Substituted benzothiadiazine, methods for their preparation, pharmaceutical composition

 

(57) Abstract:

The invention relates to benzothiadiazine General formula I, in which X represents hydrogen or halogen, Y represents-CN or-NR1R2where l denotes an integer of 1 or 2, m represents an integer of 0, 1 or 2, n denotes an integer equal to 2, 3 or 4, except for the case when Y - SP, n may be equal to 1, R1denotes hydrogen, (C1-C6)alkyl or alkoxycarbonyl, R2denotes hydrogen, (C1-C10)alkylsulphonyl, (C3-C12)cycloalkylcarbonyl, hydroxy(C1-C6)alkylsulphonyl, phenylcarbinol, possibly substituted with halogen, cryptomaterial, thienylboronic or benzotriazolyl, or R1and R2together with the nitrogen atom to which they are bound, form a loop formula II, where a denotes C=0 or CH2In stands WITH a= 0, SNON, CH2or CH2CH2and Z represents hydrogen, and their pharmaceutically acceptable additive salts of acids, provided that when X=N, n can be 4, and R1and R2cannot be both hydrogen. Also proposed methods for obtaining such compounds and pharmaceutical composition thereof. The compounds of formula I iasov. 4 C. and 11 C.p. f-crystals, 3 PL.

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This invention relates to benzothiadiazines. More specifically, this invention relates to benzothiadiazine with protivopsychoticheskogo activity, and to their use as protivopsychoticheskogo medicines.

In the appropriate technique known therapeutic treatment of patients with schizophrenia through the introduction of neuroleptic drugs such as chlorpromazine, haloperidol, sulpiride and chemically closely related compounds. Although the symptoms of schizophrenia successfully regulated the handling of such drugs is not the way to treat psychotic patient who will experience a relapse at the abolition of the drug. Therefore, continues to exist a need in the technology development of drugs for the treatment of psychosis.

In addition, some of the known neuroleptics cause unwanted side effects. For example, the side effects of many protivopsychoticheskogo medicines include the so-called extrapyramidal symptoms such as rigidity and tremor, continuous stirred poodles well as orthostatic hypotension. Thus, there is also a need to develop protivopsychoticheskogo drugs that cause fewer or less severe manifestation of these common side effects.

This invention helps to meet these needs in drug development, providing compounds of the formula:

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in which X represents hydrogen, halogen, hydroxy, (C1-C6)-alkoxy, amino or trifluoromethyl, and

Y - represents-CN or-NR1R2,

where l denotes an integer of 1 or 2,

m denotes an integer of 0, 1 or 2,

n denotes an integer equal to 2, 3 or 4, except for the case when Y is CN, then n can be equal to 1,

R1denotes hydrogen, (C1-C6)alkyl or (C1-C6-alkylsulphonyl,

R2denotes hydrogen, (C1-C10)alkylsulphonyl, (C3-C12cycloalkylcarbonyl, hydroxy-(C1-C6)alkylsulphonyl, phenylcarbinol, thienylboronic or benzotriazolyl, or

R1and R2together with the nitrogen atom to which they are bound, form a loop:

< / BR>
where A represents C=O or CH2and

B represents C=O, CHOH, CH2or CH2CH

This invention provides a pharmaceutical composition that includes a compound of the invention and a pharmaceutically acceptable carrier. In one of the embodiments of the invention the pharmaceutical composition is an antipsychotic composition comprising a compound of the invention in a quantity sufficient to cause protivopsychoticheskogo effect.

In addition, this invention provides a method of treating psychoses, which comprises administration to the patient pharmaceutically effective amount of the compounds of the invention.

The compounds of this invention can contain a variety of substituents and chemical groups.

The term "alkyl", as used here, means linear or branched hydrocarbon group containing no unsaturated bonds, such as, for example, methyl, ethyl, isopropyl, propyl, 2-butyl, t-butyl, neopentyl or hexyl.

The term "cycloalkyl" as it is used here, refers to monocyclic or bicyclic hydrocarbon ring, such as, for example, cyclopropyl, cyclohexyl or substituted.

The term "alkoxy", as the th ether oxygen, having a free valence bond from oxygen, such as, for example, methoxy, ethoxy, propoxy, butoxy, pentox or hexyloxy.

The term "alkylaryl" as it is used here, refers to a monovalent Deputy, including alkyl group linked through a carbonyl group having a free valence bond to a carbonyl group, such as, for example, acetyl, propionyl or isopropylcarbonate.

The term "phenyl" as used here, refers to the unsubstituted phenyl or phenyl substituted with 1, 2 or 3 substituents consisting of halogen, trifloromethyl, phenyl and (C1-C6)alkyl, such as, for example, 4-forfinal or 2-(4-(trifluoromethyl)phenyl)-phenyl.

The term "thienyl" as it is used here, refers to the unsubstituted thiophene or thiophene, substituted by 1 or 2 substituents selected from: halogen, alkoxy, and (C1-C6)alkyl.

The term "sensational" as it is used here, refers to the unsubstituted benzothiophene or benzothiophene, substituted 1, 2 or 3 substituents in Pensacola consisting of halogen, trifloromethyl, alkoxy, and (C1-C6)-alkyl.

Unless otherwise indicated, the term "halogen" as used Desna chemical formula or name include all geometric, optical and stereoisomers, when they exist.

More specifically, this invention relates to the compound of the formula:

< / BR>
in which X denotes hydrogen or halogen, and

Y represents-CH-or-NR1R2,

where m is an integer from 0 to 2,

n is an integer equal to 2, 3 or 4,

R1is hydrogen, (C1-C6)alkylsulphonyl,

R2is hydrogen, (C1-C10)alkylsulphonyl, (C3-C12-cycloalkylcarbonyl, hydroxy-(C1-C6)alkylsulphonyl, phenylcarbinol, thienylboronic or benzotriazolyl, or

R1and R2together with the nitrogen to which they are bound, form a loop:

< / BR>
where A represents C=O or CH2and

B represents C=O, CHOH, CH2CH2CH2and

its pharmaceutically acceptable acid salt of the merger.

One of the preferred embodiments of the invention are compounds of the formula:

< / BR>
in which X is hydrogen or halogen,

m is 0 or 2

n is 2, 3 or 4,

R1denotes hydrogen or (C1-C6)alkylsulphonyl, and

R2denotes hydrogen, (C1-C10)alkylsulphonyl, (C3-C12)cycloalkylcarbonyl, hydroxy(C1-C6-Alania.

In this embodiment preferably:

X is halogen,

m is 0, and

n is equal to 4.

Most preferably,

X is 6-F,

R1denotes hydrogen or acetyl, and

R2denotes hydrogen, isopropylcarbonate, adamantylidene, 4-fortuneserver, 2-thienylboronic, 2-benzotriazolyl, 2-hydroxy-2-methyl-ethylcarboxyl or 2-/4'-(trifluoromethyl)-1,1'-biphenyl -/.

Another preferred embodiment of the invention are compounds of the formula:

< / BR>
where X denotes hydrogen or halogen,

m is 0 or 2

n is 2, 3 or 4,

A represents C=O or CH2,

B represents C=O, CHOH, CH2or CH2CH2and their pharmaceutically acceptable acid salt of the merger.

In this embodiment, preferably,

X denotes halogen,

m is 0, and

n is equal to 4.

In this embodiment most preferably

X is 6-F,

m is 0,

n = 4,

A represents C=O or CH2and

B is equal to C=O, CHOH, CH2CH2or CH2.

The compounds of this invention receive the following way. Unless otherwise noted, the substituents R1, R2, A, B, X, Y and Z and the integers l, m and n are timeoutvalue substituted 1-(benzo[b]Tien-3-yl)piperazine (A) with a suitable haloalkylthio (B), that gives compound of formula II.

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The reaction is usually carried out in a suitable solvent, such as acetonitrile or dimethylformamide (DMF) in the presence of an acid acceptor, such as, for example, carbamate, potassium or sodium carbonate, and a small amount of potassium iodide or sodium iodide at temperatures from about 20oC to 100oC, preferably from approximately 25oC to 90oC, most preferably about 75 to 85oC.

Compound II restore suitable restoring means, such as lithium alumoweld with getting isoindole formula III.

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The reaction is usually carried out in an aprotic organic solvent such as tetrahydrofuran (THF) at a temperature of approximately 25oC to 75oC, preferably about 50oC.

Or otherwise, the recovery performed by sodium borohydride in proton solvent such as methanol or ethanol, or a mixture of alkanols and other organic solvents, such as dichloromethane or chloroform at a temperature of from about 0oC to 80oC, preferably about 50oC, which leads to hydrocelectomy formula IV.

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The connection f is islote, such as triperoxonane acid, getting a lactam of the formula V.

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Usually, the reaction is carried out in an organic solvent, such as dichloromethane, at a temperature of from about 0oC to 25oC.

Or otherwise, the compound of formula II can be successfully treated with sodium borohydride and acetic acid, which gives the primary amine of the formula VII.

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The reaction is usually performed in alcohol and water, preferably 6:1 isopropanol/water, at a temperature of from about 20oC to 80oC.

Compound of formula VII interacts with an organic acid chloride acid, giving the compound of formula VIII

< / BR>
in which R2is as defined above.

The reaction is typically performed in an aprotic organic solvent such as dichloromethane, in the presence of an acid acceptor such as a tertiary amine, e.g. triethylamine, at a temperature of approximately from 0oC to 30oC, preferably about 20oC.

The compound of formula VIII next acelerou other organic acid chloride in the above-described conditions with a compound of the formula I, in which R1is not hydrogen.

< / BR>
The sulfoxidov and sulfonates (for example, as described in US-A-5.240.927.

The parent compound of A formula known in the art, for example, methods of obtaining and references included in US-A-5.240.927 and following links.

The compounds of this invention are useful in the treatment of psychosis due to their ability to cause protivopsychoticheskogo reaction in mammals. Protivopsychoticheskogo activity determined by testing excited (tree-climbing) mice according to the method similar to that described P. Protais et al., Psychopharmacol., 50:1 (1976) and B. Costall, Eur. Y. Pharmacol., 50:39 (1978).

Used for trials of CK-1 male mice (23-27 g) were group rehabilitation in standard laboratory conditions. Mice are individually placed in cages of metal rods (4" x 10") and give one hour of adaptation and habituation to a new environment. Then injected subcutaneous apomorphine in the amount of 1.5 mg/kg, a dose which causes excitation (climbing) in all subjects mice after 30 minutes. Tested on protivopsychoticheskogo the potency of the compound injected intraperitoneally or given in the form of oral dosages at different time intervals, e.g. 30 minutes, 60 minutes, etc. before infection by apomorphine in protective dose of 10-60 mg/kg

To estimate the excitation are 3 raised the behavior of mice (climbing):

(without climbing)

4 paws on the bottom (not excited) - a 0

2 paws on the floor (rearing) - index 1

4 paws on the wall (full climbing) - index 2

Spontaneous climbing mice before injection of apomorphine is discarded.

Animals are completely dependent on apomorphine climbing hang on the walls of the cells quite motionless for a long period of time. In contrast, climbing only under the influence of a simple motor stimulation usually lasts only a few seconds.

Indicators lasagna counted individually (maximum rate: 6 on the mouse is over 3 readings) and the total score of the control group (solvent intraperitoneally-apomorphine subcutaneously) is taken for 100%. Percentage response at the dose of 20 mg/kg or ED50values with 95% confidence level, the calculated linear regression analysis, for some compounds of the present invention, as well as for standard protivopsychoticheskogo means presented in table 1.

Protivopsychoticheskogo reaction is achieved when the compounds of this invention are introduced to a patient requiring such treatment as an effective personalbanking patient requires specific medication, developed in accordance with individual need and the professional assessment of personal introduction or controlling the introduction of the above compounds. It should also be clear that the above doses are examples only and they do not limit in any way the volume or application of the present invention. Effective amounts of compounds of this invention can be administered to a patient by any of the usual ways, e.g. orally, in the form of capsules or tablets, parenterally in the form of sterile solutions or suspensions, and in some cases intravenously in the form of sterile solutions.

The compounds of this invention, while effective themselves, may be formulated and introduced in the form of their pharmaceutically acceptable acid salts of the merger for purposes of stability, convenience of crystallization, increased solubility and the like. Preferred pharmaceutically acceptable salt of joining include salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, and the like, as well as organic acids such as salts of dibasic carboxylic acids such as maleic acid, fumaric Ki is one.

Effective amounts of compounds of this invention can be administered orally, for example, with an inert diluent or edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For oral therapeutic injection of the compounds of the invention can be combined with excipients and used in the form of tablets, lozenges, capsules, Alexiou, suspensions, syrups, wafers, chewing gums and the like. These preparations should contain at least 0.5% of the active compounds of the invention.

Tablets, pills, capsules, wafers, and the like may also contain the following ingredients: a binder such as microcrystalline cellulose, gameday tragakant or gelatin, excipient, such as starch or lactose, a disconnector, such as aginova acid. Primogel, corn starch and the like: a lubricating substance, such as magnesium stearate or Sterotes, substances that cause the slide, such as colloidal silicon dioxide, sweeteners such as sucrose or saccharin, or corrigent, such as peppermint, methyl salicylate or orange corrigent. When the dosage is made in the form of capsules and other dosage unit forms may contain a variety of substances, modifying the physical form of the dosage unit, for example, such as coating. Thus, tablets or pills may be coated with sugar, gelatin or other substances forming intersolubility shell. A syrup may contain, in addition to the active compounds, sucrose as a sweetener and certain preservatives, dyes and corrigentov. The materials used in obtaining these various compositions should be pharmaceutically pure and non-toxic in the quantities used. In order parenterale therapeutic introduction of the active compounds of this invention can be incorporated into a solution or suspension. These preparations should contain at least 0.1% of active compound, but their content may vary from about 0.5 to 50% by weight. The number of active compounds in such compositions is an amount required to obtain the appropriate dose. Preferred compositions and preparations according to this invention are prepared so that a standard parenteral dose contains from 0.5 to 100 mg of active compound.

The solutions or suspensions may also include the following components: a sterile solvent, such kineticheskie solvents, antibacterial agents such as benzyl alcohol or methyl parabens, antioxidants such as ascorbic acid or bisulphite: chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates, and means for toning, such as sodium chloride or dextrose. The parenteral preparation can be enclosed in ampoules, disposable syringes or vials containing multiple dose glass or plastic.

The following examples are illustrative and are not limiting of the invention. Unless otherwise noted, all temperatures are given in degrees Celsius (oC).

Example 1

6-Chloro-3-piperazines[b]thiophene-1,1-dioxide

A mixture of 3,6-dichlorobenzo[b]thiophene-1,1-dioxide (16,00 g, 0,0681 mol), piperazine (to 20.52 g, 0,238 mol) and dichloromethane (300 ml) heated at boiling temperature under reflux. After 1 hour, TLC analysis shows that dichloromethan spent (Rf = 0.47, the 30% ethyl acetate in hexane, silica gel). The cloudy mixture was washed with a 0.25 N. NaOH (400 ml), H2O (300 ml), a solution of salt (250 ml), dried (Na2SO4) and remove the solvent under reduced pressure. The remainder chromatographic on silica gel, elewaut from a mixture of dichloromethane/diethyl ether, getting to 0.480 g of pale yellow crystals: I. pl. 154oC decomp.

Analysis

Calculated for C12H13ClN2O2: 50.61%C 4.60%H 9.84%N

Found: 50.43%C 4.59%H 9.73%N

Example 2

N-[2-[4-(6-Toranzo[b]Tien-3-yl)-1-piperazinil]ethyl]phthalimide

A mixture of N-(2-bromacil)phthalimide (8.5 g, 33,55 mmol), (6 toranzo[b] Tien-3-yl)-1-piperazine (6.6 g, 27,96 mmol), K2CO3(7,7 g and 55.8 mmol) and NaI (10 mg) in 150 ml dry CH3CN heated at 85oC under stirring in an atmosphere of N2. After 18 hours the mixture is cooled to room temperature, diluted with water and partitioned between EtOAc/H2O. the Organic phase is dried over MgSO4, filtered and concentrated in vacuo. The remaining solid orange product chromatographic on silica gel using 2:1 heptane: EtOAc eluent, giving 11,30 g crude product, (25.18 mmol, 90,07%) homogeneous by TLC (silica, 1:1 heptane:EtOAc, Rf = 0.20). This crude product is recrystallized from a mixture of heptane: EtOAc, receiving primary product to 3.92 g (9,58 mmol, 34,38%) as a white solid, So pl. 147-149, homogeneous by TLC.

Analysis:

Calculated for C22H20FN3O2S: 64.53%C 4.92%H 10.26%N

Found: 64.39%C 4.77%H 10.25%N

Example 3

2-[2-[4-(6-Toranzo[b] Tien-3-b]Tien-3-yl)-1 - piperazinil]ethyl]phthalimide (2.7 g, 6.6 mmol) in a mixture of 200 ml of absolute EtOH and 50 ml of CH2Cl2in an atmosphere of N2add sodium borohydride (0.56 g of 14.8 mmol) in one portion. The mixture is stirred at room temperature for 15 minutes, during this time, the solid product is dissolved. After 15 minutes, TLC, silica, 1:1 heptane: EtOAc shows no residual starting material and is manifested main spot with a lower Rf.

The solution was concentrated in vacuo to a solid state, and the product is filtered through a layer of silica gel, using EtOAc eluent. The filtrate is concentrated to a yellowish solid product. This crude product is triturated with EtOAc, and the resulting solid product is collected and dried in vacuum. This provides the primary collection of pure product, 1.56 g (3,79 mmol, 57,50%), So pl. 188-190o.

Analysis:

Calculated for C22H22FN3O2S: 64.21%C 5.39%H 10.21%N

Found 63.95%C 5.19%H 10.03%N

Example 4

2-[4-[4-(6-Toranzo[b] Tien-3-yl)-1-piperazinil] butyl] -1H-isoindole-1,3(2H)-dione

A mixture of 1-(6-toranzo[b] Tien-3-yl)piperazine (20,0 g, and 84.6 mmol), N-(4-bromobutyl)phthalimide (26,3 g, 93,2 mmol), anhydrous potassium carbonate (17.5 g, 127 mmol), KI (1.40 g, 8,43 mmol) and anhydrous acetonitrile (500 ml) is stirred, storymy product is washed with chloroform (2 x 100 ml), and the filtrate concentrated in vacuo. The residue is dissolved in chloroform (400 ml), washed with water (200 ml) and dried (MgSO4). The solvent is removed in vacuum and the product chromatographic on silica gel with 20% heptane/ethyl acetate as eluent, receiving, and 25.8 g of yellow solid. Recrystallization from diethyl ether gives 10,9 g (29%) named in the title compound as a yellow powder: So pl. = 94-95oC.

Analysis:

Calculated for C24H24FN3O2S: AT 65.88%C 5.53%H 9.60%N

Found: 65.82%C 5.80%H 9.54%N

Example 5

4-(6-Toranzo[b]Tien-3-yl)-1-piperazineethanol (Z)-2-butenedioate (1:2)

To stir the mixture 2-[4-[4-(6-toranzo[b]Tien-3-yl)-1-piperazinil] butyl] -1H-isoindole-1,3(2H)-dione (14.5 g, up 33.1 mmol) and 6:1 isopropanol/water (170 ml) at room temperature under nitrogen atmosphere add sodium borohydride (6,28 g, 166 mmol). After 25 hours carefully add acetic acid (35,7 g, 594 mmol). After stirring the mixture for 0.5 hours at room temperature the reaction mixture is heated at 80oC 3 hours. The reaction mixture was concentrated in vacuo to a yellow residue, which was dissolved in water (300 ml) and extracted with diethyl ether (150 ml). The aqueous layer was cooled to 0oC, the solution delayt water (100 ml), dried (K2CO3) and concentrated in vacuo, getting 9.60 g of a viscous solid product. Maleic acid (7,00 g of 60.3 mmol) are added to a solution of the crude free base (9.28 are g, 30.2 mmol) in ethanol (300 ml) and the mixture is heated to obtain a solution. The solvent is removed in vacuum, obtaining the crude salt orange-brown solid. After two precrystallization from ethanol 9,82 g (55%) named in the title compound obtained as not quite white powder, So pl. = 151-153oC.

Analysis:

Calculated for C16H22FN3S C8H8O8: 53.42%C 5.60%H 7.79%N

Found: 53.72%C 5.82%H 7.74%N

Example 6

N-[4-[4-(6-Toranzo[b]Tien-3-yl)-1-piperazinil]butyl]ndimethylacetamide

FOR 0oC to a solution of 4-(6-toranzo[b]Tien-3-yl)-1-piperazinecarboxamide (3.13 g, 10.2 mmol), triethylamine (1.45 g, and 14.3 mmol) and dichloromethane (60 ml) under nitrogen atmosphere add quickly acetylchloride (0,883 g, 11.3 mmol). The reaction mixture was stirred at 0oC for 2 hours and then further at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (140 ml), washed with 5% aqueous NaOH (100 ml) and dried (K2CO3). The solvent is removed in vacuum, obtaining a brown solid Eisney solid product. Recrystallization from ethyl acetate gives 1.85 g (52%) named in the title compound as beige crystals: I. pl. = 141-142oC.

Analysis:

Calculated for C18H24FN3OS: 61.86%C 6.92%H 12.02%N

Found: 61.82%C 7.01%H 11.95%N

Example 7

N-Acetyl-N-[4-[4-(6-toranzo[b] Tien-3-yl)-1-piperazinil] butyl] -2-methyl-propanamide

The solution isobutyryl chloride (2,34 g, 21.9 mmol) in dry dichloromethane (8 ml) is added over 2 minutes to a solution of N-[4-[4-(6-toranzo[b]Tien-3-yl)-1-piperazinil]butyl]ndimethylacetamide (of 2.51 g, 7,18 mmol), triethylamine (2,18 g, 21.5 mmol), 4-dimethylaminopyridine (0,877 g, 7,18 mmol) and dry dichloromethane (50 ml) at room temperature under nitrogen atmosphere. After 2.5 hours the reaction solution was diluted with dichloromethane (100 ml), washed with water (75 ml), dried over MgSO4and concentrated in vacuo. The remainder chromatographic on silica gel using 5% methanol/dichloromethane as eluent, giving only 2.91 g of an amber solid product.

Recrystallization from tert-butyl methyl ether/heptane gives 1.52 g (50%) named in the title compound as tan crystals: I. pl. = 98-99oC.

Analysis:

Calculated for C22H30FN3O2S: 62.98%C 7.21%H 10.02%N

FOR 0oC to a solution of 4-(6-toranzo[b]Tien-3-yl)-1-piperazine-butanamide (Android 4.04 g of 13.1 mmol), triethylamine (1.89 g, to 18.6 mmol) and dichloromethane (50 ml) under nitrogen atmosphere add isobutyryl chloride (1.63 g, and 15.3 mmol) in 6 minutes. The reaction mixture was stirred at 0oC 4 hours and then diluted with dichloromethane (140 ml). The mixture is successively washed with 5% aqueous NaOH (100 ml) and water (100 ml), dried (K2CO3) and concentrated in vacuo, obtaining off-white solid product. The crude product is cleaned chromatography on silica gel using 10% methanol/dichloromethane as eluent, obtaining off-white solid product. Recrystallization from a mixture of acetate/heptane gives 2.17 g (43%) named in the title compound as a beige needle-shaped crystals: I. pl. 130-131oC. TLC (silica gel, 10% methanol/dichloromethane) Rf = 0,37. IR (CHCl3),1H NMR (CDCl3, 200 MHz) and MS (M+377, EI, 70 eV) confirm the proposed structure.

Analysis:

Calculated for C20H28FN3OS: 63.63%C 7.48%H 11.13%N

Found: 63.65%C 7.59%H 11.00%N

Example 9

1-(6-Chlorobenzo[b]Tien-3-yl)piperazine

To a solution of 6-chloro-3-piperazinil-benzo[b] thiophene-1,1-dioxane (6.0 g) and tetrahydrofuran (THF) (30 ml) under nitrogen atmosphere add dissolve the ect stirred at 0oC 2 hours, then overnight at room temperature. To the yellow solution is added, with vigorous stirring, water (5 ml) at such a rate as to control the release of hydrogen. Then added with vigorous stirring, 5 N. NaOH (5 ml). The precipitate is filtered and washed with dichloromethane and diethyl ether. The filtrate was concentrated in vacuo. The residue is dissolved in dichloromethane (150 ml), washed with water (75 ml) and salt solution (100 ml), dried over sodium sulfate and concentrated in vacuo, getting to 5.93 g of a viscous resinous substance, which is triturated with diethyl ether. The diethyl ether fraction was concentrated in vacuo, getting to 2.75 g of residue, which chromatographic (silica gel, 50% MeOH/CH2Cl2), receiving of 1.53 g of the product as a clear oil.

Example 10

N-[4-[4-(6-Toranzo[b]Tien-3-yl)-1-piperazinil]butyl]-4-perbenzoic

FOR 0oto a solution of 4-(6-toranzo[b]Tien-3-yl)-1-piperazine-butanamine (2,45 g, 7,97 mil), triethylamine (1.23 g, 12.2 mmol) and dichloromethane (30 ml) under nitrogen atmosphere add 4-perbenzoic chloride (1,61 g, 10.2 mmol) in one portion. The reaction mixture was stirred at 0oC for 70 minutes and then at room temperature for 3 hours. The reaction mixtureSO4) and concentrated in vacuo to a tan solid product. The crude product chromatographic on silica gel with 10% ethanol/dichloromethane as eluent, giving 2,22 g not quite white solid. Recrystallization from a mixture of ethyl acetate/heptane gives 1,60 g (46%) named in the title compound as a beige needle-shaped crystals. So pl. 161-163oC.

Analysis:

Calculated for C23H25F2N3OS: 64.32%C 5.87%H 9.78%N

Found: 64.15%C 5.68%H 9.50%N

Example 11

4-(6-toranzo[b]Tien-3-yl)-1-[4-(isoindole-2-yl)butyl]piperazine

To a stirred suspension of LiAlH4(1.50 g, of 37.9 mmol) in anhydrous tetrahydrofuran (100 ml) under nitrogen atmosphere at room temperature is added dropwise a solution of 2-[4-[4-(6-toranzo[b]Tien-3 - yl)-1-piperazinil]butyl]-1H-isoindole-1,3(2H)-dione (5,95 g of 13.6 mmol) in anhydrous tetrahydrofuran (125 ml) for 20 minutes. After the addition, the reaction mixture was stirred at 50oC 4 hours and then cooled to room temperature. The reaction mixture was treated sequentially with water (1.5 ml), 15% NaOH (1.5 ml) and water (4.5 ml) and stirred at room temperature for 0.5 hour. The mixture is filtered, the insoluble products are washed with CHCl3(2 x 50 ml), and the filtrate is ) and the solvent is removed in vacuum. The crude product chromatographic on silica gel with 10% methanol in dichloromethane as eluent, obtaining 3.5 g of reddish-brown solid product. The solid product is recrystallized twice from ethyl acetate, receiving 1.48 g (26%) named in the title compound in the form of amber crystals, So pl. 118-120oC.

Analysis:

Calculated for C24H28FN3S: 70.38%C 6.89%H 10.26%N

Found: 70.52%C 7.04%H 10.18%N

Example 12

N-[4-[4-(6-Toranzo[b] Tien-3-yl)-1-piperazinil] butyl] adamantane-1 - carboxamide maleate

FOR 0oC to a solution of 4-(6-toranzo[b]Tien-3-yl)-1-piperazine-butanamine (2.50 g, 8,13 mmol), triethylamine (1.23 g, 12.2 mmol), and dichloromethane (50 ml) under nitrogen atmosphere add a solution of 1-adamantanecarbonyl chloride (2.00 g, 10.1 mmol) in dichloromethane (25 ml) quickly. The reaction mixture was stirred at 0oC for 45 minutes and then 18 hours at room temperature. The reaction solution was diluted with dichloromethane (75 ml) and washed sequentially with 5% aqueous NaOH (75 ml) and water (75 ml), dried (Na2SO4) and concentrated in vacuo. The crude product chromatographic on silica gel, 2-10% of a mixture of methanol/dichloromethane as eluent, getting 2.86 g not quite white solid product. To a solution of free what about a solution and give salt to crystallize at room temperature. Salt is collected and recrystallized from methanol/ethyl acetate, receiving of 1.93 g (38%) named in the title compound in the form of not quite white powder, So pl. 200-201oC (decomp.).

Analysis:

Calculated for C27H36FN3OS C4H4O4: 63.57%C 6.88%H 7.17%N

Found: 63.36%C 7.02%H 7.12%N

Example 13

N-[4-[4-(6-Toranzo[b] Tien-3-yl)-1-piperazinil] butyl]-2-thiophencarboxylic (Z)-2-butenedioate (1:1)

FOR 0oC to a solution of 4-(6-toranzo[b]Tien-3-yl)-1-piperazine-butanamine (2.50 g, 8,13 mmol), triethylamine (1.23 g, 12.2 mmol) and dichloromethane (150 ml) under nitrogen atmosphere is added 2-thiophencarboxylic chloride (1,37 g, 9,34 mmol) in one portion. The reaction mixture was stirred at 0oC for 10 minutes and then at room temperature for 17 hours. The reaction mixture is washed successively with 5% aqueous NaOH (75 ml) and water (75 ml), dried (Na2SO4) and concentrated in vacuo. The crude product chromatographic on silica gel, 3-12% ethanol in chloroform as eluent, giving 2.66 g of solid product. To a solution of free base (2.50 g, of 5.99 mmol) in ethanol (25 ml) was added maleic acid (at 0.730 g of 6.29 mmol), the mixture is heated to obtain a solution and the solvent is removed in vacuum. Salt paracrystal osca. So pl. 123-126oC.

Analysis:

Calculated for C21H24FN3OS2C4H4O4: AT 56.27%C 5.29%H 7.87%N

Found: 56.06%C 5.48%H 7.81%N

Example 14

4-(6-Toranzo[b] Tien-3-yl)-1-piperazineethanol (Z)-2-butenedioate (1: 1)

A mixture of 1-(6-toranzo[b] Tien-3-yl)piperazine (25,0 g, 0,106 mol), 4-bromuconazole (18,8 g to 0.127 mmol), anhydrous potassium carbonate (21,9 g, 0,158 mol) and anhydrous acetonitrile (250 ml), stirred under heating up to the boiling temperature under reflux for 5.5 hours. The thick suspension was filtered, the insoluble products was washed with dichloromethane (2 x 50 ml) and the filtrate concentrated in vacuo. The residue is dissolved in dichloromethane (300 ml), washed sequentially with 5% aqueous NaOH (150 ml) and water (150 ml) and dried (Na2SO4). The solvent is removed in vacuum and the crude product chromatographic on silica gel with ethyl acetate as eluent, getting 24,3 g (75%) yellow solid.

To a solution of free base (2,03 g, 6,69 mmol) in ethanol added maleic acid (815 mg, 7.02 mmol) and the resulting mixture is heated to obtain a solution. After removal of the solvent in vacuum, the obtained salt is recrystallized from ethanol, getting 2,30 g called on C16H18FN3S C4H4O4: 57.27%C 5.29%H 10.02%N

Found: 57.27%C 5.19%H 9.98%N

Example 15

4-(6-Toranzo[b] Tien-3-yl)-1-[4-(isoindole-2-yl)butyl]piperazine (Z)-2-butenedioate (1:2)

THE 63oC to a solution of 4-(6-toranzo[b]Tien-3-yl)-1-[4-(isoindole - 2-yl)butyl] piperazine (1,09 g of 2.66 mmol) in ethanol (40 ml) was added maleic acid (0,633 g, the 5.45 mmol) and the resulting solution was concentrated in vacuo to a dark foam. Rubbing foam with ethanol/ethyl acetate to give a grey powder. Salt is treated with bleaching with activated charcoal and recrystallized from ethanol, getting 1,08 g (63%) named in the title compound as a gray powder. So pl. 153 to 155oC.

Analysis:

Calculated for C24H28FN3S 2C4H4O4: 59.89%C 5.65%H 6.55%N

Found: 59.80%C 5.74%H 6.53%N

Example 16

N-[4-[4-(6-Toranzo[b] Tien-3-yl)-1-piperazinil] butyl] -2-hydroxy-2-methylpropanamide (Z)-2-butenedioate (1:1)

To a solution of 2-hydroxyisovaleric acid (1,30 g, 12.5 mmol), pyridine (2.20 ml of 27.2 mmol), DMAP (190 mg, 1.56 mmol) and dichloromethane (60 ml) at ambient temperature under nitrogen atmosphere add chlorotrimethylsilane (3,40 ml, 26.8 mmol), dropwise, over 3 minutes. After 4 hours the reaction mixture was cooled to 0oC and catalinita (1.20 ml, 13.7 mmol). The reaction mixture was stirred at 0oC and then for 1 hour at room temperature for 30 minutes. The reaction mixture was cooled to 0oC and added in one portion a solution of 4-(6-toranzo[b]Tien-3-yl)-1-piperazine-butanamine (3.50 g, to 11.4 mmol), pyridine (3,30 ml of 40.8 mmol) and dichloromethane (40 ml). After 35 minutes at 0oC, the reaction mixture was stirred at room temperature for 18 hours. Add the citric acid solution (4,60 g of 23.9 mmol) and methanol (50 ml) and the reaction mixture was stirred at room temperature for 50 minutes. After removal of the solvent in vacuo the residue is dissolved in dichloromethane (125 ml), sequentially washed with 5% aqueous NaOH (100 ml) and water (100 ml), dried (K2CO3). The solvent is removed in vacuo and the resulting brown liquid chromatographic on silica gel with 5% methanol in dichloromethane as eluent, giving a 2.36 g of resin.

The free base (2,10 g of 5.34 mmol) was dissolved in ethanol (50 ml), filtered and to the filtrate is added maleic acid (650 mg, the ceiling of 5.60 mmol). The resulting mixture is heated to obtain a solution and the solvent is removed in vacuum, obtaining an orange solid product. The salt is recrystallized again from methanol/ethyl CLASS="ptx2">

Analysis:

Calculated for C20H28FN3S C4H4O4: 56.57%C 6.33%H 8.25%N

Found: 56.12%C 6.30%H 8.20%N

Example 17

N-[4-[4-(6-Toranzo[b]Tien-3-yl)-1-piperazinil]butyl]- 4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamid (Z)-2-butenedioate (1:1)

To a mixture of 4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid (2,60 g, 9,77 mmol), catalytic DMF and anhydrous dichloromethane (30 ml) at room temperature under nitrogen atmosphere add oxalyl chloride (1,38 g, 10.9 mmol) dropwise over 15 minutes and the reaction mixture was stirred at room temperature. After 18 hours the yellow reaction solution was concentrated in vacuo, obtaining of 2.51 g of 4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carbonyl chloride in the form of a turbid yellow fluid, which is used without further purification.

FOR 0oC to a solution of 4-(6-toranzo[b]Tien-3-yl)-1-piperazinecarboxamide (2.50 g, 8,13 mmol), triethylamine (1.31 g, 12.9 mmol) and dichloromethane (75 ml) under nitrogen atmosphere add a solution of 4'-(trifluoromethyl)-[1,1-biphenyl]-2-carbonyl chloride (of 2.51 g, 8,82 mmol) and dichloromethane (25 ml) in one portion. The reaction mixture was stirred at 0oC for 0.5 hour and then at room temperature for 21.5 hours. The reaction mixture is washed successively with 5% aqueous NaOH (75 m is barely 5% dichloromethane as eluent, getting 3,29 g of the product as a white foam.

To a solution of free base (2,99 g, 5,38 mmol) in ethanol (50 ml) was added maleic acid (0,656 g, the 5.65 mmol) and the resulting solution was concentrated in vacuo. The salt is recrystallized from ethyl acetate, getting to 2.57 g (47%) named in the title compound as a white powder, So pl. 158-160oC.

Analysis:

Calculated for C30H29F4N3O C4H4O4: 60.80%C, 4.95%H, 6.26%N

Found: 60.52%C 5.06%H 6.15%N

Example 18

N-[4-[4-(6-Toranzo[b] Tien-3-yl)-1-piperazinil] butyl]benzo[b]thiophene-2-carboxamid (Z)-2-butenedioate (1:1)

To the solution at 0oC 4-(6-toranzo[b]Tien-3-yl)-1 - piperazinecarboxamide (2.50 g, 8,13 mmol), triethylamine (1.24 g, 12.2 mmol) and dry dichloromethane (100 ml) under nitrogen atmosphere is added dropwise benzo[b]thiophene-2-carbonyl chloride (1,76 g of 8.95 mmol) for 15 minutes. Stirring is continued at 0oC for 1.5 hours and 17.5 hours at room temperature. The reaction mixture was then washed sequentially with 5% aqueous NaOH (75 ml) and water (75 ml), dried (Na2SO4) and concentrated dichloromethane as eluent, getting to 3.34 g of a white product.

To a solution of free base (is 3.08 g, 6,59 mmol) in boiling methanol (300 solid product. The salt is recrystallized from methanol/ethyl acetate, receiving of 3.07 g (64%) named in the title compound as white crystals. So pl. 133-135oC.

Analysis:

Calculated for C25H26FN3S2C4H4O4: 59.67%C 5.18%H 7.20%N

Found: 59.60%C 5.13%H 7.24%N

It should be understood that the description and examples above are for illustration and not limitation, and that can be implemented with various modifications and changes without going beyond the scope of this description of the invention, as defined by the attached items.

1. Substituted benzothiadiazine General formula I

< / BR>
in which X represents hydrogen or halogen;

Y represents-CN or-NR1R2,

where l denotes an integer of 1 or 2;

m denotes an integer of 0, 1 or 2;

n denotes an integer equal to 2, 3 or 4, except for the case when Y is CN, then n can be equal to 1;

R1denotes hydrogen, (C1-C6)alkyl or (C1-C6)alkylsulphonyl, (C3-C12)cycloalkylcarbonyl, hydroxy(C1-C6)alkylsulphonyl, phenylcarbinol, possibly substituted with halogen or cryptomaterial, thienylboronic or

where a denotes C=0 or CH2;

In stands WITH a=0, SNON, CH2or CH2CH2;

Z denotes hydrogen,

and their pharmaceutically acceptable additive salt of the acid, with the proviso that when X=N, n can be 4, and R1, R2cannot be both hydrogen.

2. The compounds of formula I under item 1, in which X represents halogen, Y represents-CN or-NR1R2where l is an integer 1, m is an integer 0 or 2, n is an integer 2, 3 or 4, R1is hydrogen or (C1-C6)alkylsulphonyl, R2- as defined in paragraph 1, or R1and R2together with the nitrogen to which they are bound, form a loop

< / BR>
where a and b are as defined in paragraph 1, and their pharmaceutically acceptable additive salt of the acid.

3. Connection under item 1 or 2, where X represents halogen, Y represents - NR1R2, 1 integer 1, m is 0 or 2, n is 2, 3 or 4, R1denotes hydrogen or (C1-C6)alkylaryl, and R2denotes hydrogen, (C1-C10)alkylsulphonyl, (C3-C12)cycloalkylcarbonyl, hydroxy(C1-C6)alkylsulphonyl, thienylboronic or benzotriazolyl, and pharmaceutically acceptable additive salt of the acid.

4. Connection PP.1 to 3, where X about the location or acetyl, and R2denotes hydrogen, isopropylcarbonate, adamantylidene, 4-fortuneserver, 2-thienylboronic, 2-benzotriazolyl, 2-hydroxy-2-methyl-ethylcarboxyl or 2-[4-(trifluoromethyl)1,1-biphenyl].

6. Connection to any one of the preceding paragraphs, selected from 4-(6-toranzo [ -] Tien-3-yl)-1-piperazineethanol (Z)-2-butenedioate, N-[4-[4-(6-toranzo[in] Tien-3-yl)-1-piperazinil] butyl - ndimethylacetamide, N-acetyl-N-[4-[4-(6-toranzo[in] Tien-3-yl)-1-piperazinil] butyl] -2-methyl-propanamide, N-[4-[4-(6-toranzo[in] Tien-3-yl)-1-piperazinil[butyl] -2-methyl-propanamide, N-[4-[4-(6-toranzo[in] Tien-3-yl)-1-piperazinil] butyl] -4-perbenzoic, N - N-[4-[4-(6-toranzo[in] Tien-3-yl)-1-piperazinil] butyl]-adamantane-1-carboxamide maleate, N-[4-[4-(6-toranzo[in]Tien-3-yl)-1-piperazinil]butyl]-2-thiophencarboxylic(Z)-2-butenedioate, N-[4-[4-(6-toranzo[in]Tien-3-yl)-1-piperazinil] butyl] -2-hydroxy-2-methyl-propanamide (Z)-2-butenedioate, N-[4-[4-(6-toranzo[in] Tien-3-yl)-1-piperazinil] butyl]-4-(trifluoromethyl)-[1.1-biphenyl] -2-carboxamid (Z)-2-butenedioate and N-[4-[4-(6-toranzo[in]Tien-3-yl)-1-piperazinil]butyl]-benzo[b]thiophene-2-carboxamid (Z)-2-butenedioate.

7. Connection under item 1 or 2, where X is halogen - refers to a group

< / BR>
I - 1;

m is 0 or 2;

n is 2, 3 or 4;

And RA is by the acid salt of the merger.

8. Connection on p. 7, in which X denotes a halogen, m is 0 and n is 4.

9. Connection on p. 7 or 8, where X is 6-F, m is 0, n is equal to 4, And equal to C=O or CH2and indicates C=O, SNON or CH2.

10. Connection to any one of paragraphs.1, 2, 7, 8 or 9, which are selected from N-[2-[4-(6-toranzo[in] Tien-3-yl)-1-piperazinil]-ethyl]-phthalimide, 2-[2-[4-(6-toranzo[in] Tien-3-yl)-1-piperazinil] -ethyl]-2,3-dihydro-3-hydroxy-1H-isoindole-1-he, 2-[2-[4-(6-toranzo[in]Tien-3-yl)-1-piperazinil]-butyl]-1H-isoindole-1,3(2H)-dione, 4-(6-toranzo[in] Tien-3-yl)-1-[4-(isoindole-2-yl)-butyl] piperazine and 4-(6-toranzo[in]Tien-3-yl)-1-[4-(isoindole-2-yl)-butyl]piperazine (Z)-2-butenedioate.

11. Connection under item 1 or 2, which is 4-(6-toranzo[in]Tien-3-yl)-1-piperazineethanol (Z)-2-butenedioate.

12. The compounds of formula I according to any one of the preceding paragraphs, with protivopsychoticheskogo activity.

13. Protivopsychoticheskogo pharmaceutical composition that includes a pharmaceutically acceptable carrier and an active ingredient, wherein the active ingredient contains a pharmaceutically effective amount of a compound according to any one of the preceding paragraphs.

Nachine, Y represents a group NR1R2where R1and R2together with the nitrogen atom to which they are bound, form a loop

< / BR>
where a, b and Z are specified in paragraph 1 values, wherein interact the compounds of formula II

< / BR>
where X, Z and integers l, m and n are such as defined in paragraph 1,

subjected to interaction with a suitable regenerating agent in an organic solvent to form the compounds of formula III

< / BR>
or the compounds of formula IV

< / BR>
and, optionally, restore the connection of the formula IV with the formation of the compounds of formula V

< / BR>
15. The method of obtaining substituted benzothiadiazine General formula I on p. 1, where X, l, m, n are specified in paragraph 1 values, refers to the group NR1R2where R1denotes hydrogen, (C1-C6)alkyl or (C1-C6)alkylsulphonyl, R2denotes hydrogen, (C1-C10)alkylsulphonyl, (C3-C12)cycloalkylcarbonyl, hydroxy(C1-C6)alkylsulphonyl, phenylcarbinol, possibly substituted with halogen or cryptomaterial, thienylboronic or benzotriazolyl, wherein interact the compounds of formula II, as defined by the I

< / BR>
and, optionally, the compound of formula VII is subjected to interaction with an organic acid chloride with the formation of compound VIII

< / BR>
where R2defined in paragraph 1.

 

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