CS241471B2 - Method of pyrimido-2-benzazepines production - Google Patents

Description

The present invention provides a process for the preparation of the pyrimido-2-benzazepines of formula (I)

in which

A is a radical of formula a or b

trifluoromethyl, ethyl, α-hydroxyethyl or acetyl,

Y represents a hydrogen or halogen atom and

R ⁸ and R ⁹ are each independently hydrogen or C 1 -C 7 alkyl, and pharmaceutically acceptable acid addition salts thereof.

These compounds exhibit pharmacological activity as anxiolytics and sedatives.

Alkyl groups are straight-chain or branched hydrocarbon groups having preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl and the like.

The term "halogen" refers to all four halogens, ie fluorine, chlorine, iodine and bromine, unless expressly stated otherwise.

Alkylmercapto means -S-alkyl, wherein alkyl is as defined above.

The term "pharmaceutically acceptable salts" includes salts with both inorganic and organic pharmaceutically acceptable strong acids, such as sulfuric acid, hydrochloric acid, nitric acid, methanesulfonic acid, and p-toluenesulfonic acid. Such salts can be readily prepared by methods known per se

M (b)

R ¹ represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a radical of the formula NR ⁸ R ®, a mercapto group or an alkyl mercapto group having 1 to 7 carbon atoms,

X represents a hydrogen atom, a halogen atom,

41471 way with consideration I? of the compound to be converted into a salt.

Of the compounds of formula I above, those wherein A is a radical of formula a are preferred.

Particularly preferred compounds of formula I are those wherein A is a radical of the above formula and and R @ ¹ is hydrogen, C1 -C7 alkyl or NR @ ⁸ R @ ⁹ , (wherein R @ ⁸ and R @ ⁹ are each R @ ⁸ ; a hydrogen atom or an alkyl group having 1 to 7 carbon atoms), with particularly preferred radicals being hydrogen, amino and an alkyl group having 1 to 7 carbon atoms.

Further preferred of the compounds of the formula I are those in which X represents a halogen atom, in particular chlorine, and / or in which Y represents a hydrogen, chlorine or fluorine atom.

A particularly preferred compound of the invention is 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine.

Further examples of preferred compounds of the invention are:

9-chloro 7- (2-fluorophenyl) -5 H -pyrimido [5,4-d] [2] benzazepine,

9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [3,4-d] [2] benzazepine;

9-chloro-N, N-dimethyl-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-amine.

In accordance with the invention, the compounds of formula I and their pharmaceutically acceptable acid addition salts are prepared by preparing a compound of formula IV

in which

X and Y are as defined above, p is 0 or 1 and

R ²¹ is C 1 -C 7 dialkylamino in each alkyl moiety, reacted with cyanamide or a compound of formula V

NH

OF

R ¹² —C \

NH 2 (V) wherein

R ¹² is hydrogen, mercapto, C 1 -C 7 alkyl, C 1 -C 7 alkyl or NH ⁸ R ⁹ where R ⁸ and R ⁹ are as defined above, and the resulting compound of Formula I optionally converted to its pharmaceutically acceptable acid addition salt.

The reaction of a compound of formula (IV) with cyanamide is illustrated, for example, by the following reaction scheme:

IVa - +ο + Ip

The compound of formula IVa is known (see, for example, U.S. Patent Nos. 3,947,585, 4,022,800 and 4,028,381). This compound is reacted with cyanamide in a C 1 -C 4 alcohol, for example ethanol, at a temperature of about 25 to 80 ° C, preferably with the boiling of the corresponding alcohol.

In this way a mixture of the amino compound and the? N, N-disubstituted amino compounds which may be separated, for example, by traction crystallization and / or chromatography.

The reaction of compounds of formulas IV and V consists in reacting a compound of formula IV with amidine or guanidine salts, or with thiourea or the corresponding S-alkylisothiourea. Any inert organic solvent such as dioxane, tetrahydrofuran or dimethylformamide may be used in the reaction with the amidine or guanidine salt. The reaction may be carried out at a temperature ranging from about room temperature to the boiling point of the solvent, preferably at room temperature. The reaction with thiourea or S-alkylisothiourea can be carried out in the presence of an alcoholic, for example methanolic, solution of an alkali metal alkoxide, for example sodium methoxide. The reaction may be carried out at a temperature of from about 0 to 65 ^C C, preferably at about room temperature.

For completeness, the following Reaction Scheme II, in which X and Y are as hereinbefore defined, illustrates the preparation of those intermediates of formula IV wherein p is 1:

CHNCl-1fr

(Vlil)

Scheme II (IVb)

(VI) (VII)

The compound of formula VI can be reacted with a peracid, such as m-chloroperbenzoic acid, in an inert organic solvent, such as a halogenated hydrocarbon, for example methylene chloride, or ether. The reaction may be carried out at a temperature of about 0 to 40 ° C, preferably at room temperature. The product mixture can then be separated by fractional crystallization. Thin layer chromatography analysis revealed the presence of both products.

The compound of formula VII can be reacted with dimethylformamide dimethylacetal in an inert solvent such as a halogenated hydrocarbon, for example methylene chloride, or dimethylformamide, optionally in high boiling ether. The reaction temperature may be about 0 to 100 ° C, preferably at room temperature.

The pyrimido-2-benzazepines of formula (I) above and their pharmaceutically acceptable acid addition salts are useful as pharmaceuticals. These substances are effective as sedatives and anxiolytics. The disclosed compounds can be used in the form of conventional pharmaceutical compositions. For example, the compounds may be mixed with conventional organic or inorganic, inert pharmaceutical carriers suitable for parenteral or enteral administration such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, acacia, polyalkylene glycols, vaseline and the like. The compounds of the invention may be administered in conventional dosage forms, for example in solid forms such as tablets, dragees, capsules, suppositories and the like, or in liquid forms such as solutions, suspensions or emulsions. In addition, the pharmaceutical compositions containing the compounds of the invention may be subjected to conventional pharmaceutical treatments such as sterilization and may further contain conventional pharmaceutical auxiliaries such as preservatives, stabilizers, wetting agents, emulsifiers, salts for adjusting the osmotic pressure or buffers. The disclosed compositions may also contain other therapeutically active materials.

The following table shows the results of certain well-known tests to which some of the compounds of the present invention have been subjected. This is an inclined grid test, a test in which test animals are given pulses of electrical impulses, a test with a non-anesthetized cat, and an antipentamethylenetetrazole test (metrazole test).

The tests were performed with the following substances:

9-Chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] [2] benzazepine

B 9-Chloro-7- (2-chlorophepyl) -5H-pyrimido [5,4d] [2] benzazepine

C 9 -Chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-amine

D 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine

E 9-Chloro-7- (2-fluorophenyl) -N, N-dimethyl-5H-pyrimido [5,4-d] [2] benzazepin-2-amine

The abbreviations used in the table have the following meanings: *

after. = per os

i.p. = intraperitoneally

MED = minimum effective dose.

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Λ Λ Λ Λ

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CM t> t- ^ in in · o o o o d t-i

£ 60, £ £ 60 60 5? = 5 = * AS US

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A suitable pharmaceutical unit dose may contain from about 1 to 500 mg of an active compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof) with a range of about 1 mg to 100 mg for oral administration and a parenteral administration for parenteral administration. about 1 mg to 50 mg. However, for each individual patient, the particular dosage regimen should be adjusted according to his individual needs and the professional judgment of the person administering or supervising the application. It should be noted that the above dosage range is exemplary only and that it is by no means restricted to the scope of the compounds of the invention.

As used herein, the term "unit dose" refers to separate pharmaceutical dosage units suitable as unitary dosages for administration to mammals, each containing a predetermined amount of active ingredient that is calculated to produce the desired therapeutic effect in combination with a suitable pharmaceutical diluent, carrier or excipient.

The invention is illustrated by the following non-limiting examples.

Example 1

2-Amino-9-chloro-7-phenyl-5H-pyrimido [5,4-d] [2] benzazepine

To a suspension of 10 g (0.032 mol) of 8-chloro-3,4-dihydro-4- (dimethylaminomethylene) -1-phenyl-5H-2-benzazepin-5-one and 8.5 g (0.047 mol) of guanidine carbonate in Methanol (250 ml) was added with a single portion of sodium methoxide (5.1 g, 0.094 mol) under stirring at room temperature under argon. After 10 minutes, 150 mL of methylene chloride was added and stirring was continued. At two-hour intervals, add the same amounts of sodium methoxide and guanidine carbonate two times as above and continue stirring overnight. The reaction mixture is diluted with 250 ml of methylene chloride, washed with water, dried over sodium sulfate and concentrated under reduced pressure. Crystallization of the residue from ethanol gives slightly red-yellow colored crystals, m.p. 209-210 ° C. Recrystallization of the product sample from methylene chloride / ethyl acetate gave off-white prismatic crystals melting at 210-211 ° C.

Example 2

2-Amino-9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine

To a suspension of 16 g (0.047 mol) of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one and 12.5 g (0.07 mol) guanidine carbonate in

With stirring at room temperature under argon atmosphere, 460 ml of methanol are added in one portion 7.5 g (0.14 mol) of sodium methoxide. After 10 minutes, 290 mL of methylene chloride was added and stirring was continued. At two-hour intervals, add the same amounts of sodium methoxide and guanidine carbonate two times as above and continue stirring overnight. The reaction mixture was diluted with 460 ml of methylene chloride, washed with water, dried over sodium sulfate and evaporated under reduced pressure. Recrystallization of the residue from a mixture of ethanol and methylene chloride gave off-white crystals, m.p. 245-248 ° C.

Dihydrochloride

A warm solution of the above final product in 100 ml of a mixture of equal parts of methanol and methylene chloride is filtered and concentrated to half volume on a steam bath. To the filtrate was added 5 ml of a 5.7N ethanolic HCl solution and the mixture was allowed to stand at room temperature for 2 hours. The pale yellow crystals are filtered off and air-dried after washing with ethanol. The desired dihydrochloride, m.p. 232-237 ° C, is obtained.

Example 3

9-chloro-2-methyl-7-phenyl-5H-pyrimido [5,4-dj [2] benzazepine

To a suspension of 1.6 g (0.005 mol) 8-chloro-3,4-dihydro-4- (dimethylaminomethylene) -1-phenyl-5H-2-benzazepin-5-one and 0.7 g (0.0075 mol) of acetamidine hydrochloride in 50 ml of methanol, while stirring at room temperature under argon, is added 0 · 8 g (0.015 mol) of sodium methoxide. The entire amount of sodium methoxide is added in one portion. After stirring for 10 minutes, 30 ml of methylene chloride are added and stirring is continued. After 2 hours an additional 0.8 g (0.015 mol) of sodium methoxide and 0.7 g (0.0075 mol) of acetamidine hydrochloride were added. After a further 2 hours, 0.015 mol of sodium methoxide and 0.0075 mol of acetamidine hydrochloride were added again, and stirring was continued overnight. The reaction mixture was diluted with 50 mL of methylene chloride, washed with water, dried over sodium sulfate and evaporated under reduced pressure. Dissolve the residue in 20 mL of warm hexane and cool to crystallize. Evaporation of the solvent gave a second crop. Recrystallization from hexane (decolourising with charcoal) gave off-white crystals, m.p. 120-122 ° C.

Example 4

9-chloro-7- (2-fluorophenyl) -2-methyl-5H-pyrimido [5,4-d] [2] benzazepine

471

Í1

To a suspension of 5.1 g (0.015 mol) of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one and 2.1 g (0.0225 mol) of acetamidine hydrochloride in 150 ml of methanol was added with stirring at room temperature under argon atmosphere in a single portion, 2.4 g (0.045 mol) of sodium methoxide, after stirring for 10 minutes, 90 ml of methylene chloride was added. After 2 hours, an additional 2.4 g (0.045 mol) of sodium methoxide and 2.1 g (0.0225 mol) of e.cetamidine hydrochloride were added. The reaction mixture was diluted with 150 ml of methylene chloride, the resulting mixture was washed with water, dried over sodium sulfate and evaporated under reduced pressure. decolourisation with activated charcoal gave white crystals melting at 104-107 ^and C.

Example 1 a d 5

9-chloro-7- (2-fluorophenyl) -5H-pyrimido (5,4-dl [2] benzazepin-2-amine and 9-chloro-7- (2-fluorophenyl) -N, N- dimethyl-5H-pyrimido [5,4-d] [21benzazepin-2-amine

A solution of 7.0 g (0.0204 mol) of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one and 3.5 g (0.0833 mol) of cyanamide in 300 ml of absolute ethanol are refluxed for 18 hours and then evaporated to dryness. The residue was washed with water, filtered off and recrystallized twice from methanol to give the Ν, Ν-dimethylamino compound. The filtrates were concentrated to give the amine compound after filtration and recrystallization from methanol. The filtrates were evaporated, the residue was dissolved in dichloromethane and chromatographed on a silica gel column. The column was washed with dichloromethane, the eluates were combined, evaporated and the residue crystallized from methanol to give an additional Ν, Ν-dimethylamino compound. A sample was recrystallized from dichloromethane-ether-white needle crystals, mp 175-180 ° C ^Q

The above column is further eluted with 5% ether in dichloromethane and then with ether. Combine the ether fractions, evaporate and crystallize the residue from methanol to give additional amine compound. A sample of this product, after recrystallization from methanol, gave white prism crystals of m.p. 242-247 ° C.

To a solution of 0.2 g (0.5 mmol) of the N, N-dimethylamino compound in 5 ml of methanol was added 0.05 g (0.5 mmol) of methanesulfonic acid. The methanol was evaporated, the oily residue crystallized from isopropanol and then recrystallized from methanol / ether to give yellow prism crystals, m.p. 190-195 ° C.

Example 1 a d 6

9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] (2) benzazepine

To a solution of 3.5 g (10 mmol) of 8-chloro-1- (2-chloro-phenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one in 140 ml of methanol and 140 ml of methylene chloride were added in five equal portions of 5.5 g (58 mmol) of acetamidine hydrochloride and 15 ml (62 mmol) of a 4.12 M methanolic sodium methoxide solution. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to an amber oil which was dissolved in 10 mL (10 mmol) of a 1M methanolic methanesulfonic acid solution and the resulting salt precipitated by addition of ether. 193 DEG-197 DEG C. Recrystallization from a mixture of methanol and ether gave yellow prism crystals, melting at 197 DEG-198 DEG.

Example 7

9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine

To a solution of 7.2 g (20 mmol) of 8-chloro-1- (2-chlorophenyl) -3,4-dihydro-4- (dimethylamino) methylene-5H-2-benzazepin-5-one in 270 ml of methanol and 270 ml of methylene chloride are added in five equal portions over 3 hours to 21 g (200 mmol) of formamidine acetate and 32.5 ml (135 mmol) of a 4.12M methanolic sodium methoxide solution. The solution was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to an amber oil. Purification of the oil by column chromatography on 100 g of silica gel eluting with a mixture of equal parts of methylene chloride and ethyl acetate gave the desired product. G. ο · ο Recrystallization from ether gives pale yellow prism crystals of m.p. 122 DEG-125 ^DEG C. Example 8

9-chloro-7- (2-chlorophenyl) -2-isopropyl-5H-pyrimido [5,4-d] (21 benzazepine).

A mixture of 3.5 g (10 mmol) of 1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino-methylene) -5H-2-benzazepin-5-one, 4.8 g (40 mmol) of isobutyramide hydrochloride 10 ml (41 mmol) of a 4.12 M methanolic solution of me241471 sodium thoxide and 100 ml of methanol are stirred at room temperature for 2 hours, then diluted with water and extracted with methylene chloride, dried over anhydrous sodium sulfate and concentrated in vacuo to a yellow oily residue which was crystallized from ether to give a yellowish solid, mp 127 DEG C. 1.29 ^G Recrystallization from a mixture of ether and petroleum ether gave colorless rod crystals melting at 127-129 ° C.

Example 1 a d 9

2-Amino-9-chloro-7- (2-chlorophenyl) -5H-pyrimido] 5,4-d] [2] benzazepine

To a solution of 3.6 g (10 mmol) of 8-chloro-1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one in 100 ml of methanol 14.4 g (80 mmol) of guanidine carbonate and 20 ml (82 mmol) of a 4.12 M methanolic sodium methoxide solution are added in two equal portions over 90 minutes, the mixture is diluted with water and extracted with methylene chloride. 240 DEG-241 ^DEG C. and crystallized from methylene chloride to give a white solid, m.p. 240 DEG-241 ^DEG C. Recrystallization from ether / methylene chloride gave colorless needle crystals, m.p. 240 DEG-241 DEG. .

Example 10

7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] [2] benzazepine methanesulfonate

To a solution of 4.5 g (10 mmol) of 1- (2-chlorophenyl) -3,4-dihydro-4 [(dimethylainino) methylene] -5H-2-henzazepin-5-one in 180 ml of methanol and 180 ml of methylene chloride 7.2 g (76 mmol) of acetamidine hydrochloride and 18 ml (80 mmol) of 4.46 M methanolic sodium methoxide solution are added in four equal portions over 3 hours, the mixture is diluted with water and extracted with methylene chloride. The oil is dissolved in a mixture of 15 ml of isopropanol and 1.3 g (14 mmol) of methanesulfonic acid, the isopropanol is evaporated under reduced pressure and the residue is crystallized. 147-151 [deg.] C., which, after recrystallization from ether / methylene chloride, gives yellow prisms in the corresponding wire position, melting at 159-160 [deg.] C.

Example 11

2-methyl-7-phenyl-5H-pyrimido [5,4-d] [2] benzazepine dihydrochloride

To a solution of 4.5 g (15 mmol) of 1-phenyl-3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one in 180 mL of methanol and 180 mL of methylene chloride was added during 9.0 g (95 mmol) of acetamidine hydrochloride and 22.5 ml (0.1 mol) of a 4.46 M methanolic sodium methoxide solution were added in five equal portions, the methylene chloride solution was washed with water, dried over anhydrous sodium sulphate and The oily residue is dissolved in an excess of 6% methanolic hydrogen chloride solution and the solvent is evaporated to dryness under reduced pressure, and the residue is crystallized from ether / methylene chloride to give a white solid, mp 211-221 ° C. from a mixture of methanol and ether, white, flaky crystals having a melting point of 217-280C are obtained.

Example 12

9-chloro-7- (2-chloro-phenyl) -5H-pyrimido [5,4-di [2] benzazepine-2-thiol

A mixture of 2.8 g (7.8 mmol) of 8-chloro-1- (2-chlorophenyl) -3,4-dihydro 4 - [(dimethylamino) methylene-5H-2-benzazepin-5-one, 2.8 g. (37 mmol) of thiourea and 8.0 ml (32 mmol) of a 4.0 M methanolic sodium methoxide solution in 80 ml of methanol are stirred at room temperature for 18 hours, then diluted with water and extracted with ether. The aqueous layer was neutralized with acetic acid and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to a yellow solid of melting point 238-239 ^C. C after recrystallization from tetrahydrofuran gave yellow crystals melting at 232 to 234 ^Q C

Example 13

9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine

A mixture of 34.2 g (0.1 mol) of 8-chloro-3,4-dihydrol- (2-fluorophenyl) -4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one, 62 4 g (0.6 mol) of formamidine acetate and 35 g (0.63 mol) of sodium methoxide in 700 ml of methanol are stirred at room temperature for 3 hours under nitrogen, the reaction mixture is diluted with water and extracted with ethyl acetate. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a red oily residue, which was suspended in boiling hexane and the hexane solution was evaporated.

16 decantes. After cooling, the precipitated product is filtered off. Recrystallization from cyclohexane gave off-white crystals, m.p. 123-125 T.

Example 14

2-Amino-9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine 6-oxide

To a solution of 7.0 g [20 mmol] of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one-2- of oxide in 210 ml of methanol are added in two equal portions over 2 hours, 28 g (150 mmol) of guanidine carbonate and 38 ml (150 mmol) of a 4.09 M methanolic sodium methoxide solution are diluted with water and extracted with methylene chloride. It is dried over anhydrous sodium sulphate and evaporated under reduced pressure to a red solid which is recrystallized from a mixture of methanol and ethyl acetate to give the desired product in the form of fine yellow needles melting at 320 to 323 ° C.

Example 15

9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] [2] benzazepine-6-oxide

1 g (2.8 mmol) of 8-chloro-1- (2-chlorophenyl) -4 - ((dimethylamino) methylene] -3,4-dihydro-5H-2-benzazepin-5-one-2-oxide 1.0 g (11 mmol) of acetamidine hydrochloride and 2.0 ml (9.9 mmol) of a 4.46M methanolic sodium methoxide solution were stirred at room temperature for 2 hours in a mixture of 20 ml of methanol and 20 ml of methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure to give a colorless solid, m.p.

Example 16

9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine

A mixture of 90.5 g (0.25 mol) of 8-chloro-1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one, 100 g ( 0.96 mol) of formamidine acetate and 1.0 liter of formamide were heated on a steam bath for 16 hours, cooled to 0 ° C, the precipitate formed was filtered off and dried to constant weight after washing with water to give off-white crystals. mp 120-121 ° C.

Example 17

9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine-6-oxide

A mixture of 0.4 g (1.1 mmol) of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one-2 -oxide, 1.0 g (9.6 mmol) formamidine acetate and 20 ml formamide were heated on a steam bath for 6 hours. The reaction mixture was poured onto ice and extracted with methylene chloride. The methylene chloride solution was washed with water and, after drying over anhydrous sodium sulfate, concentrated under reduced pressure. The residue crystallized after addition of an ether / methylene chloride mixture to give off-white crystals melting at 186-188 °.

Example 18

9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine-6-oxide

A mixture of 0.4 g (1.1 mmol) of 8-chloro-1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one-2- of oxide and 1.0 g (9.6 mmol) of formamidine acetate in 20 ml of formamidine was heated on a steam bath for 7 hours. The reaction mixture was poured onto ice and extracted with methylene chloride. The methylene chloride solution was washed with water and, after drying over anhydrous sodium sulfate, evaporated under reduced pressure. Trituration of the residue with ether gives an off-white solid, m.p. 215-217 ^° C.

Example 19

9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine-2-thiol-6-oxide

A mixture of 1.5 g (4 mmol) of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene) -5H-2-benzazepin-5-one-2-oxide, 1 Thiourea (5 g, 20 mmol) in methanol (30 ml) was stirred at room temperature for 5 hours. The reaction mixture was poured into water and extracted with ether. The aqueous solution was acidified with acetic acid and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure. Trituration of the residue with methylene chloride gave an orange-colored solid which, after recrystallization from methylene chloride, gave the desired product as orange crystals melting at 323 DEG-325 DEG C. with decomposition.

Example 20

9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-amide-6-oxide and 9-chloro-7- (2-fluorophenyl) -N, N-dimethyl241471

5H-pyrimido [5,4-d] [2] benzazepine-2-amine-6-oxide

A solution of 0.5 g (1.39 g mmol) of 8-chloro-1- (2-fluorophenyl) -4 - ((dimethylamino) methylene] -3,4-dihydro-5H-2-benzazepine-5- On-2-oxide and 0.5 g (11.9 mmol) of cyanamide in 6 ml of N, N-dimethylformamide are heated at 85 DEG C. for 4 hours, after cooling, the mixture is partitioned between 75 ml of dichloromethane and 50 ml of water. The residue was purified by thin layer chromatography on silica gel using ethyl acetate / methanol (20: 1) as the eluent to remove the R _f 0.5 and 0.7 bands and recrystallize separately from dichloromethane. and methanol to give 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-amine-6-oxide and 9-chloro-7, respectively. - (2-fluorophenyl) -N, N-dimethyl-5H-pyrimido [5,4-d] [2] benzazepin-2-amine-6-oxide.

9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-amine-6-oxide results in the form of off-white prism crystals melting at 310-350 with decomposition %: and 9-chloro-7- (2-fluorophenyl) -N, N-dimethyl-5H-pyrimido [5,4-d] [2] benzazepin-2-amine-6-oxide results in the form of pale yellow rod-like crystals o mp 212-218 ° C.

Example A

Composition and preparation of tablets (wet granulation)

Number Component mg mg mg mg 1 2-amino-9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine, or 7-Phenyl-5H-pyrimido [5,4-d] benzazepin-2-amine 1 5 10 25 2 lactose 202 232 261 280 3 modified starch 25 35 45 55 4 pregelatinized starch 20 May 25 30 35 5 distilled water (as needed) - - . - - 6 magnesium stearate 2 3 4 5 tablet weight 250 mg 300 mg 350 mg 400 mg

Preparation:

1) The components No. 1 to 4 are mixed in a suitable mixer.

2) The mixture is granulated with the required amount of distilled water to the desired consistency and milled.

3) Dry the granulate in a suitable oven.

4) The dried granulate is ground and mixed with magnesium stearate for 3 minutes.

5) Tablets are compressed from a mixture on a suitable press provided with the punch.

Example 1 a d B

Composition and preparation of tablets (direct compression)

Number Component mg mg mg mg 1 2-amino-9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine, or 7-Phenyl-5H-pyrimido (5,4-d) benzazepin-2-amine 1 5 10 25 2 lactose 221 217 212 181 3 Avicel 45 45 45 55 4 starch for direct compression 30 30 30 35 5 magnesium stearate 3 3 3 4 tablet weight 300 mg 300 mg 300 mg 300 mg

Preparation:

1) Folder. 1 is mixed with an equal amount of lactose and mixed thoroughly.

2) Add components 3 and 4 and the remainder of component 2, and mix thoroughly.

3) Add magnesium stearate and mix for 3 minutes.

4) Tablets are compressed from a mixture on a suitable punch equipped with a punch.

20 May

Example ϋ

Composition and preparation of capsules

Number Component mg mg mg mg 1 2-amino-9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine, or 7-Phenyl-5H-pyrimido [5,4-d] benzazepin-2-amine 1 5 10 25 2 lactose 203 293.5 328 372.5 3 starch 30 35 40 30 4 talc 15 Dec 15 Dec 20 May 20 May 5 Aerosol OT 1 1.5 2 2.5 capsule filling weight 250 mg 350 mg 400 mg 450 mg

Preparation:

1) Components 1, 2, 3 and 5 are mixed in a suitable mixer and ground.

2) Add talc and mix thoroughly.

3) The capsules are filled using suitable equipment,

The following examples illustrate the preparation of starting materials of formula IV.

Example D

8-chloro-1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one

A mixture of 18.6 g (61 mmol) of 8-chloro-3,4-dihydro-1- (2-chlorophenyl) -5H-2-benzazepin-5-one and 149 ml of dimethylformamide dimethyl acetal is gently heated for about 12 hours (ca. 50 ml). The resulting mixture was concentrated to dryness under reduced pressure, and the residue was crystallized from a mixture of ether and methylene chloride to give a yellow solid melting at 170-171 ° C. Recrystallization from ether gave yellow prism crystals melting at 170-171 ° C. Celsius.

Example E

1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one

A mixture of 3.4 g (12.5 mmol) of 1- (2-chlorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one and 28 ml of dimethylformamide dimethyl acetal is refluxed for 2 hours, then concentrated. under reduced pressure and the solid residue was triturated with ether. 155 DEG-157 ^DEG C., which, after recrystallization from methylene chloride / ether, gives yellow prism crystals of m.p. 158 DEG-159 DEG.

Example F

3,4-dihydro-1-phenyl-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one

A mixture of 3,4-dimethylamino-1-phenyl-5H-2-benzazepin-5-one (5.2 g, 22 mmol) and dimethylformamide dimethyl acetal (43 ml) was refluxed for 4 hours and then concentrated to dryness under reduced pressure. Crystallization of the residue from ether gave a yellow solid, m.p. 131-133 ° C, which, after recrystallization from ether, gave yellow prism crystals melting at 131-132 ° C.

Example G.

8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepine-5-ene

Procedure

A mixture of 7.2 g (25 mmol) of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-5H-2 benzazepin-5-one and 50 ml of dimethylformamide dimethyl acetal is refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure and the black-yellow crystalline residue was recrystallized from ether. Yellow prismatic crystals of m.p. 228-233 ^and C. are obtained

A mixture of 10 g (35 mmol) of crude 8-chloro-3,4-dihydro-1- (2-fluorophenyl) -5H-2-benzazepin-5-one and 10 g (84 mmol) of dimethylformamide dimethylacetal in 10 ml of dimethylformamide 12 is added. The precipitate formed is filtered off and washed successively with ethanol and ether to give red-yellow colored crystals which are in all respects identical to the authentic sample.

Example H

8-chloro-1-phenyl-3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one

8-chloro-1-phenyl-3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one is prepared in the same manner as 8-chloro-1- (2-fluorophenyl) -3, 4-Dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one (Procedure A1). Yellowish prism-like crystals, m.p. 180-183 ° C.

i Example

8-Chloro-1- (2-fluorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one 2-oxide

A mixture of 6.4 g (22 mmol) of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one and 6.4 g (34 mmol) of m-chloroperbenzoic acid in Methylene chloride (350 ml) was stirred at room temperature for 2 hours. The methylene chloride solution was washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to a yellow oil. The oily residue was crystallized from ether / petroleum ether to give off-white prism crystals, m.p. 166-168 ° C. Recrystallization from ether / methylene chloride gave colorless prism crystals, m.p. 168-170 ° C.

Example J

8-Chloro-1- (2-chlorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one 2-oxide

8-Chloro-1- (2-chlorophenyl) -3,4-dihydr o22

The 5H-2-benzazepin-5-one-2-oxide was prepared in the same manner as 8-chloro-1- (2-fluorophenyl-3,4-dihydro-5H-2-benzazepin-5-one-2-ox). Yellow crystals having a melting point of 184 DEG-187 ^DEG C. are obtained.

Example K

8-Chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one-2-oxide

A mixture of 3.4 g (11 mmol) of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one-2-oxide and 25 ml of dimethylformamide dimethyl acetal is stirred for 12 hours. at room temperature. The resulting mixture was diluted with ether and the precipitate was filtered off. A yellow solid is obtained, m.p. 175-178 ° C, which, after recrystallization from ether / ethyl acetate, gives yellow needle crystals melting at 193-194 ° C.

Example L

8-chloro-1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one-2-oxide

8-Chloro-1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one-2-oxide is prepared in an analogous manner to 8-chloro- 1- (2-Fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene) -5H-2-benzazepin-5-one-2-oxide. Yellow prismatic crystals of m.p. 196-198 are obtained

Claims (9)

SUBJECT OF THE INVENTION Process for the preparation of pyrimido-2-benzazepines of the general formula I A is a radical of formula a or b R ¹ represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a radical of the formula NR ⁸ R ⁹ , a mercapto group or an alkylmercapto group having 1 to 7 carbon atoms, X represents a hydrogen atom, a halogen atom, a trifluoromethyl group, an ethyl group, an α-hydroxyethyl group or an acetyl group, Y represents a hydrogen or halogen atom and R ⁸ and R ⁹ are each independently hydrogen or C 1 -C 7 alkyl, and their pharmaceutically acceptable acid addition salts, characterized in that the compound of formula (IV): X and Y are as defined above, p is 0 or 1 and R ²¹ represents a C 1 -C 7 dialkylamino group in each alkyl moiety, reacted with a cyanide or a compound of formula V NH OF R ¹² —C \ NH 2 (V) wherein R ¹² represents a hydrogen atom, a mercapto group, a C 1 -C 7 alkylmercapto group, a C 1 -C 7 alkyl group or a radical of the formula NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are as defined above, and the resulting compound of formula I is optionally converting it to a pharmaceutically acceptable acid addition salt thereof. 2. The process of claim 1, wherein the compounds of formulas (IV) and (V) are reacted with one another in which: X represents a hydrogen atom, a halogen atom to atomic number 35 or a trifluoromethyl group, Y represents a hydrogen atom or a halogen atom to atomic number 35, R ²¹ is dimethylamino, p is 1 a R ¹² is amino. 3. Process according to claim 1, characterized in that cyanamide is reacted with a compound of formula IV in which p is 0 and X, Y and R ²¹ are as described below or is cross-reacting compounds of the formulas IV and In which R ²¹ 'is dimethylamino and R ¹² represents a hydrogen atom, a mercapto group, an alkyl group having 1 to 7 carbon atoms or a radical of the formula NR ⁸ R ⁹ , wherein R ⁸ and R ⁹ are as defined in point 1, p is 0 when R ¹² is mercapto or when R ¹² is amino, X is hydrogen, halogen to atomic number 35 or trifluoromethyl, and Y is hydrogen or halogen to atomic number 35 , and the resulting compound of formula (I) is optionally converted into its pharmaceutically acceptable acid addition salt. 4. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of formula I wherein: A is a radical of formula a, R ¹ represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms or a radical NR ⁸ R ⁹ , where R ⁸ and R ^{9 each} independently represent a hydrogen atom or an alkyl group having 1 to 7 carbon atoms, X represents a halogen atom, preferably chlorine, and Y represents a hydrogen, chlorine or fluorine atom. 5. A method according to claim 4, characterized by applying the appropriate starting materials to give compounds of formula I in which R ¹ represents hydrogen, amino or alkyl of 1-7 carbon atoms, and other symbols are as in point 4. 6. The process of claim 1, wherein the corresponding starting materials are used to give 9-chloro-7- (2-chlorophenyl) -5H-pyrimido] 5,4-di [2] benzazepine. 7. A process according to claim 1, wherein the corresponding starting materials are used to give 9-chloro-7- (2-fluorophenyl) -5H-pyrrido [5,4-d] j [2] benzazepine . 8. The process of claim 1, wherein the corresponding starting materials are used to form 9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] [2] benzazepine. 9. A process according to claim 1, wherein the corresponding starting materials are used to give 9-chloro-N, N-dimethyl-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepin-2-amine.