2,3,4,5-tetrahydro-1h-3-benzazepine, pharmaceutical composition, method of treatment and methods of obtaining

 

(57) Abstract:

Describes 2,3,4,5-tetrahydro-1H-3-benzazepine General formula (I) in which R1Is Cl or Br; R3is hydrogen or halogen, R4- halogen, NO2or NH2. Methods for their preparation and pharmaceutical composition based on them having antidopaminergic activity, such as binding of D1receptor in the treatment of diseases of the nervous system, as well as the method of binding D1receptor 6 s and 6 C.p. f-crystals, 2 tab.

The invention relates to new 2,3,4,5-tetrahydro-1H-3-benzazepines and their pharmaceutical acid additive salts, methods of obtaining, pharmaceutical compositions containing them and their use for the treatment of certain disorders of the Central nervous system, for example, psychoses, pain, or suffering, depression, sleep disorders, dyskinesias, Parkinson's disease, shock (paralysis).

In the last decade was conducted intensive pharmacological studies concerning benzazepines. Pharmacological properties of benzazepines largely depend on the substituents. There are various substituted benzazepine showing neirolepticeski, antiaggressive deist (Novo industry a/s) described 2, 3,4,5-tetrahydro-1H-3-benzazepine with or heterocyclic ortho-condensed heterocyclic ring system in position 5. It is stated that these compounds have antipsychotic and antidepressant effects.

Presently discovered that the 5' - or 6' - substituted or 5', 6' - di substituted (2,3-dihydrobenzofuran-7-yl)-2,3,4,5-tetrahydro-1H-3-benzazepine compounds have strong antidopaminergics properties that makes it useful for psychopharmaceuticals applications.

It was unexpectedly found that the compounds of this invention exhibit a surprisingly high antidopaminergics activity upon oral administration in comparison with known compounds.

According to the invention are represented 2,3,4,5-tetrahydro-1H-3-benzazepine General formula (I)

,

where

R1Is Cl or Br;

R3represents Cl or Br;

R4- halogen, NO2or NH2; and their pharmaceutically acceptable acid additive salt.

Specific compounds of formula (I) are:

(+) 8-chloro-5-[5-bromo-2,3-dihydrobenzofuran-7-yl] -7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

(+) 8-chloro-5-[2,3-dihydro-5-iodantipyrin-7-yl] -7-hydroxy-3-methyl-2,3,4 the ro-1H-3-benzazepin;

(+) 8-chloro-5-[5-chloro-2,3-dihydrobenzofuran-7-yl] -7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

8-chloro-5-[5-nitro-2,3-dihydrobenzofuran-7-yl] -7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

8-chloro-5-[5-amino-2,3-dihydrobenzofuran-7-yl] -7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin;

8-chloro-5-[5-amino-2,6-dihydrobenzofuran-7-yl] -7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin.

The compound of formula (I) can be represented as a mixture of enantiomers, which can be divided into individual pure enantiomers. This separation may conveniently be carried out by fractional crystallization and various solvents salts of compounds of formula (I) with an optically active acid or by other methods known from the literature, for example using chiral column chromatography. Thus, the invention includes all isomers or in divided form, or in the form of a mixture.

Especially valuable embodiments of the invention are non-toxic, pharmaceutically acceptable acid additive salts of benzazepines formula (I). Such salts include salts derived from inorganic and organic acids, such as hydrochloric, Hydrobromic, sulfuric, phosphoric, methansulfonate, known by qualified personnel.

The invention also concerns the compounds of formula (I) in which R3or R4are radioactive isotopes of iodine or bromine, such as used in clinical practice: 1221, 1231, US1, 1311, 77Br, 82Br76Br.

Discovered that these compounds are useful as visualizeus agents in single photon emission computed tomography (SPECT) or positron emission tomography (PET).

In addition, the invention is pharmaceutical compositions comprising compounds of the invention. The content of active compounds in dosage formulations preferably is in the range from 0.1 to about 1000 mg per dose for oral administration. The usual dosage to achieve antipsychotic impact varies between about 0.5 and 10 mg/kg / day divided into two or three doses used orally.

Compounds of the invention can be obtained in various ways. These methods include:

a) gorodilova the compounds of formula (II)

,

where

R1has the values defined above;

R2- O-C1-4- alkyl or O-CO-C1-4- alkyl, installed above;

R3is halogen or H;

R4- halogen;

and diallylamine or dealkylation of compounds of formula (III) with the formation of the compounds of formula (I), where R1, R3and R4have the meanings as defined above;

b) nitration of compounds of formula (II)

,

defined in paragraph a) with the formation of compounds of General formula (III)

,

where

R1and R2matter in paragraph (a);

R3- H;

R4- NO2,

and diallylamine or dealkylation of compounds of formula (III) with the formation of the compounds of formula (I), where R1, R3and R4are as defined above;

or

(C) restoration or catalytic hydrogenation of the compounds of formula (IV)

,

where

R1has the values defined above;

R2- O-C1-4- alkyl or O-CO-C1-4- alkyl;

R3- H,

in the compound of formula (III)

,

where

R1, R2and R3have the meanings as defined above:

R4- NH2,

and diallylamine or dealkylation of compounds of formula (III) with the formation of the compounds of formula (I), where R1, R3and R4have the meanings given above.

Source materiana useful due to their pharmacological activity. In particular, these compounds are active when the test indicating antipsychosis impact. Thus, the compounds of formula (I) were tested for their binding to the D1-dopamine receptor in the striatum homogenates in rats using described methods (Life Scitnce vol.37 p. 1971 (1985) P, Andersen et al.); the results are presented in table. 1 IC50shows the affinity of the investigated compounds for D1the receptor dopamine.

The previously mentioned high oral antidopaminergics activity of the compounds of the invention compared with known compounds without the claimed 5' - or 6' - substituents (EP 200.455) can be illustrated by calculating the correlation between the ability to inhibit behavior stereotyped settings mice when administered after methylphenidate (Acta Pharmacol. Tox col. 31, 1972, 488) and inhibition of the binding3H - CH 23390 in vitro (a measure of antagonism of D1- receptor). This gives the following relations (PL. 2).

The compound of the invention together with a conventional auxiliary agent (adjuvant) a carrier or diluent, if necessary in the form of a pharmaceutically acceptable acid additive salt of this compound, can the s substances such as tablets or capsules filled with solid or liquid form, e.g. as solutions, suspensions, emulsions, elixirs, or capsules filled with them, all for oral administration, suppositories for rectal or in the form of sterile injectable solutions for parenteral use (including subcutaneous. Such pharmaceutical compositions and their form of unit doses may include conventional ingredients in conventional proportions, with an additional active compounds or components, or without them, and such form of unit doses may contain any suitable effective amount of the active ingredient that facilitates disease of the Central nervous system, commensurate with the assigned interval daily dose that you should take. Tablets containing 0.1 - 1000 mg of active ingredient or, more specifically 0.5 to 10 mg of active ingredient per tablet, respectively, are suitable example of a form with a single dose.

Thus, the compounds of this invention can be used in the formulation of pharmaceutical preparations, for example, for oral or parenteral destination mammals, including humans, in accordance with accepted methods of g is organic or inorganic carriers, suitable for oral or parenteral application which do not enter in harmful interaction with the active connection.

Examples of such carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyalkane castor oil, syrup, peanut oil, olive oil, gelatine, lactose, terralba, sucrose, agar, pectin, acacia (Arabian gum), amylose (starch), magnesium stearate, talc, silicic acid, stearic acid, monoglycerides and diglycerides of fatty acids, esters of pentelicon.

The pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, such as lubricating, protecting agents, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers and/or dyes, and other, not entering into harmful interaction with the active connection.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxyalkane castor oil.

A convenient form of a unit dosage are Alka and/or carbohydrate or similar substances, preferably, the carrier is lactose and/or corn and/or potato starch.

When you can use sweetened the media, that can be used syrup, elixir or similar substances. In General the wider the spacing of the compounds of the invention are produced in the form of a unit dose comprising from 0.05 to 100 mg per dose in a pharmaceutically acceptable carrier.

A typical tablet which can be obtained using conventional tabletting techniques, contains mg:

Active connection - 1,0

Lactose and 67.8 mg Pharm. Heb.

AvicelR- 31,4

AmberlitRIPP 88 - 1,0

Magnesium stearate - 0.25 mg Pharm. Heb.

The following examples illustrate the obtaining of new compounds of this invention.

Example 1. (+)8-Chloro-5-(5-bromo-2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin.

a) (+)8-Chloro-5-(2,3-dihydrobenzofuran-7-yl)-7 - methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin (1.0 g; 2.9 mol) was dissolved in acetic acid (10 ml). To the solution under stirring was added bromine (0,20 ml, 4.0 mol) in acetic acid (5 ml) for 2 h were Formed precipitate. White solid was filtered and washed with diethyl ether.

NMR (200 MHz1H-him. shift in M. D.) of free base. With Cl3as solvent, TMS as internal standard.

(, memorial plaques): 2,42 (C., 3H); 2.40 a is 2.55 (m, 1H); 2.95 and (m, 5H);or 3.28 (t, 2H); 3,70 (C., 3H); 4,43 (D., 1H); 4,58 (t, 2H); 6,38 (S., 1H); 6,98 (D., 1H); 7.18 in (S., 1H); 7,26 (D., 1H).

b) (+)8-Chloro-5-(5-bromo-2,3-dihydrobenzofuran-7-yl)-7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin (3,9 g; 9.2 mmol) was dissolved in dichloromethane (50 ml). The solution was cooled in an ice bath. Thereto under stirring solution was added BBr3concentrations of 10 vol.% in dichloromethane (14 ml; of 14.8 mmol). The reaction mixture was stirred for 2 h, then was heated to room temperature. The mixture was added to methanol and concentrated under reduced pressure. Was added methanol (50 ml), and boil the mixture under reflux for 2 h, then stirred at room temperature overnight. Concentrated mixture to a thick oily substance. Was added methanol (15 ml) and then with stirring, was added NaOH (0.5 M) to the sediment. The mixture was stirred for 1 h, then was cooled in an ice bath. The brown solid was filtered and washed with water.

The output of the connection specified in the header, as crystal brown is as a solvent, TMS as internal standard.

(, memorial plaques): 2,25 (t, 1H); 2,35 (C., 3H); 2,90 (m, 5H); up 3.22 (t, 2H); 4.35 the (doctor , 1H); 4,51 (t, 2H); 6.30-in (S., 1H); of 6.96 (D., 1H); 7,10 (S., 1H); 7,22 (D., 1H).

Example 2. (+)8-Chloro-5-(2,3-dihydro-5-iodantipyrin-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin.

a) Iodine (4,2 g; 16.3 mmol) and 32% peracetic acid (10.3 ml, 49 mmol) was stirred in acetic acid (50 ml) for 15 min at room temperature. To the mixture for 1 h was added (+) 8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin (5.6 g; 16.3 mmol) in acetic acid (50 ml). The mixture was stirred for another 3 hours was Treated with a mixture of sodium thiosulfate and evaporated under reduced pressure before formation of a brown solid powder. Added dichloromethane and the organic phase is washed with water, aqueous NaOH solution, water and then dried over anhydrous magnesium sulfate. The extract was filtered and concentrated to education brown solid. The product was purified by column chromatography (silica gel: CH2Cl2- MeOH).

Output (+)8-Chloro-5-(2,3-dihydro-5-iodantipyrin-7-yl)-7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine in the form of a brownish crystalline powder was 4.8 g (63%).

(, memorial plaques): 2,32 (m, 1H); 2,36 (C., 3H); 2,92 (m, 5H); up 3.22 (t, 2H); 4,70 (C., 3H); 4,37 (DD., 1H); to 4.52 (t, 2H); 6,35 (S., 1H); 7,13 wide. S. , 2H); 7,42 (D., 1H).

b) (+)8-Chloro-5-(2,3-dihydro-5-iodantipyrin-7-yl)-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin (300 mg; of 0.65 mmol) in dichloromethane solvent (15 ml). To the solution was added with stirring for 1 h the solution was added 10% BBr3in dichloromethane (2.0 ml; 2.1 mmol). The mixture was stirred at room temperature for 15 min, diluted with methanol (25 ml) and concentrated under reduced pressure. Was added methanol (20 ml) and with stirring was added NaOH (0.5 M) to pH 7. The mixture was stirred for 1 h and added water to sediment. The solid was filtered and washed with water.

The output specified in the title compound was 207 mg (70%).

NMR (200 MHz1H-him. shift in M. D.) of free base. With Cl3as solvent, TMS as internal standard.

(, memorial plaques): 2,28 (t, 1H); 2,38 (C., 3H); 2,90 (m, 5H); up 3.22 (t, 2H); 4,37 (D. , 1H); to 4.52 (t, 2H); 6.30-in (S., 1H); 7,10 (S., 1H); 7.18 in (D., 1H) 7,40 (D., 1H).

Example 3. (+) 8-Chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin.

1,65 (0,005 mol) (+) 8-Chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-is and 1 o'clock Clean the solution was concentrated in vacuum and again stirred with glacial acetic acid. Then the residue was again dissolved in 10 ml of acetic acid and to the solution under stirring was slowly added at room temperature of 7.2 ml (0,0055 mmol) of 0.77 - molar solution of chlorine in glacial acetic acid. After 1 h was added and 7.1 ml of a solution of chlorine. The reaction mixture was stirred for 1 h Then was added 20 ml of ethanol and 1 ml of concentrated HCl and boil the mixture under reflux for 1 h After cooling the solution was diluted with 20 ml of ethanol and brought the pH to 8 by careful addition of 10% aqueous solution of Na2CO3.

The crude product was spontaneously cooled and collected by filtration. Using column chromatography (stationary phase: C18 silica; eluent: ammonium sulfate/acetonitrile 70 : 30; pH 3,3) received net connection specified in the header. So pl. 224 - 225oC.

1H-NMR in CDCl3(, memorial plaques): 2,23 (t, 1H); 2.40 a (C., 3H); 2,73 (DD., 1H); 2,80 - 3,37 (m, 6H); of 4.57 (t, 2H); 4,93 (D., 1H); 6,17 wide. S., 1H); 7,07 ( S., 1H); 7,25 (S., 2H).

Example 4. (+)8-Chloro-5-(5-chloro-2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin.

Synthesis and processing were carried out according to methods which t was purified chromatographically, as described above, and has obtained the free base in the form of crystalline powder so pl. 182 - 186oC.

1H-NMR in CDCl3(, memorial plaques): 2,40 (C., 3H); 2,30 - 3,20 (m, 8H); 3,90 (DD. , 1H); 4,15 (t, 2H); 5,96 (S., 1H); 6,40 (D., 1H); 6,65 (S., 1H); 6,70 (D., 1H).

Example 5. 8-Chloro-5-(5-nitro-2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin.

a) 1.50 g (0,00386 mol) of 8-Chloro-5-(2,3-dihydrobenzofuran-7-yl)-7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine was dissolved in 20 ml of acetic acid. Added 2,80 g (0,0116 mol) of three-hydrate sodium copper and the mixture was stirred at room temperature for 18 hours the Solvent was evaporated in vacuo, the residue was treated with an aqueous solution of ammonia and was extracted with dichloromethane. Washed solution, water and brine, concentrated in vacuo and the residue was dissolved in ether. Insolubles were separated by filtration and obtained 8-Chloro-5-(5-nitro-2,3-dihydrobenzofuran-7-yl)-7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin in the form of a hydrochloride by adding an excess of HCl in ether and precipitation filtration. White crystals with so pl. 251 - 254oC.

1H-NMR of the free base in CDCl3(, memorial plaques): 2,37 (C., 3H); 2.40 a is 3.25 (m , 6H); to 3.34 (t, 2H); 3,70 (C., 3H); 4,45 (D., 1H); to 4.73 (t, 2H); 6,36 (S., 1H); 7,l-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride was dissolved in 10 ml of dry dichloromethane and cooled in an ice bath. To the solution under stirring was added 5 ml of 1 M solution of trichloride boron in hexane. The reaction mixture was left to warm to room temperature and stirred it for 4.5 hours Then the solution was cooled in an ice bath and held hydrolysis, carefully adding 15 ml of methanol. The resulting crystalline hydrochloride of the compound indicated in the title, was isolated by filtration and dried. Pinkish crystalline powder. So pl. 265 - 270oC with decomposition.

1H-NMR in d6-DMCO (, memorial plaques): 2,80 (D., 3H); 2,85 - of 3.85 (m, 8H); 4.75 V (t , 2H); 4,90 (D., 1H); 6.22 per (C., 1H); 7,27 (S., 1H); 8,02 (D., 1H); 8,25 (D., 1H); 9,95 (S., 1H); 11,30 wide.S., 1H).

Example 6. 8-Chloro-5-(5-amine-2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin.

a) a Mixture of 2.50 g (to 0.011 mol) of sodium sulfide and of 0.60 g (to 0.011 mol) of aluminium chloride in 10 ml of n-propanol was heated under stirring to the boiling temperature under reflux and was added dropwise a solution of 0.44 g (0,0011 mol) of 8-Chloro-5-(5-nitro-2,3-dihydrobenzofuran - 7-yl)-7-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin; kept boiling under reflux for 16 hours the Solvent was removed in vacuum; the residue was again dissolved in dichloromethane. Washed with a solution of 0.1 G. of NaOH, water and brine. UE-benzazepine in the form of foam.

1H-NMR in CDCl3(, memorial plaques): 2,37 (C., 3H, +m, 1H); of 2,75 3,30 (m, 7H); 3,35 wide. S., 2H); 3,68 (C., 3H); to 4.33 (t, 1H); to 4.46 (t, 2H); 6,21 (D., 1H); to 6.43 (SD, 1H); 6,53 (D., 1H); 7,12 (S., 1H).

b) of 2.8 ml (0,0056 mol) of 2 M solution of trichloride boron in dichloromethane was added with stirring to a cooled to ice temperature to a solution of 200 mg (0,00056 mol) of the product of stage a) in 10 ml of dichloromethane. The reaction mixture was stirred for 8 h at room temperature and then concentrated in vacuum. The residue was again dissolved in ether, washed with saturated solution of NaHCO3, water and brine and dried over Na2O4. The deposition of a solution of HCl in ether resulted in the formation specified in the title compound as hydrochloride. So pl. 241 - 244oC.

1H-NMR in d6-DMCO (, memorial plaques): 2,80 (D., 3H); 3,00 (m, 2H); and 3.31 (t, 2H); 3,35 - to 3.67 (m, 4H); 4,60 (t, 2H); 4,77 (D., 1H); 6,23 (S., 1H); 6,98 (S., 1H); 7,26 (S. , 1H); 7,33 (S., 1H); 10,00 (S., 1H); of 10.25 (broad. S., 2H); 10,00 (S., 1H).

1. 2,3,4,5-Tetrahydro-1H-3-benzazepine General formula I

< / BR>
in which R1is chlorine or bromine;

R3is hydrogen or halogen;

R4halogen, nitro or amino group,

and their pharmaceutically acceptable acid additive salt.

2. Connection on p. 1, in which R1- chlorine.

3. Connect-3-benzazepin; (+)-8-chloro-5-(2,3-dihydro-5-iodine-benzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (+)-8-chloro-5-(5,6-dichloro-2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (+)-8-chloro-5-(5-chloro-2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (+)-8-chloro-5-(5-nitro-2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine; (+)-8-chloro-5-(5-amino-2,3-dihydrobenzofuran-7-yl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin.

4. Pharmaceutical composition having antidopaminergic activity, including an active agent and a pharmaceutically acceptable carrier or diluent, wherein the active agent composition contains a compound according to any one of paragraphs.1 to 3, or its pharmaceutically acceptable acid additive salt in an effective amount.

5. The composition according to p. 4, suitable for binding of the D1-receptor in the treatment of diseases of the Central nervous system.

6. The composition according to PP.4 and 5, wherein the unit dose for oral administration contains 0.1 to 100.0 mg of active compound.

7. The compound according to any one of paragraphs.1 to 3, which is useful for obtaining a pharmaceutical composition having antidopamine nervous system, includes the administration of a medicinal product, wherein the patient in need of such treatment, enter the connection PP.1 to 3 in number, facilitating disease.

9. The method according to p. 8, characterized in that the connection PP.1 - 3 is administered in the form of pharmaceutical compositions, in which the connection is together with a pharmaceutically acceptable carrier or diluent.

10. The method of obtaining compounds of formula I under item 1, in which R1is chlorine or bromine, R3is hydrogen or halogen and R4- halogen, characterized in that the compound of General formula II

< / BR>
in which R1has the specified values;

R2- O-C1- C4-alkyl or O-CO-C1- C4-alkyl, are subjected to galoidirovaniya and thus obtained compound of General formula III

< / BR>
in which R1- R4have the specified values,

are decelerating or dialkylamino with obtaining the compounds of formula I, defined above.

11. The method of obtaining compounds of formula I under item 1, in which R1is chlorine or bromine; R3is hydrogen and R4- the nitro-group, characterized in that the compound of formula II under item 10 is subjected to nitration to obtain compounds of General is the place or dialkylamino with obtaining the compounds of formula I, specified above.

12. The method of obtaining compounds of formula I under item 1, in which R1is chlorine or bromine, R3is hydrogen and R4- amino group, characterized in that the compound of General formula IV

< / BR>
in which R1and R3have the specified values;

R2- O-C1- C4-alkyl or O-CO-C1- C4-alkyl,

subjected to catalytic hydrogenation to obtain compounds of General formula III

< / BR>
in which R1, R2and R3have the specified values;

R4- NH2,

which are decelerating or dialkylamino with obtaining the compounds of formula I, defined above.

 

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