalian class of higher vertebrates. The term "mammal" includes, but is not limited to humans. As used herein, the term "treatment" includes, but is not limited to, prevention of the symptoms indicated and alleviation or elimination of symptoms once they occur.

As used herein, the term palliative treatment refers to a treatment that alleviates the symptoms of cognitive dysfunction rather than treating the disease. Symptoms of cognitive dysfunction include memory, cognition, reason, judgment, gradual loss of higher cortical function, decreased creativity, hyperconfusion, language, motility, perceptual perception, exaggerated or satirical personality traits, irritability, excessive anger , Violence, hard-to-control mental disorders and delusions. The method of the present invention is particularly useful for treating delusions and perceptual disorders caused by such cognitive impairment. In addition, the methods of the present invention are particularly desirable for treating excessive personality traits, irritability, excessive anger, violence and uncontrollable mental disorders.

The term "cognitive dysfunction" refers to a dysfunction in perception, reason, ability to recall, and the ability to acquire knowledge. Such dysfunction may be associated with Alzheimer's disease, AIDS and other central nervous system symptoms that cause this dysfunction.

The pharmaceutical findings indicate that 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine has muscarinic cholinergic receptor activity. It is shown. The compound is 3H-SCH233390 (Billard et al., Life Science 35: 1885 (1984)) and 3H Spiferon (Seeman et al., Nature 216: 717 (1976) ) Is active at dopamine D-1 and D-2 receptors, as shown by IC ₅₀ <1 uM in binding assays, respectively. In addition, anhydrous Form I compounds are active at the 5-HT-2 receptor and the 5-HT1C receptor. The complex pharmaceutical profile of the compound provides a drug that may be useful for treating cognitive dysfunction.

Animal and clinical observations in vivo showed that 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine is a complex muscarinic receptor Supporting having a subtype profile. For example, rats given an excess of compound showed severe softening. In addition, pupil contractions occurred rather than expected pupillary relaxation.

Compound 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine is in its free base and acid addition salt form in the process of the invention Can be used by everyone. Acid addition salts are preferably pharmaceutically acceptable non-toxic addition salts with suitable acids, which acids are for example inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or organic carboxylic acids such as glycolic acid, male Acids, hydroxymaleic acid, fumaric acid, malic acid, tartaric acid, citric acid or lactic acid, or organic sulfonic acids such as methane sulfonic acid, ethane sulfonic acid, 2-hydroxyethane sulfonic acid, p-toluene-sulfonic acid or naphthalene-2-sulfonic acid Organic acids may be mentioned.

Compound 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine is prepared by (a) N-methylpiperazine of Formula II Reacting with the compound, or (b) ring-closing the compound of formula III.

Wherein Q is a detachable leaving group.

Appropriate reaction conditions and suitable Q values can be readily selected for these methods.

The radicals Q in reaction (a) are for example amino groups or mono- or dialkyl-substituted amino groups (each alkyl substituent suitably contains 1 to 4 carbon atoms), hydroxyl, thiol, or suitably It may be an alkoxy, alkylthio or alkylsulfonyl group containing 1 to 4 carbon atoms, for example a methoxy or methylthio group, or a halogen atom, in particular a chlorine atom. Preferably, Q is amino (-NH ₂ ), hydroxyl or thiol, with amino most preferred. Preferably, the reaction is carried out at a temperature of 50 ° C to 200 ° C.

When Q is amino, the intermediate of formula (II) may also exist in the following imino form,

When Q is hydroxyl or thiol, the intermediate of formula (II) may be present in the following amide or thioamide form.

The amidine of formula II (Q is —NH ₂ ) may be in the form of a salt, for example a salt of an inorganic acid such as hydrochloric acid, preferably anisole, toluene, dimethylformamide or dimethyl in the temperature range of 100 to 150 ° C. React with N-methylpiperazine in an organic solvent such as sulfoxide.

의 티오펜 화합물을 염기, 예를 들어 테트라하이드로푸란과 같은 용매 중의 수소화나트륨 또는 테트라하이드로푸란 중의 n-부틸 리튬 또는 디메틸술폭시드 중의 탄산칼륨 또는 수산화리튬 또는 디메틸술폭시드중의 수성 수산화나트륨의 존재하에 오르토-할로니트로벤젠과 축합시키거나, 또는 2상계 중에서 테트라알킬-암모늄염과 축합시켜 하기 화학식 IIa의 니트로니트릴을 형성시키고, 생성물을 동시에 예를 들면 에탄올 수용액 중의 염화주석 및 염화수소를 사용하거나, 또는 다른 방법으로서 수소 및 팔라듐/탄소 또는 암모늄 폴리술피드로 환원시키고 이어서 산 촉매된 폐환을 수행 하여 화학식 II의 아미딘으로 환원 및 폐환시킬 수 있다. 화학식 IIa의 중간체는 염화암모늄 (NH₄Cl) 또는 암모늄 아세테이트 (NH₄OAc)를 사용하여 단리시킬 수 있다.Amidine is a chemical formula

The thiophene compound of is prepared in the presence of a base, for example sodium hydride in a solvent such as tetrahydrofuran or potassium carbonate in n-butyl lithium or dimethyl sulfoxide in tetrahydrofuran or aqueous sodium hydroxide in lithium hydroxide or dimethyl sulfoxide. Condensation with ortho-halonitrobenzene or with a tetraalkyl-ammonium salt in a biphasic system to form nitrinitrile of formula (IIa) and the product simultaneously using tin chloride and hydrogen chloride in, for example, aqueous ethanol solution, or other As a method, hydrogen and palladium / carbon or ammonium polysulfide can be reduced followed by acid catalyzed ring closure to reduce and ring down to amidine of formula II. Intermediates of formula (IIa) can be isolated using ammonium chloride (NH ₄ Cl) or ammonium acetate (NH ₄ OAc).

When Q is hydroxyl, reaction (a) is preferably carried out in the presence of titanium tetrachloride which can react with N-methylpiperazine to form a metal amine complex. Chlorides of other metals such as zirconium, hafnium or vanadium can also be used. The reaction can be carried out in the presence of an acid binder such as a tertiary amine, for example triethylamine.

Alternatively, the reaction can be carried out using an excess of N-methylpiperazine, which acts as an acid-binding agent. Suitable organic solvents such as toluene or chlorobenzene can be used as the reaction medium, but at least the use of anisole as cosolvent is particularly preferred in that it can form soluble complexes with TiCl ₄ .

If desired, an elevated temperature, for example a temperature below 200 ° C., may be used to promote the reaction, with a preferred temperature range of 80 ° C. to 120 ° C. for carrying out the reaction.

Intermediate amides of formula II (Q is -OH) can be prepared by alkaline hydrolysis from the corresponding amidine (Q is -NH ₂ ), or in a suitable solvent such as, for example, dimethyl sulfoxide By ring closure using sodium methylsulfinyl memide, it can be derived from the compound of formula (IV).

Wherein R is an allyl group, preferably C _1-4 alkyl.

Alternatively, the amide can be prepared by ring closure of the amino acid using, for example, dicyclohexylcarbodiimide (DCC) in a suitable solvent such as, for example, tetrahydrofuran. Amino acids can be obtained from the esters, for example, by basic hydrolysis using sodium hydroxide in ethanol.

Thioamides of formula II (Q is -SH), iminothio-ethers, iminoethers or iminohalides, or other derivatives containing active Q radicals as mentioned above are more preferred for N-methylpiperazine. It tends to be reactive and can often be reacted using the same conditions of temperature and solvent, without the need for TiCl ₄ to be present.

Thioamides of formula II (Q is -SH) can be prepared by treating a corresponding solution of amide in anhydrous basic solvent, such as pyridine, with phosphorus pentasulfide. In a similar manner, the amide can be treated with conventional reagents such as, for example, iminochloride, phosphorus pentachloride, to iminothioethers, iminoethers or iminohalides, or other derivatives containing active Q radicals. You can switch.

Intermediate compounds of formula (II) wherein Q is a separable leaving group, in particular Q is -NH ₂ , -OH or -SH, and its salts when Q is -NH ₂ are novel compounds and form another aspect of the invention do.

In the reaction (b), the compound of formula III can be closed using, for example, titanium tetrachloride as a catalyst and anisole as a solvent, and the reaction is preferably from 100 ° C to 250 ° C, for example 150 ° C. To a temperature of from 200 ° C.

The intermediate compound of formula III is preferably heated by heating the compound of formula IV to a temperature of 30 ° C. to 120 ° C., for example about 100 ° C., using TiCl ₄ as catalyst in a suitable solvent such as, for example, anisole. Prepared in situ without isolation by reacting with N-methylpiperazine.

<Formula IV>

Wherein R is an allyl group, preferably C _1-4 alkyl.

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

The compound of formula (V), wherein R is an allyl group, such as, for example, C _1-4 alkyl, is novel and is another aspect of the present invention.

In some cases, the nitro compound may be converted to an amine of formula IV before being isolated and reacting with N-methylpiperazine. Intermediate compounds of formula (V) may be selected from a base such as (a) sodium hydride in a solvent such as for example tetrahydrofuran at a temperature of -20 ° C to 30 ° C, or (b) dimethyl at a temperature of 90 ° C to 120 ° C In the presence of a base such as anhydrous potassium carbonate or lithium hydroxide in a solvent such as sulfoxide, thiophene of formula (VI) can be prepared by condensation with ortho-halonitrobenzene, preferably ortho fluoro- or chloro-nitrobenzene Can be. Compounds of formula (V) are for example catalytically reduced by using hydrogen and palladium / carbon, or chemically by reducing with tin chloride and hydrogen chloride in aqueous ethanol solution or ammonium polysulfide or zinc in aqueous ammonium chloride solution Convert to a compound of.

It will be appreciated that the compounds of formula (I) can be isolated on their own or converted to acid addition salts using conventional methods.

Compounds of the present invention are described in Yamamura, HI and Snyder, SH in Proc. Nat. Acad. Sci. USA, 71 , 1725 (1974) have an IC ₅₀ of less than 1 mM in the ³ H-QNB binding assay, indicating that the compounds of the present invention have muscarinic cholinergic activity. Alzheimer's disease usually occurs in the basal ganglia, the obscure region, by degeneration of up to 90% of the muscarincholinergic neurons that extend to the frontal cortex and hippocampus, which have a general stimulating effect on the cognitive function of the forebrain and hippocampus. Although cholinergic neurons degenerate, posterior synaptic muscarinic receptors in the forebrain and hippocampus still exist. Thus, these muscarinic cholinergic agonists may be useful for treating Alzheimer's disease.

Double-blind multicenter clinical trials demonstrated 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1 in 237 elderly patients with cognitive impairment. , 5] was designed to evaluate the safety and effectiveness of benzodiazepines, wherein the age of patients was 65 years or older. Patients were randomly treated with 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine or placebo. Changes in behavior were measured using BEHAVE-AD, BPRS, and CGI assessment scales that are known and used by those skilled in the art. The findings suggest that 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine may be useful in treating behavioral patterns of cognitive impairment. It was shown.

2-Methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine compounds are effective over a wide range of dosage and Depends on the condition being treated. For example, when treating an adult, a dosage of about 0.25 to 50 mg, preferably 1 to 30 mg, most preferably 1 to 20 mg can be used per day. Usually, one dose per day is sufficient, but can be divided several times. In order to treat cognitive dysfunction, dosages of 1 to 30 mg, preferably 1 to 20 mg per day are suitable. 2-Methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepines labeled with radioisotopes can be detected in saliva The compound can potentially be monitored in the patient to assess compliance.

Preferred formulations of the invention are active anhydrous form I 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] as an effective amount of the active ingredient Solid oral formulation comprising about 1 to about 20 mg or 1 to 10 mg of benzodiazepine.

Most preferably, the solid oral formulation is placed in a packaging that protects the formulation from moisture and light. Suitable packaging materials, for example, include amber high density polyethylene bottles, amber glass bottles and other containers made of materials that inhibit the passage of light. Most preferably, the packaging will comprise a dry pack. The container can be preferably sealed by sealing with an aluminum foil blowing agent and can maintain product stability.

For this purpose 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine compounds are usually administered orally or by injection. And can usually be used in the form of pharmaceutical compositions.

Thus, it contains 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine as an active ingredient with a pharmaceutically acceptable carrier. Pharmaceutical compositions can be prepared. Conventional techniques for preparing pharmaceutical compositions can be used to prepare the compositions of the present invention. For example, the active ingredient can usually be mixed with the carrier, diluted with the carrier, or wrapped in a carrier that can be in the form of a capsule, sachet, paper or other container. If the carrier acts as a diluent, then the carrier may be a solid, semisolid or liquid substance which acts as a vehicle, excipient or medium for the active ingredient. The active ingredient can be adsorbed, for example, on granular solid containers in sachets. Examples of some suitable carriers include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propyl-hydroxy- Benzoate, talc, magnesium stearate or mineral oil. In some cases, the compositions of the present invention may be formulated to rapidly, slowly or delayed release the active ingredient after administration to a patient. For example, one such preferred rapid release formulation is described in US Pat. Nos. 5,079,018, 5,039,540, 4,305,502, 4,758,598 and 4,371,516, which are incorporated herein by reference. Such formulations are most preferably 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine, water, hydrolyzed gelatin and Contains mannitol.

Depending on the method of administration, the compositions for treating central nervous system diseases may be formulated as tablets, capsules, parenteral injection solutions, transdermal delivery gels or suspensions, oral or suppository suspensions or elixirs. Preferably, the composition is formulated in unit dosage forms, each dosage containing 0.25 to 100 mg, more generally 1 to 30 mg of the active ingredient. If a sustained release formulation is desired, the unit dosage form may contain 0.25 to 200 mg of the active ingredient. Preferred formulations of the invention are capsules or tablets comprising 0.25 to 75 mg or 1 to 30 mg of active ingredient together with a pharmaceutically acceptable carrier thereof. More preferred formulations are injections comprising 0.25 to 30 mg or 1 to 30 mg of the active ingredient in unit dosage form thereof with a pharmaceutically acceptable carrier.

Materials for the present invention can be purchased or prepared by various routes known to those skilled in the art. 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine compound is chakrarabarti, which is hereby incorporated by reference in its entirety. ) US Pat. No. 5,229,382 ('382). Rapidly dissolving formulations comprising 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine in substantially pure crystalline Form I Most preferred. 2-Methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine of the substantially pure crystalline Form I is part of the preparation examples herein It can manufacture using the technique as described in.

The mixing step used herein can be accomplished using conventional stirring methods such as stirring, shaking and the like. As used herein, the phrase "producing a crystalline product from a mixture" means crystallizing from an already mentioned mixture of compounds and solvents. The skilled person also recognizes that the crystallization method may include seeding, cooling, scratching the glass portion of the reaction vessel and using other such conventional techniques.

Compound characterization methods include, for example, X-ray powder pattern analysis, heat specific gravity analysis (TGA), differential scanning calorimetry (DSC), titration analysis on water and ¹ H-NMR analysis on solvent contents.

The following examples are presented for purposes of illustration and are not intended to limit the scope of the claimed invention.

Preparation Example 1

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

10 g of a sample of crude 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine were suspended in methylene chloride (100 mg) Stir at ambient temperature (20-25 ° C.) for 1 hour. The slurry was vacuum filtered and the filtrate was recovered. The stirred filtrate was cooled to 0-5 [deg.] C. in an ice bath and the solvent was slowly evaporated under a nitrogen stream to form a high viscosity paste. Approximately 3/4 of solvent was removed by evaporation. A predetermined amount of methylene chloride (30 gm, 0-5 ° C.) cooled in advance was mixed in a high viscosity paste. The resulting slurry was vacuum filtered and naturally dried on filter paper. The isolated solid was again dried in a vacuum oven at 50 ° C. for 30 minutes. Isolation amount: 4.8 gm. X-ray powder properties: Form II + CH ₂ Cl ₂ solvate.

The isolated solid was re-dried in a vacuum oven at 50 ° C. under a stream of nitrogen for 30 minutes. Isolation amount: 4.5 gm. X-Ray Powder Properties: Form II (described above).

Preparation Example 2

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

A sample of ethyl acetate saturated with industrial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine was converted to form 2-methyl- 4- (4-Methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine (0.3 g), 2-methyl-4- (4-methyl in anhydrous Form I It was contacted with a seed of -1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine and stirred 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 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine in anhydrous Form I.

Preparation Example 3

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

Intermediate 1

The following ingredients were added into a suitable three neck flask:

Dimethylsulfoxide (Analysis): 6 doses

Intermediate 1: 75 g

N-methylpyrazine (reagent): 6 equivalents

Intermediate 1 can be prepared using methods known to those skilled in the art. For example, the preparation of Intermediate 1 is taught in the '382 patent.

A nitrogen sparge below the surface was added to remove the ammonia formed during the reaction. The reaction was heated to 120 ° C. and maintained at this temperature for the duration of the reaction. The reaction was then treated with HPLC until the unreacted portion was 5% or less of intermediate 1. After the reaction was complete, the mixture was slowly cooled to 20 ° C. (about 2 hours). Each reaction mixture was then transferred to an appropriate three necked round bottom flask and water bath. While stirring this solution, 10 volumes of reagent methanol were added thereto, and the reaction was stirred at 20 ° C. for 30 minutes. Three volumes of water were added slowly for about 30 minutes. 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 dried overnight at 45 ° C. under vacuum. The product was found to be industrial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine.

Yield: 76.7%; Efficacy: 98.1%

The procedure of Preparation 3 was repeated virtually as described above, yielding a product of 101.1% efficacy, 81% yield.

Preparation Example 4

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

Intermediate 1 (see above) was suspended in DMSO (3.2 vol) and toluene (4.5 vol). A portion of the solvent (about 0.65 vol) was removed by distillation at 120-125 ° C. The mixture was cooled to 110 ° C., N-methylpyreazine (NMP, 4.2 equiv) was added and the mixture was heated to reflux (120-125 ° C.). Another portion of the solvent (about 1 volume) was removed by distillation to dry the reaction mixture. The reaction was terminated (about 7 hours) by vigorously refluxing to remove ammonia from the reaction. The product was isolated by slowly adding water (12.75 vol) to the cooled (10 ° C.) reaction solution. The product was collected by filtration and washed with cold water (2 vol). Crude 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine was dried at 60 ° C. under vacuum. The product was recrystallized from hot toluene (5 vol) to give industrial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine It was. After drying in vacuo at 50 ° C., industrial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine was diluted with ethyl acetate (10 Volume) / toluene (0.62 volume) / methanol (3.1 volume) and recrystallized again to yield 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1, 5] benzodiazepines were obtained as methanol solvates. Methanol solvate was dried at a temperature above 50 ° C. to dry anhydrous industrial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine Switched to

Preparation Example 5

Preparation of Form I from Acetone

A 3.0 g sample of industrial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine was suspended in acetone (30 g). The mixture was stirred and heated to about 60 ° C. The mixture was kept at about 60 ° C. for about 30 minutes. The mixture was cooled to about 25 ° C. The product was isolated by vacuum filtration. The product was identified as 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine of Form I using X-ray powder analysis It became. Yield: 0.8 g.

Preparation Example 6

Preparation of Form I Using Tetrahydrofuran

8.0 g of an industrial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine sample were suspended in tetrahydrofuran (25 g). . The mixture was stirred and heated to about 60 ° C. The mixture was kept at about 60 ° C. for about 30 minutes. The mixture was cooled to about 25 ° C. The product was isolated by vacuum filtration. The product was subjected to X-ray powder analysis to form 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine of Form I. Number: 1.3 g.

Preparation Example 7

Preparation of Form I with Ethyl Acetate

270 g of a commercial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine sample were suspended in ethyl acetate (2.7 L). The mixture was heated to about 76 ° C. and held at about 76 ° C. for about 30 minutes. The mixture was cooled 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] benzodiazepine of Form I It became.

Yield: 197 g.

Preparation Example 8

Preparation of Form I from t-butanol

1.0 g of an industrial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine sample was suspended in tert-butanol (30 g). . The stirred mixture was heated to about 60 ° C. and maintained at about 60 ° C. for about 30 minutes. The mixture was cooled to about 25 ° C. The product was isolated by vacuum filtration. Using X-ray powder analysis, the product was converted to 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine of Form I. It turned out.

Yield: 0.3 g

Preparation Example 9

Preparation of Form I from Slurry Conversion of Form II in Toluene

0.5 g of industrial 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine sample and 2-methyl-4- ( 0.5 g of 4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine sample was previously 2-methyl-4- (4-methyl-1-piperazinyl) It was suspended in toluene (5 ml) saturated with -10H-thieno [2,3-b] [1,5] benzodiazepine. The mixture was stirred in a sealed vial at approximately ambient temperature for about 22 hours. The product was isolated by vacuum filtration and dried under vacuum at about 45 ° C. Using X-ray powder analysis the product was identified as 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine of Form I It became.

Example 1

A portion of hydroxypropyl cellulose was dissolved in purified water to form a granulation solution. The best residual hydroxypropyl cellulose (total 4.0% w / w final tablet weight) was added to 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3 in a high shear granulator. -b] [1,5] benzodiazepine (1.18% w / w), lactose (79.32% w / w) and crospovidone (5% w / w). Sure sieved and dry blended in granulator before all ingredients were added. This mixture was then granulated with hydroxypropyl cellulose solution in a high shear granulator. The granules were wet sized using standard methods. The wet granules were then dried and sized in a fluid bed drier. Subsequently, the material was added to a Tumble Bin mixer.

A powder consisting of microcrystalline cellulose (granular) (10% w / w), magnesium stearate (0.5% w / w) and residual crospovidone was added to the sized granules. The mixture was blended and pressed with a suitable tool on a tablet compaction apparatus.

Sub-coating:

Hydroxypropyl methylcellulose (10% w / w) was mixed with purified water to form a solution. The core tablets were divided approximately evenly and spray coated with hydroxypropyl methylcellulose solution. The operation was carried out in perforated coating pans.

Coating of Core Tablets:

Color Mixture White (hydroxypropyl methylcellulose, polyethylene glycol, polysorbate 80 and titanium dioxide) was mixed with purified water to form a coating suspension. The subcoated tablets were divided roughly equally and spray coated with the coating suspension mentioned above. The operation was carried out in perforated coating pans.

Slightly sprayed carnauba wax on the coated tablets and the tablets were pressed with an appropriate recognizer.

Example 2

The procedure was substantially repeated as described in Example 1 using the following ingredients to yield 1, 2.5, 5, 7.5 and 10 mg of 2-methyl-4- (4-methyl-1-piperazinyl), respectively, for each tablet Pharmaceutically good tablet formulations containing -10H-thieno [2,3-b] [1,5] benzodiazepine were obtained:

Tablets containing 1 mg 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine :

Ingredient Name Content (mg / tablet) Active ingredient: 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine 1.0 Other ingredients Lactose 67.43 Hydroxypropyl cellulose 3.40 Crospovidone 4.25 Microcrystalline cellulose 8.50 Magnesium stearate 0.42 Sub Coating Hydroxypropyl methylcellulose 1.70 Coating Color Mixture White 3.47 Polish Carnauba wax a very small amount Seal Edible Blue Ink a very small amount

Tablets containing 2.5 mg of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine :

Ingredient Name Content (mg / tablet) Active ingredient: 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine 2.5 Other ingredients Lactose 102.15 Hydroxypropyl cellulose 5.20 Crospovidone 6.50 Microcrystalline cellulose 13.00 Magnesium stearate 0.65 Sub Coating Hydroxypropyl methylcellulose 2.60 Coating Color Mixture White 5.30 Polish Carnauba wax a very small amount Seal Edible Blue Ink a very small amount

Tablets containing 5.0 mg of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine :

Ingredient Name Content (mg / tablet) Active ingredient: 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine 5.00 Other ingredients Lactose 156.00 Hydroxypropyl cellulose 8.00 Crospovidone 10.00 Microcrystalline cellulose 20.00 Magnesium stearate 1.00 Sub Coating Hydroxypropyl methylcellulose 4.00 Coating Color Mixture White 8.16 Polish Carnauba wax a very small amount Seal Edible Blue Ink a very small amount

Tablets containing 7.5 mg 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine :

Ingredient Name Content (mg / tablet) Active ingredient: 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine 7.50 Other ingredients Lactose 234.00 Hydroxypropyl cellulose 12.00 Crospovidone 15.00 Microcrystalline cellulose 30.00 Magnesium stearate 1.50 Sub Coating Hydroxypropyl methylcellulose 6.00 Coating Color Mixture White 12.24 Polish Carnauba wax a very small amount Seal Edible Blue Ink a very small amount

Tablets containing 10 mg 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine :

Ingredient Name Content (mg / tablet) Active ingredient: 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine 10.00 Other ingredients Lactose 312.00 Hydroxypropyl cellulose 16.00 Crospovidone 20.00 Microcrystalline cellulose 40.00 Magnesium stearate 2.00 Sub Coating Hydroxypropyl methylcellulose 8.00 Coating Color Mixture White 16.32 Polish Carnauba wax a very small amount Seal Edible Blue Ink a very small amount

Example 4

Powder Formulation

Powdered formulations were prepared by blending the active ingredient with silicone starch and filling it into hard gelatin capsules.

Per 300 mg capsule Compound of the Invention 30.0 mg silicon 2.9 mg Fluid starch 267.1 mg

Example 5

Tablet formulation

Tablet formulations are prepared by granulating and compressing the active ingredient with the appropriate diluent, lubricant, disintegrant and binder.

Compound of the Invention 10.0 mg Magnesium stearate 0.9 mg Microcrystalline cellulose 75.0 mg Povidone 15.0 mg Direct compressible starch 204.1 mg

Example 6

Aqueous injection formulations

Aqueous injections of the active ingredient were prepared as lyophilized plugs for recombination in a suitable sterile diluent prior to use.

The compounds of the present invention were contacted with mannitol N hydrochloric acid and / or N sodium hydroxide to adjust the pH to 5 to 5.5.

Compound of the Invention 20.0 mg Mannitol 20.0 mg N hydrochloric acid and / or N sodium hydroxide Amount adjusted to pH 5 to 5.5

Example 7

Controlled Release IM Formulations

Controlled release injectable drugs for intramuscular injection were prepared from sterile suspensions of the finely divided active ingredient in the oily vehicle.

Compound of the Invention 50.0 mg Aluminum stearate 0.04 mg Sesame oil 2 ml

Example 8

Capsule Formulation

The formulations were prepared by blending the active ingredient with silicone starch and starch and filling into hard gelatin capsules.

Per 300 mg capsule Compound of the Invention 2.5 mg Flowable Starch Mixed with 0.96% Silicon 220 222.5 mg Fluid starch 75.0 mg

Example 9

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

The granules are blended with mannitol and hydroxymethyl propyl cellulose in a high shear mixer, 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [ 1,5] Prepared by granulating with an aqueous suspension of benzodiazepine and polysorbate 20, wet sizing, and then drying in a fluid bed drier. These were dry sized, reblended and packaged.

1a. 250 mg sachet

ingredient MG / detergent Active ingredient: 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine 250 Other Ingredients: Mannitol 234.97 Hydroxypropyl methyl cellulose 3cps 12.50 Polysorbate 20 0.028

1b. 750 mg sachet

ingredient MG / detergent Active ingredient: 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine 750 Other Ingredients: Mannitol 704.93 Hydroxypropyl methyl cellulose 3cps 37.49 Polysorbate 20 0.08

1c. 1000 mg sachet

ingredient MG / detergent Active ingredient: 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine 1000 Other Ingredients: Mannitol 939.90 Hydroxypropyl methyl cellulose 3cps 49.99 Polysorbate 20 0.11

If a suspension or solution is desired, most preferably the granules are contacted with an acidic medium.

Claims (10)

Alzheimer's, comprising an effective amount of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine or a pharmaceutically acceptable salt thereof Pharmaceutical composition for treating cognitive dysfunction associated with disease, AIDS and central nervous system disease. The 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine is a Sieman's D5000 diffractometer. Measured using P-substituted substantially methyl 2- (Methyl-4- (4-methyl-l-piperazinyl) -10H-thieno [3] having substantially the typical X-ray powder diffraction pattern 2,3-b] [1,5] benzodiazepine. 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 d is the spacing between crystal faces. The pharmaceutical composition of claim 1, wherein the effective amount is about 1 mg to about 20 mg per day. Alzheimer's, comprising an effective amount of 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine or a pharmaceutically acceptable salt thereof Pharmaceutical compositions for the palliative treatment of cognitive dysfunction associated with disease, AIDS and central nervous system disease. 5. The method of claim 4, wherein memory, perception, reason, judgment, gradual loss of higher cortical function, reduced creativity, excessive distraction, language, motility, perceptual perception, exaggerated or satirized personality traits, irritability, excessive anger, violence And pharmaceutical compositions for palliatively treating mental disorders and delusions that are difficult to control. 6. A pharmaceutical composition according to claim 5 for palliatively treating reduced creativity, excessive distraction, language, motility, perceptual perception, exaggerated or satirical personality traits, irritability, excessive anger, violence and uncontrollable mental disorders. 7. A pharmaceutical composition according to claim 6 for the treatment of excessive personality traits, irritability, excessive anger, violence and uncontrollable mental disorders. 5. The method of claim 4, wherein 2-methyl-4- (4-methyl-1-piperazinyl) -10H-thieno [2,3-b] [1,5] benzodiazepine is subjected to the use of a D'Omans D5000 diffractometer. A pharmaceutical composition that is substantially pure Form I, as measured and having a typical X-ray powder diffraction pattern substantially as shown in the table below. 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 d is the spacing between crystal faces. 9. The method of claim 8, wherein the constraints for relieving reduced creativity, excessive distraction, language, motility, perceptual perception, exaggerated or satirical personality traits, irritability, excessive anger, violence, uncontrollable mental disorders and delusions Composition. The pharmaceutical composition of claim 4, wherein the effective amount is about 1 mg to about 20 mg per day.