Thienobenzodiazepine or their pharmaceutically acceptable salts, method of production thereof and pharmaceutical composition

 

(57) Abstract:

The proposed pharmaceutical compounds that have useful activity against the Central system of formulas (I), where R1is hydrogen or halogen, R2- C1-10alkyl, C2-10alkenyl, C2-10quinil, C3-6cycloalkyl, C1-14alkyl or phenyl C1-4alkyl or their pharmaceutically acceptable salts. The proposed pharmaceutical composition based on compounds of formula (I), which has activity against receptor dopamine L-1. Method for obtaining compounds on p. 1 consists in the fact that the compound of formula (II), where the values of R1above, is subjected to alkylation with compounds of General formula R2X, where the value of R2above, X is the group to delete.

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3 s and 5 C.p. f-crystals.

The invention relates to new thienobenzodiazepine, method of production thereof and to pharmaceutical compositions based on them, and may find application in medicine.

It is known that some thienobenzodiazepine derivative used in the treatment of disorders of the Central nervous system. They are described, for example, in the United Kingdom patent 1533235 and in the European patent 045443 is no hydrogen or halogen;

R2represents C1-10alkyl, C2-10alkenyl, C2-10quinil, C3-6cycloalkyl, C1-4alkyl or phenyl C1-4alkyl,

or in the form of their pharmaceutically acceptable salts.

A specific group of compounds of General formula (I) are compounds where R2represents C1-4alkyl, C2-4alkenyl, C2-4quinil, C3-6cycloalkyl, C1-4alkyl or phenyl C1-4alkyl.

The following preferred group of compounds of General formula I are compounds where R2represents C3-10alkyl, C3-10alkenyl or C3-10quinil.

More preferably, when R1denotes hydrogen.

Even more preferably, when R1denotes hydrogen and R2represents C3-8alkyl.

Thienobenzodiazepine General formula (I) active in the experimental selection in the study of their action on the Central nervous system, namely, they possess activity against receptor dopamine D-1.

Thus, the proposed compounds have useful properties that can be used in the treatment of a wide range of diseases of the Central nervous system.

The invention including the General formulas II

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where the values of R1above,

subjected to alkylation with compounds of General formula

R2X,

where the values of R2specified above;

X denotes a group to delete.

The reaction can be carried out in accordance with well known methods, X can be, for example, halogen, especially chlorine or bromine, or C1-4-alkylsulfonates, as well as the appropriate base, such as n-utility or sodium hydride. The reaction temperature is preferably from -70oC to +80oC, and uses an organic solvent, such as tetrahydrofuran or dimethylformamide.

Alkylating agents of the formula R2X are well known, and the compound of formula (II) can be obtained according to the method described in UK patent 1533235 and European patent 0454436.

As indicated above, the compounds according to the invention have useful activity against Central nervous system. This activity was determined by the models using well-known techniques. For example, the compounds exhibit activity in in vitro tests, binding, intended to measure the extent of binding of receptor neurons is less than 1 μm in the study of binding in3H-SCH 23390 (Billard, et. al. Life Sciences 35 1885 (1984). Compounds have antimuskarinovoe act occurs-anticholinergic activity.

In addition, compounds active against serotonin receptors. For example, some of the compounds in which R1is hydrogen, and R2is C3-8-alkyl, C3-10-alkenyl or C3-10-quinil in the formula (I) above, and especially C3-4-alkyl and especially propylene or isopropyl, exhibit high activity against 5-HT3receptors, which are determined according to the method described by Wong D. T. et.al., European Journal of Pharmacology, 166 (1989) 107-110. They also have some selectivity for these receptors compared with 5-HT1and 5-HT2the receptors.

The compounds are also active in the standard in vivo tests on determination of antipsychotic activity. They suppress induced by apomorphine excited state in mice (Moore. N. A. et. al. Psychopharmacology 94 (2), 263 - 266 (1988) and 96 539 (1988). The compounds also inhibit the conditional effect of avoidance in rats.

These tests show that the compounds are potential neiroleptikami with relaxing, relieving anxiety Sofronitsky disease and acute manic state. Low doses of compounds can be used in the treatment of weak States of anxiety.

Moreover, preferred compounds exhibiting a high level of activity against 5-HT3the receptors can also be used to treat depression, memory loss, abnormal memory loss, migraines, pain and drug dependence, such as unwanted consumption of drugs-drugs such as alcohol, morphine, nicotine and haloperidol. They are also potentially useful in the treatment of anxiety, such as panic disorder and depression.

Compounds of the present invention are effective in a wide range of used doses and prescribed dose depends on the conditions of treatment. For example, in the treatment of adults dose of from 0.05 to 30 mg, preferably from 0.1 to 20 mg per day. A single dose per day is usually sufficient, although may be assigned separate doses. For the treatment of psychotic disorders dose ranging from 2 to 15 mg, preferably from 2.5 to 10 mg per day, is appropriate, and to treat conditions weak disturbance low doses, such as from 0.1 to 5 mg, preferably from 0.5 to 1 mg can bitto it is necessary to start with doses ranging from 2 to 15 mg per day, and when the disease is under control, be reduced to 0.5 to 1 mg per day.

Compounds according to the invention can be administered orally or by injection and used for this purpose usually in the form of pharmaceutical compositions.

Thus, the invention includes a pharmaceutical composition comprising as active ingredient a compound of formula I or its pharmaceutically acceptable salt accession, combined with a pharmaceutically acceptable carrier. To obtain the compositions of the present invention can be used well-known techniques for the preparation of pharmaceutical compositions. For example, the active ingredient may usually be mixed with a carrier, or diluted them, or can be placed inside carrier, which may be in the form of a capsule, sachet, paper or other container. In the case when the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a carrier of excipient or medium for the active ingredient. The active ingredient may be absorbed on a granular solid container, for example, the active ingredient may be in the sachet. Some examples of suitable nosey, tragakant, gelatin, purified syrup, methylcellulose, methyl - and propylhydroxybenzoate, talc, magnesium stearate or mineral oil. The compositions of the present invention can, if desired, be such as to ensure rapid release, hold, or slow release of the active ingredient after taking the medicine by the patient.

Depending on the method of taking the medicine, the composition can be made in the form of tablets, capsules, injectable solutions for parenteral use, suspensions or elixirs for oral administration or in the form of suppositories.

Preferably the compositions are in the form of a unit dose containing from 0.1 to 20 mg, more often from 0.5 to 10 mg of the active ingredient.

The preferred form according to the invention are capsules or tablets containing from 0.1 to 20 mg, or from 0.5 to 10 mg of active ingredient together with a pharmaceutically acceptable carrier. In addition, the preferred form according to the invention are injection, in which a single dose contains from 0.1 to 20 mg, or from 0.5 to 10 mg of active ingredient together with a pharmaceutically suitable diluent. The injectable form, which is inicia dosage preferably contains up to 100 mg.

The invention is illustrated by the following examples,

Example 1. 2,10-Dimethyl-4-(4-methyl-1-piperazinil)-10H-thieno [2,3-b] [1,5] -benzodiazepine. A solution of 2-methyl-4-(4-methyl-1-piperazinil)-10H-thieno [2,3-b] [1,5]-benzodiazepine (3.1 g) (Publication of the European Patent 04545436 in dry tetrahydrofuran (distilled over sodium/benzophenone) was stirred and cooled to -70oC. was added tetramethylethylenediamine (1,15 g) and then n-utility (6.25 ml, 1.6 M solution), while keeping the temperature below - 60oC. the Solution is a deep red color was stirred 15 min and then added iodomethyl (1.42 g). The reaction mixture was left to stand at room temperature for a time until there is no longer red. Added water and the product was extracted with ethyl acetate. The solvent was washed with water, dried and evaporated to dryness under reduced pressure. The product was purified by chromatography on Florisil using ethyl acetate as eluent, and crystallizability from acetonitrile to obtain specified in the connection header, so pl. 126 - 128oC. in a Similar manner from the same source of the product obtained: 10-Ethyl-2-methyl-4-(4-methyl-1-piperazinil)-10H-thieno (2,3-b) [1,5]-benzodiazepine, so pl. 125 - 127oC. 2-Methyl-4-(4-methyl-1-piperazinil)-10(prop-2-enyl)-no [2,3-b] [1,5] -benzodiazepine, so pl. 155 - 156oC. 10-Benzyl-2-methyl - 4-(4-methyl-1-piperazinil)-10H-thieno [2,3-b] [1,5]-benzodiazepine, so pl. 188 - 190oC (as hydrochloride) 10-Butyl-2-methyl-4- (4-methyl-1-piperazinil)-10H-thieno [2,3-b] [1,5] -benzodiazepine, so pl. 235 - 237oC (as hydrochloride). 2-Methyl-4-(4-methyl-1-piperazinil)- 10-(2-methylpropyl)-10H-thieno [2,3-b] [1,5]-benzodiazepine, so pl. 238 - 240oC (as hydrochloride). 2-Methyl-4-(4-methyl-1-piperazinil)- 10-pentyl-10H-thieno [2,3-b] [1,5]-benzodiazepine, so pl. 210 - 212oC (hydrochloride) 2-Methyl-4-(4-methyl-1-piperazinil)-10-octyl - 10H-thieno [2,3-b] [1,5]-benzodiazepine, so pl. 208 - 210oC (as hydrochloride)

Similarly, from 7-fluoro-2-methyl-4-(4-methyl-1-piperazinil)-10H-thieno [2,3-b] [1,5] -benzodiazepine (Patent UK N 1533235). 7-Fluoro-2,10-dimethyl-4-(4-methyl-1-piperazinil)-10H-thieno [2,3-b] [1,5]-benzodiazepine, so pl. 145 - 130oC. 10-Ethyl-7-fluoro - 2-methyl-4-(4-methyl-1-piperazinil)-10H-thieno [2,3-b] [1,5] -benzodiazepine, so pl. 128 - 130oC. 7-fluoro-2-methyl-4- (4-methyl-1-piperazinil)-10-propyl-10H-thieno [2,3-b] [1,5]-benzodiazepine, so pl. 67 - 70oC. 10-Cyclopropylmethyl-7-fluoro - 2-methyl-4-(4-methyl-1-piperazinil)-10H-thieno [2,3-b] [1,5]-benzodiazepine, so pl. 50 - 52oC. 7-fluoro-2-methyl-4- (4-methyl-1-piperazinil)-10-(prop-2-enyl)-10H-thieno [2,3-b] [1,5]-benzodiazepine, so pl. 108 - 111oC. 7-fluoro-2-methyl-4-(4-me the-1-piperazinil)-10H-thieno [2,3-b] [1,5]-benzodiazepine, so pl. 65 - 67oC.

Example 2. 2-Methyl-10-(1-methylethyl)-4-(4-methyl-1-piperazinil)- 10H-thieno [2,3-b] [1,5]-benzodiazepine. To a solution of 2-methyl-4-(4-methyl-1-piperazinil)-10H-thieno [2,3-b] [1,5]-benzodiazepine (3.12 g) in dry dimethylformamide (50 ml) was added sodium hydride (0,63 g, 50% dispersion). The reaction mixture was stirred 30 min at room temperature, then at 60 - 70oC. was Cooled to 40oC, was added isopropyl bromide (1.13 ml) and left for one hour. The reaction mass was diluted with water and extracted with ethyl acetate, the extract washed with water, dried and evaporated under reduced pressure. Chromatography using 2% methanol/dichloromethane on silica gel gave specified in the title compound, so pl. 120 - 121oC. Similarly, from the same original product is received:

2-Methyl-4-(4-methyl-1-piperazinil)-10-propyl-10H-thieno [2,3-b] [1,5]-benzodiazepine, so pl. 122 - 123oC. 10-Cyclopropylmethyl - 2-methyl-4-(4-methyl-1-piperazinil)-10H-thieno [2,3-b] [1,5]-benzodiazepine, so pl. 105 - 106oC. the Following forms can be manufactured using the active compounds according to the present invention.

Example 3. Tablets manufactured by granulating the active compound with a suitable diluent, a lubricant, the powder is recrystallizes cellulose - 75,0 mg

Povidone - 15,0 mg

Starch directly compression - to 204.1 mg

Example 4. Water injection with an active connection is made in the form of pellets obtained by drying, freezing and before use, dilute the appropriate sterile diluent (to a total volume of 10 ml)

The connection according to the invention - 20.0 mg

Mannitol - 20.0 mg

1 N. hydrochloric acid and/or

1 n sodium hydroxide to establish a pH of 5 to 5.5 mg

Example 5. Injection controlled release for intramuscular injection is obtained from a sterile suspension of dispersed active compound in oily media.

The connection according to the invention is of 65.0 mg

Stearate aluminum - 0.04 mg

Sesame oil - 2 mg

Example 6. The form is made by mixing the active compound with starch and starch and silicone fill gelatin capsules.

The connection according to the invention is 2.5 mg per capsule 290 mg

Granular starch with 0,96% silicone 220 - to 217.5 mg

Granular starch - 70,0 MHD

1. Thienobenzodiazepine General formula I

< / BR>
where R1denotes hydrogen or halogen;

R2represents C1- C10alkyl, C2- C10alkene is B>alkyl,

or their pharmaceutically acceptable salts.

2. Thienobenzodiazepine under item 1, where R2represents C1- C4alkyl, C2- C4alkenyl, C2- C4quinil, C3- C6cycloalkyl, C1- C4alkyl or phenyl C1- C4alkyl.

3. Thienobenzodiazepine under item 1, where R2represents C3- C10alkyl, C3- C10alkenyl or C3- C10quinil.

4. Thienobenzodiazepine according to any one of paragraphs.1 to 3, where R1denotes hydrogen.

5. Thienobenzodiazepine under item 4, where R2represents C3- C8alkyl.

6. The pharmaceutical composition exhibiting activity against receptor dopamine D-1, characterized in that it contains an effective dose of a compound according to any one of paragraphs.1 - 5 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or diluent.

7. Connection on p. 1 or its pharmaceutically acceptable salt, characterized in that it has activity against receptor dopamine D-1.

8. A method of obtaining a connection on p. 1, characterized in that the compound of General formula II

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where the values of R1specified in paragraph 1,

po in paragraph 1;

X denotes a group to delete.

Priority signs:

29.05.92 - R1is hydrogen, R2- C1- C4alkyl, C2- C4alkenyl, C2- C4quinil, C3- C6cycloalkyl, C1- C4alkyl or phenyl C1- C4alkyl;

30.04.93 - R1- halogen, R2- C5- C10alkyl, C5- C10alkenyl, C5- C10quinil.

 

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< / BR>
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< / BR>
in which

R1is a hydrogen atom;

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< / BR>
where

n is the number 2, 3, 4 or 5,

A - uglerodsesola communication or unbranched Allenova group with 1 to 4 carbon atoms, unsubstituted or substituted by one or two alkyl groups,

X - nitromethylene group, cyanomethylene group, unsubstituted or substituted by a residue R6with the following for R4values except tetrazole, or a group of formula =N-R7where R7is cyano, alkanesulfonyl group, phenylsulfonyl group, phenylalkylamine group, aminosulfonyl group, alkylaminocarbonyl group, dialkylaminoalkyl group, phenylcarbonylamino group, aminocarbonyl group, alkylaminocarbonyl group or dialkylaminoalkyl group,

Y - alkoxygroup, fenoxaprop, allylthiourea, phenylthiourea or a group of the formula-R8NR9where R8means a hydrogen atom, an unbranched or branched alkyl group with 1 to 10 carbon atoms, which is in the 2nd, 3rd or 4th position can be C is POI or peredelnoj group, alkyl group with 1 to 4 carbon atoms, which may optionally be substituted with hydroxyl group in the 2 nd, 3rd or 4th position, cycloalkyl group with 3 or 4 carbon atoms, cycloalkyl group with 5-8 carbon atoms, in which one ethylene bridge can be replaced on-phenylenebis group, bicycloalkyl group with 6 to 8 carbon atoms, unsubstituted or substituted 1, 2 or 3 alkyl groups, adamantly group, alkoxygroup or trimethylsilylethynyl group, and R9is a hydrogen atom or an unbranched alkyl group, or R8and R9together with in between the nitrogen atoms form an unsubstituted or substituted by one or two alkyl groups or phenyl group, cyclic alkalinising with 4 to 6 carbon atoms, in which one ethylene bridge in the provisions of 3.4 can be replaced on-phenylenebis group, morpholinopropan or piperazinone, unsubstituted or substituted in the 4-position of the alkyl group with 1 to 3 carbon atoms or phenyl group,

R1is a hydrogen atom or an alkyl group with 1 to 3 carbon atoms,

R2and R3is a hydrogen atom or together form a carbon-carbon bond,

Pyr - Peregrina group, unsubstituted or sameena the group, alkylaminocarbonyl group, dialkylaminoalkyl group, group, translated in vivo metabolic by carboxyl group or carboxyl group, if Y represents the group R8NR9where R8and R9have the above meaning,

R5is a hydrogen atom or the halogen, alkyl, alkoxy or trifluoromethyl,

all of the aforementioned alkyl and CNS remains, if nothing else is mentioned, have 1 to 3 carbon atoms, and, if nothing else is mentioned, all the above-mentioned phenyl nuclei may be mono - or tizamidine identical or different substituents from the group comprising an atom of fluorine, chlorine, or bromine, alkyl, hydroxyl, alkoxyl, carboxyl, phenyl, nitro-, amino-, alkylamino, dialkylamino, alkanolamine, cyano, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl and dialkylaminoalkyl,< / BR>
their enantiomers, CIS - or TRANS-isomers, if R2and R3together denote a carbon-carbon bond, and their salts

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(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases

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< / BR>
the method of production of these compounds, their use as levogyrate and programalso, optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl] -piperazine
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