FI68832B - REFERENCE FORM OF A THERAPEUTIC FRAME THERAPEUTIC PYIMIDO (5,4-D) (2) - Google Patents

Abstract

Pyrimido-2-benzazepines of the formula <IMAGE> wherein A is one of the groups <IMAGE> R<1> is hydrogen, chlorine, bromine, lower alkyl, the group NR<4>R<5>, the group -CH2-CO-R<7>, the group -NH(CH2)mNR<8>R<9>, hydroxy, lower alkoxy, mercapto or lower alkyl mercapto, R<2> is hydrogen, amino or di-lower alkyl amino, R<3> is hydrogen, lower acyloxy or hydroxy, X is hydrogen, halogen, trifluoromethyl, ethyl alpha -hydroxy ethyl or acetyl, Y is hydrogen or halogen, R<4> and R<5> each are hydrogen or lower alkyl or, together complete a five to seven membered heterocyclic ring, R<7> is hydroxy, lower alkoxy or NR<8>R<9>, R<8> and R<9> each are hydrogen or lower alkyl, n is 0 or 1 and m is 1 to 7, with certain provisos, and pharmaceutically acceptable acid addition salts thereof, exhibit pharmacological utility as anxiolytics and sedatives.

Description

ΓΒ1 «« NOTICE OF PUBLICATION, Ofi70 l J (11; utläggningsskrift o -> co 1 C (45) Patent granted 11 11 1935 (51) Kv.lk. * / Lnt.CI.4 C 07 0 i * 87/04 FINLAND - FINLAND (21) Patent application - Patentansökning 800367 (22) Application date - Ansökningsdag 06 02 8 0 fFh '/ (23) Start date - Giltighetsdag 06.02.80 (41) Published public - Blivit offcntlig Qg gg gg

National Board of Patents and Registration / 44) Date of display and publication. - (17 8 ^

Patent and registration authorities' 7 Ansökan utlagd och utl.skriften publicerad J 1 u / .03 (32) (33) (31) Privilege claimed - Begärd priority 07.02.79 01.03.79 USA (US) 10118, I67O9 22.01.80 Switzerland -Schweiz (CH) 510/80 (71) F. Hoffmann-La Roche & Co. Aktiengesel1schaft, Grenzacherstrasse 12 ^ -184, Basel, Switzerland-Switzerland (CH) (72) Eugene J. Trybulski, Montclair, NJ, Rodney Ian Fryer, North Caldwell, NJ, Norman W. Gilman, Wayne, NJ, Armin Walser, West Caldwell, NJ, USA (US) (7 ^) Oy Koister Ab (5 ^) Process for the preparation of therapeutically useful pyrimido (S ^ -d // 2) benzazepines - Förfarande för framstälIning av terapeutiskt användbara pyrimido (S ^ - d) / ^ z / bensazepiner

The invention relates to a process for the preparation of pharmaceutically usable pyrimido [5,4-c] H 2 benzazepines of the general formula I

R1 (O) x? n N. /).

il ^ 1

* sS / "" 'C = N x k .Y

σ 2 68832 wherein R · * · is hydrogen, lower alkyl, amino, di-lower alkylamino, mercapto or lower alkyl mercapto, X is hydrogen or halogen, Y is hydrogen or halogen, n is 0 or 1, wherein the groups referred to as "lower" mean a group having up to 7 carbon atoms, provided that when n is 1, then p is 1 and R · * · does not represent mercapto or lower alkyl mercapto, and to prepare pharmaceutically acceptable acid addition salts thereof. These compounds are pharmacologically active anxiolytics and sedatives.

As used herein, the term "lower alkyl" means a straight-chain or branched hydrocarbon group having 1 to 7, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, and the like.

The term "halogen" encompasses all four halogens, i. fluorine, chlorine, iodine and bromine, unless otherwise specified.

The terms "lower alkoxy" and "lower alkyl mercapto" refer to groups of the formulas -O-lower alkyl and -S-lower alkyl, wherein lower alkyl is as defined above.

The term "pharmaceutically acceptable salts" refers to salts of 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 formed by methods known in the art and taking into account the nature of the compound to be salified.

Of the compounds of formula I above, those are preferred in which p is 0 and n is 0, X is halogen, preferably chlorine, and Y is hydrogen, chlorine or fluorine.

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

Other preferred compounds are 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] 2H-benzazepine; 9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [4,5-d] benzazepine; 9-chloro-N, N-dimethyl-7- (2-fluorophenyl) -5H-pyrimido [4,5-d] [2,2] benzathepin-2-amine.

3,63832

According to the invention, the compounds of formula I and their pharmaceutically acceptable acid addition salts can be prepared by:

a) for the preparation of a compound of formula I wherein n is 0, a compound of general formula IV is obtained

21

0 CH-R

t jj. ;>

X X 'I IV

JwY p! ’J 21

wherein p, X and Y are as defined above and R is di-Alem-pi-alkylamino, to react with a compound of general formula V

. O NH 1 f '' "RC. V 'nh 2 wherein R 1 is as defined above, or b) for the preparation of a compound of formula I wherein R 1 is amino or di-lower alkylamino and n is 0, a compound of formula V or c) to prepare a compound of formula I wherein p is 0, R · * "is hydrogen, lower alkyl, amino or di-lower alkylamino and n is 0, 1) cyclizing a compound of the general formula the formula is II R11 o li I Xch2-nh2 ix v, -. :: 0 X i

s1 .. Y

Wherein X and Y are as defined above and R 1 is hydrogen, lower alkyl, amino or di-lower alkylamino, or

2) dehydrogenating a compound of general formula III

r11--

Hdj li / 7 111

x N

\ yi j where X, Y and R11 have the same meaning as above, and if desired

d) deoxidizing a compound of general formula II

R11

'N

OF

'M' y "x 'I - / x' J, °

ιΓ T

wherein R 11, X and Y are as defined above, or if desired e) oxidizing a compound of general formula Ie R 11 V UJ - ··

Y

5 68832 wherein R 1 · * ·, Y and X have the same meaning as above, and / or if desired f) the compound of formula I is converted into a pharmaceutically acceptable acid addition salt.

The above process variants c1) and c2) and the preparation of the starting materials used therein are shown in the following Reaction Scheme I, in which X, Y and R11 have the same meanings as above: 6 68832

Reaction Scheme I

Γ

I / VI I VII I VIII

o

/ ^^ CCH5CN ^ \ ^ CO CH

^ N> ^^ ch2ci x / (J x U ix R11

)-OF

/ \ O CHNICHt) o n.,) ^ JuUn

jf fT O> ^ | CN

XI I ^ XII

r "Γ 'x b") = \ rft - rft J I o CH2— ^ H2

I In | ^ II

k ^ k L \ k 7 60832

The compounds of formulas VI, VII and VIII are known. Their production method is shown below.

VI * VII

The compound of formula VI, which is a known compound, is treated with sulfuric acid, sodium nitrite and optionally sodium tetrafluoroborate, respectively, and then reacted with cuprocyanide. The mixture is then hydrolysed or sucked with hydroxide, e.g. sodium or potassium hydroxide, at reflux temperature.

VII - »VIII

A compound of formula VIII is prepared by reacting a carboxylic acid of formula VII with methanol in the presence of an acid catalyst such as sulfuric acid at reflux for about 3-18 hours.

VIII ___ »IX

The compound of formula VIII is then reacted with 1-chloro-2,3-epoxypropane or another suitable epoxide ketalization reagent such as ethylene oxide and 1,2-epoxypropane in the presence of a Lewis acid such as aluminum chloride or boron trifluoride or preferably stannic chloride in an inert atmosphere. in an organic solvent such as toluene, carbon tetrachloride or benzene. A suitable reaction temperature is 20 to 110 ° C, preferably 25 ° C.

IX '- »X

The compound of formula IX is then reacted with acetonitrile (CH 3 CN) in the presence of an early metal amide such as sodium or potassium amide in liquid ammonia in the presence of an inert organic solvent such as diethyl ether, tetrahydrofuran or dioxane. The reaction temperature can range from the reflux temperature of liquid ammonia to room temperature.

X - »XI

The compound of formula V is then reacted with a dialkoxyacetal of dimethylformamide, such as dimethylformamide-dimethylacetal. A suitable reaction temperature is about 25 to 120 ° C, preferably the reflux temperature of dimethyl acetal.

68832 8

XI - »XII

The compound of formula XI is converted to the compound of formula XII in two steps, namely in the reaction of formula

/ NH

With an appropriate acid addition salt of an amidine or guanidine (as defined above) of P11R R 2 N 2 H 2, and then by acid hydrolysis of the ketal function. When X and Y are both hydrogen, the acid hydrolysis of the ketal function is preferably performed before the reaction with the amidine or guanidine salt, while when X and / or Y is other than hydrogen, the acid hydrolysis of the ketal function is preferably performed after the reaction with the amidine or guanidine salt. Prior to the next reactions, by-products must be removed from the reaction mixture.

The reaction with an appropriate acid addition salt of an amidine or guanidine of formula Va such as formamidine acetate, acetamidine hydrochloride, guanidine carbonate or substituted guanidine carbonate is conveniently carried out in an aprotic polar organic solvent such as dimethyl sulfoxide at a temperature in the range of about 25 ° C to about 25 ° C.

The ketal function is hydrolyzed with an aqueous inorganic acid such as sulfuric acid, phosphoric acid or preferably a hydrohalic acid such as hydrochloric acid in the presence of a lower alkyl alcohol, preferably ethanol. The reaction is carried out at about room temperature.

XII -> II

A compound of formula II is formed by hydrogenating a compound of formula XII in the presence of a metal catalyst such as a platinum, palladium or Raney nickel catalyst to self-cyclize to give a compound of formula In. The hydrogenation may be carried out in a suitable organic solvent such as a lower alkyl alcohol or a lower alkyl carboxylic acid, e.g. acetic acid. Depending on the hydrogenation conditions, in addition to or instead of the compound of formula In, a hydropyrimidio compound of formula III may be obtained. The resulting dihydro-9,68832 pyrimido compound can be converted to a compound of formula In by treatment with a weak oxidant * such as manganese dioxide, air and the like.

Process variant b) can be described by the following reaction scheme II:

Reaction Scheme II

H2N, (CH,) _ N

/ = N \ CO CO Oi IVa Io lp IVa fr Io and lp

The compound of formula IVa is known, for example, from U.S. Pat. Nos. 3,947,585, 4,022,800 and 4,028,381. The compound is reacted with cyanamide in a C 1 -C 4 alcohol, e.g. ethanol at a temperature in the range of 25 to 80 ° C, preferably the alcohol used. the reflux temperature.

A mixture of an amino compound and a Ν, Ν-disubstituted amino compound is obtained, which can be separated, for example, by fractional crystallization and / or chromatography.

In process variant a) a compound of formula IV is reacted with an amidine or guanidine salt or with a thiourea or S-lower alkylthiourea. Any organic solvent such as dioxane, tetrahydrofuran or dimethylformamide can be used in the reaction with the amidine or guanidine salt, and the reaction temperature can be from about room temperature to reflux temperature, preferably the reflux temperature of the solvent. The reaction with a thiourea or S-lower alkylthiourea can be carried out in an alcoholic solution of an alkali metal alkoxide, e.g. sodium methoxide, e.g. in methanol. The reaction may be carried out at about 0 to 65 ° C, preferably at room temperature.

Optional process option e) can be described by the following reaction scheme IV, in which R 1 represents the same as above: 11 68832 11

Reaction Scheme IV R11

-OF

^ y} ^ I ^) \ R "

> = \ M

68832

The compound of formula In is reacted with a suitable oxidizing agent such as m-chloroperbenzoic acid in an inert organic solvent such as methylene chloride. The reaction can be carried out at a temperature of about 0 ° C to room temperature, preferably at room temperature. The reaction time varies depending on whether it is desired to prepare N-oxide or di-N-oxide. N-oxide Iq is predominantly formed when the reaction time is about 2-25 hours, while di-N-oxide is predominantly obtained with a reaction time of ^0-60 hours.

Deoxidation according to optional process variant f) in a manner known per se, e.g. with reagents such as phosphorus trioxychloride, tri-lower alkyl phosphites (e.g. triethyl phosphite), hexachlorodisilane, Raney-Nikke and others.

For the sake of completeness, the following reaction scheme VII, in which X and Y are as defined above, describes the preparation of starting materials of formula IV in which p is 1: 6 8 8 32 13

Reaction Scheme VII 0 nHN (CH3) 2 o

XJD

Y

| IVb I.

JOO · XXD

a XIX i. XVIII

m 68832

The compound of formula XVII may be reacted with a peracid such as m-chloroperbenzoic acid in an inert organic solvent such as a halogenated hydrocarbon, e.g. methylene chloride, or ether. The reaction may be carried out at about 0 to 40 ° C, preferably at room temperature. The reaction products can then be separated from the mixture by fractional crystallization. The thin layer chromatogram shows that both products are present.

The compound of formula XVIII may be reacted with dimethyl acetal in an inert solvent such as a halogenated hydrocarbon, e.g. methylene chloride, or methylene formamide or a high boiling ether. The reaction temperature may be about U-10 ° C, preferably room temperature.

The pyrimido-2-benzazepines of formula I and their pharmaceutically acceptable acid addition salts are useful drugs that can be used as hypnotics and antianxiety agents. These compounds can be used in the form of conventional pharmaceutical preparations; said compounds may, for example, 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, gums, polyalkylene glycols, polyalkylene glycols, with. They can be administered as a medicine in conventional pharmaceutical forms, e.g. solid, such as tablets, granules, capsules, suppositories, etc., or liquids, such as solutions, suspensions or emulsions. In addition, pharmaceutical compositions containing the compounds of the present invention may be subjected to conventional pharmaceutical procedures, such as sterilization, and may contain conventional pharmaceutical additives such as preservatives, stabilizers, wetting agents, emulsifiers, salts for adjusting the osmotic pressure or buffers. The compositions may also contain other therapeutically active substances.

The following compounds were subjected to certain well-known experiments, such as a sloping test, an electric shock test, an anesthetized cat test, and an anti-pentanethylenetetrazole test (metrazole test). The results of these experiments as well as the toxicity values of the compounds are summarized in the table below.

Il 15 688 32 1. Prepared compounds A according to the invention: 9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido-

Z1, 4-d. [2] benzazepine B: 9-chloro-7- (2-chlorophenyl) -5H-pyrimido [4,5-b] [2,7-benzazepine C: 9-chloro-7- 2-fluorophenyl) -5H-pyrimido [4,5-d] 27-benzazepin-2-amine D: 9-chloro-7- (2-chlorophenyl) -6,7-dihydro-2-methyl-5H- pyrimidoZ "5,4-d (Z2_) benzazepine dihydrochloride H: 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [4,5-d] [2.7,7] benzazepine K: 9-chloro-7- (2 (fluorophenyl) -N, N-dimethyl-5H-pyrimido [4,5-d] benzazepin-2-amine P: 9-chloro-7- (2-chlorophenyl) -5H-pyrimido 1,4-d] 2,7-benzazepine-6-oxide Q: 9-Chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [7,4-d] [2] benzazepine-2,6 -dioxide.

2. Known compounds (DE-A-2 524 048) X: 8-chloro-6-phenyl-1,4-dihydropyrazolo [4,3-d] [77] benzazepine Y: 8-chloro-6- (2- fluorophenyl) -1,4-dihydrol-methylpyrazolo [4,3-d] benzazepine Z: 8-chloro-2-methyl-6-phenyl-2H, 4H-pyrazolo [4,3-b] 7,7-benzazepine hydrochloride.

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AA / \ / \ a) • a 1 co, P · A <CQOQeCACXO'X> - * [Sl _L ____________—-— -—---- 17 688 32

A suitable pharmaceutical dosage unit may contain from about 1 to about 500 mg of a compound of formula I, or a pharmaceutically acceptable acid addition salt thereof, wherein the preferred oral dose is from about 1 to about 100 mg, and the preferred parenteral dose is from about 1 to 50 mg. However, the dosage should be individualized for each subject, depending on the individual need and the judgment of the person prescribing the dosage. It is to be understood that the above dosages are exemplary only and are not intended to limit the scope of the present invention in any way.

As used herein, the term "dosage unit" refers to pharmaceutically separate units that can be administered to a lactating subject, each containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect, and the required pharmaceutical diluent, carrier, or vehicle.

The following examples illustrate the invention. Examples I-XVII illustrate the preparation of starting materials and Examples 1-27 illustrate the process of the invention. All temperatures are in degrees Celsius unless otherwise noted.

Example 1 2-Amino-9-chloro-7-phenyl-5H-pyrimido [4,5-d] 2 / benzazepine 8-Chloro-3,4-dihydro-4- (dimethylaminomethylene) -1-phenyl- To a suspension of 1 H-2H-2-benzazepin-5-one (10 g, 0.032 mol) and guanadine carbonate (8.5 g, 0.047 mol) in 250 mL of methanol was added 5.1 g (0.094 mol) of the mixture at room temperature with stirring under argon. mol) sodium methylate. After 10 minutes, 150 ml of methylene chloride was added and stirring was continued. The same amounts of sodium methylate and guanadine carbonate were added 2 more times at 2 hour intervals, and stirring was continued overnight. The reaction mixture was diluted with 250 ml of methylene chloride, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from ethanol to give light brown crystals, m.p. 209-210 ° C. Recrystallization from methylene chloride / ethyl acetate gave off-white prisms, m.p. 210-211 ° C.

63832 18

Example 2 2-Amino-9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] 2H-benzazepine 8-Chloro-1- (2-fluorophenyl) -3,4-dihydro To a suspension of -4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one (1G g, 0.047 mol) and guanidine carbonate (12.5 g, 0.07 mol) in 460 ml of methanol was added with stirring at room temperature. 7.5 g (0.14 mol) of sodium methylate in one portion at room temperature under argon. After 10 minutes, methylene chloride (290 mL) was added and stirring was continued. The same amounts of sodium methylate and guanidine carbonate were added 2 more times at 2 hour intervals and stirring was continued overnight. The reaction mixture was diluted with 460 ml of methylene chloride, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from ethanol / methylene chloride to give off-white crystals, m.p. 245-248 ° C.

The dihydrochloride

A warm solution of the compound prepared above in 100 mL of methanol / methylene chloride (1: 1) was filtered and evaporated on a steam bath to half volume. To the filtrate was added 5 ml of 5.7 N HCl-ethanol solution, and the mixture was allowed to stand at room temperature for 2 hours. The resulting pale yellow crystals were filtered, washed with ethanol and air dried. The resulting dihydrochloride salt had m.p. 232-237 ° C.

Example 3 9-Chloro-2-methyl-7-phenyl-5H-pyrimido [5,4-d] benzazepine 8-Chloro-3,4-dihydro-4- (dimethylaminomethylene) -1-phenyl A suspension of -nyl-5H-2-benzazepin-5-one (1.6 g, 0.005 mol) and acetamidine hydrochloride (0.7 g, 0.0075 mol) in 50 ml of methanol was stirred at room temperature under argon and added 0.8 g (0.015 mol) of sodium methylate in one portion.

After stirring for 10 minutes, 30 ml of methylene chloride was added to the mixture, and stirring was continued. After 2 hours, an additional 0.8 g (0.015 mol) of sodium methylate and 0.7 g (0.0075 mol) of acetamidine hydrochloride were added. After another 2 hours, 0.015 mol of sodium methylate and 0.0075 mol of acetamidine hydrochloride were added and stirring was continued at room temperature overnight. The reaction mixture was diluted with 50 ml of methylene chloride, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized by dissolving it in 20 ml of warm hexane and cooling the solution. Evaporation of the solvent gave a second crop of product. Recrystallization from hexane (activated carbon) gave off-white crystals, m.p. 120-122 ° C.

Example 4 9-Chloro-7- (2-fluorophenyl) -2-methyl-5H-pyrimido [4,5-d] p-benzazepine 8-Chloro-1- (2-fluorophenyl) -3,4-dihydro To a suspension of -4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one (5.1 g, 0.015 mol) and acetamidine hydrochloride (2.1 g, 0.0225 mol) in 150 mL of methanol was added. 2.4 g (0.045 mol) of sodium methylate in one portion under stirring at room temperature under argon. After stirring for 10 minutes, 90 ml of methylene chloride was added, and stirring was continued. After 2 hours, an additional 2.4 g (0.045 mol) of sodium methylate and 2.1 g (0.0225 mol) of acetamidine hydrochloride were added. The addition of sodium methylate (0.045 mol) and acetamidine hydrochloride (0.0225 mol) was repeated again after 2 hours, and the mixture was stirred at room temperature overnight.

The mixture was diluted with 150 ml of methylene chloride, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from hexane (activated carbon) to give white crystals, m.p. 104-107 ° C.

Example 5 9-Chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] 2 / benzazepin-2-amine and 9-chloro-7- (2-fluorophenyl) -N, N-dimer -thyl-5H-pyrimido [5,4-d] benzazepine-2-amine 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] A solution of -5H-2-benzazepin-5-one (7.0 g, 0.0204 mol) and cyanamide (3.5 g, 0.0833 mol) in 300 ml of absolute ethanol was refluxed for 18 hours, then the mixture was evaporated to dryness. . The residue was washed with water, filtered and crystallized twice from methanol to give the N, N-dimethylamino compound. The filtrates were concentrated, the precipitate was filtered and recrystallized from methanol to give the amino compound. The filtrates were evaporated, the residue was dissolved in dichloromethane and the solution was chromatographed on Florisil *. The column was eluted with dichloromethane, the eluate evaporated and the residue crystallized from methanol to give an additional portion of N, N-dimethylamino. Crystallization from dichloromethane / ether gave white needle-like crystals, m.p. 175-180 ° C.

The column was then eluted with 5% ether in dichloromethane and then ether. The ether fraction was evaporated and the residue was crystallized from methanol to give an additional portion of the amino compound. Recrystallization from methanol gave white prisms, m.p. 242-247 ° C.

To a solution of the N, N-dimethylamino compound (0.2 g, 0.5 mmol) in 5 mL of methanol was added 0.05 g (0.5 mmol) of methanesulfonic acid. The methanol was evaporated and the residual oil was crystallized from methanol / ether to give yellow prisms, m.p. 190-195 ° C.

Example I

2- (2-Fluorobenzoyl) -4-chlorobenzoic acid methyl ester A solution of 2- (2-fluorobenzoyl) -14-chlorobenzoic acid (2.0 g, 7.19 mmol) in 40 mL of methanol was boiled in the presence of sulfuric acid (0.3 mL). hours, then the mixture was evaporated.

The residue was partitioned between dichloromethane (50 ml) and dilute ammonium hydroxide (30 ml), the organic layer dried and evaporated. The resulting oil was dissolved in 20 mL of dichloromethane, the solution was poured into a Florisil layer (25 g) and eluted with dichloromethane. The solvent was evaporated, the oil obtained was crystallized from ether and then from dichloromethane / ether / petroleum ether to give white rods, m.p. 115-116 ° C.

Es imerkkiII

4-Chloro-2- [4- (chloromethyl) -2- (2-fluorophenyl) -1,3-dioxolan-2-yl] benzoic acid methyl ester To a solution of the final product of Example i (47 g, 0.16 mol) in 350 mL dry toluene was added 21.4 ml (0.18 mol) of stannous chloride and after 5 hours with stirring over 30 minutes 25 ml of 21,68832 (0.308 mol) of 1-chloro-2,3-epoxypropane in 25 ml of toluene were added.

After 18 hours, an additional 12 mL (0.154 mol) of 1-chloro-2,3-epoxypropane was added over 15 minutes. After 4 hours, the reaction mixture was cooled in an ice bath and basified with concentrated ammonium hydroxide. The mixture was filtered through celite and the Celite was washed with toluene. The combined filtrates were washed with 200 ml of water, dried over sodium sulfate and evaporated. The resulting oil was dissolved in 100 ml of dichloromethane and the solution was chromatographed on 500 g of alumina. The column was eluted with 4 liters of dichloromethane / petroleum ether (2: 1) to give an oil which was about 90-95% pure by thin layer chromatography. A sample crystallized from ether / petroleum ether as white prisms had m.p. 117-122 ° C.

Example III

2- [4-Chloromethyl-2- (2-fluorophenyl) -1,3-dioxolan-2-yl] -N - [(dimethylamino) methylene] -N-oxo- (4-chloro -phenyl) propanenitrile To 800 ml of liquid ammonia was added a small piece of sodium and some crystals of ferric nitrate. A total of 8.7 g (0.378 mol) of sodium was added with stirring over 30 minutes and after 15 minutes 20.1 ml (0.378 mol) of acetonitrile in 70 ml of ether were added over 15 minutes. After 10 minutes, a solution of the final product of Example II (56 g, 0.145 mol) in 250 ml of ether was added. The reaction mixture was stirred for 2 hours, then 700 ml of ether were added. The ammonia was also allowed to evaporate overnight, ice was added to the mixture and it was acidified with acetic acid. The reaction mixture was neutralized with saturated sodium bicarbonate solution, the aqueous phase was separated and extracted again with 500 ml of ether. The combined ether layers were washed with brine (200 mL), dried over sodium sulfate and evaporated to dryness. The crude oil obtained as a residue was dissolved in 150 ml of dichloromethane, the solution was applied to a Florisil column (400 g) and the column was eluted with 1.5 liters of dichloromethane to give 90-95% pure oily product by TLC.

48 g of an oil were refluxed and stirred with Ν, Ν-dimethylformamide dimethylacetal for 90 minutes, then the mixture was evaporated to dryness. The residue was triturated in 300 ml of ice water, the water was decanted. The residual oil was dissolved in 300 ml of dichloromethane, the solution was washed with 200 ml of water and dried over sodium sulfate. The solution was evaporated and the residue was crystallized from dichloromethane / ether to give the final product. The filtrates were evaporated, the residue was dissolved in 100 ml of dichloromethane and the solution was taken up in 300 g of Florisil. Elution with dichloromethane (400 ml) and ether (1.5 L), evaporation and crystallization of the evaporation residue from dichloromethane / ether gave the final product. The oily final product from the filtrates was about 85% pure by TLC. An analytical sample was obtained by crystallization from the same solvent, off-white prisms were obtained, m.p. 143-147 ° C.

Example IV

2-Amino-4- [2- / 4- (chloromethyl) -2- (2-fluorophenyl) -1,3-dioxolan-2-yl] -4-chlorophenyl] pyrimidine-5-carbonitrile The final product of Example III (1.0 To a solution of g, 0.00223 mol) in 8 ml of dry dimethyl sulfoxide were added 4 g of molecular sieves (type 5A) and 0.7 g (0.00389 mol) of guanidine carbonate. The mixture was stirred at 90-95 ° C for 5 hours, cooled and treated with 50 ml of dichloromethane. The solution was decanted and the solid was washed several times with dichloromethane and water. The combined solutions were separated, the organic phase was washed with dilute brine (2x), dried over sodium sulfate and evaporated to a small volume. This solution was developed on a 4: 1 thick layer silica gel plate with dichloromethane / ethyl acetate (3: 1). Zone Rf 0.4 was removed, crystallized twice from methanol to give off-white prisms, m.p. 184-191 ° C.

Example y 2-Amino-4- [2- (2-fluorobenzoyl) -4-chlorophenyl] pyrimidine-5-carbonitrile

A solution of the final product of Example IV (0.2 g, 0.448 mmol) in 20 mL of methanol and 10 mL of 3N hydrochloric acid was refluxed for 20 minutes, then the solvent was evaporated. The residue was partitioned between dichloromethane (50 ml) and dilute ammonium hydroxide (30 ml), the organic layer dried, concentrated and applied to a Florisil column (15 g Florisil). The column was eluted with 200 ml of ether, the eluate was concentrated, filtered and the product obtained as white prisms by crystallization from dichloromethane / ether / petroleum ether, m.p. 153-157 ° C.

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

To a solution of the final product of Example v (50 mg, 0.142 mmol) in 10 mL of acetic acid was added 1/4 spatula of Raney nickel, and the mixture was hydrogenated for 2.5 hours. The reaction mixture was filtered, pre-evaporated and the residue was partitioned between dichloromethane (30 ml) and dilute ammonium hydroxide (15 ml). The organic layer was dried over sodium sulfate, evaporated, and the residue was refluxed in ethanol for 1 hour, then the mixture was evaporated to dryness. The residue was dissolved in dichloromethane, and the solution was developed on a thick pad of silica gel with ethyl acetate / ethanol (20: 1). Zone Rf 0.3 was separated and recrystallized from etheric white prisms, m.p. 243-248 ° C. The melting point with the authentic product prepared in Example 2 was 244-248 ° C.

Example VI

2- [4- (Chloromethyl) -2-phenyl-1,3-dioxolan-2-yl] benzoic acid methyl ester To a solution of 2-benzoylbenzoic acid methyl ester (33 g, 0.138 mol) in 200 mL of dry carbon tetrachloride was added. 10.1 ml (0.13 mol) of 1-chloro-2,3-epoxypropane. The reaction mixture was cooled in an ice bath, and 1.5 ml (0.013 mol) of stannous chloride in 10 ml of carbon tetrachloride was added over 20 minutes with stirring. The reaction mixture was allowed to stand over the end of the week, then the same amount of 1-chloro-2,3-epoxypropane and stannous chloride were added. After 18 hours of reaction, the reaction mixture was cooled in an ice bath and neutralized with concentrated ammonium hydroxide.

The precipitate was filtered and washed with dichloromethane, and the combined filtrates were washed with 150 ml of water, dried over sodium sulfate and evaporated. The resulting oil was dissolved in 100 ml of dichloromethane, and the solution was chromatographed on 500 g of neutral alumina. Elution with 3 liters of dichloromethane gave the final product as an oil which was about 95% pure by TLC. Crystallization of a small sample twice from ether / petroleum ether gave white rods, m.p. 90-91 ° C.

Example VII

2- [4- (Chloromethyl) -2-phenyl-1,3-dioxolan-2-yl] -O4- (dimethylamino) methylene] -N-oxobenzenepropanenitrile To 75 ml of liquid ammonia was added a small piece of sodium and some crystals of ferric nitrate. . A total of 1.15 g (0.0502 mol) of sodium was added over 20 minutes, and after 5 minutes a solution of acetonitrile (2.9 ml, 0.050 mol) in 10 ml of ether was added dropwise. A solution of the final product of Example VI (6.6 g, 0.0198 mol) in 40 ml of ether was then added dropwise and after 2 hours 100 ml of ether were added and the ammonia was allowed to evaporate. About 100 g of ice was added to the reaction mixture, the mixture was acidified with acetic acid and then neutralized with saturated sodium bicarbonate solution. The aqueous layer was separated and extracted once more with 100 ml of water, dried over sodium sulfate and evaporated. The residual oil was dissolved in 15 ml of dichloromethane, and the solution was poured onto 100 g of Florisil. Elution with dichloromethane and evaporation of the eluate gave 2- [4- (chloromethyl) -2-phenyl-1,3-dioxolan-2-yl] -bb-oxobenzenepropanenitrile, which was used as such without purification.

A solution of the propanenitrile (20 g, 0.0585 mol) obtained above in 75 ml of N, N-dimethylformamide dimethyl acetal was refluxed with stirring for 90 minutes, then the solution was evaporated to dryness. The resulting oil was triturated in ice water, the water was decanted and the residue was partitioned between dichloromethane (150 ml) and water (150 ml). The organic layer was dried over sodium sulfate, concentrated and poured onto 150 g of Florisil. The column was eluted with ether, the ether was evaporated and the resulting oil was crystallized from ethanol. A portion of the resulting final product was recrystallized from dichloromethane / ether to give white prisms, m.p. 107-110 ° C.

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Example VIII

2-Amino-4- (2-benzoylphenyl) pyrimidine-5-carbonitrile and 1-oxo-3-phenyl-1H-indene-2-carbonitrile To a solution of the final product of Example VII (2.0 g, 0.00504 mol) in 10 mL: In dichloromethane were added 10 ml of methanol and 2 ml of 0.0192 mol) of 9.6 N HCl in ethanol. After 90 minutes, the solvent was evaporated and the oil partitioned between dichloromethane (50 ml) and saturated sodium bicarbonate solution (30 ml). The organic layer was dried over sodium sulfate and evaporated. The obtained oil (1.5 g) was dissolved in 30 ml of methanol, and 1.5 g (0.00833 mol) of guanidine carbonate was added to the solution. The solution was stirred for 90 minutes and then refluxed for 2 hours. The reaction mixture was evaporated and then partitioned between dichloromethane (50 ml) and dilute ammonium hydroxide (30 ml). The organic layer was dried over sodium sulfate and taken up in 50 mL of Flori-Silia. The column was eluted with dichloromethane (200 ml) and then ether (300 ml). The dichloromethane fraction was evaporated, the title indene compound was crystallized twice from dichloromethane / petroleum ether to give yellow rods, m.p. 173-175 ° C.

The ether fraction was evaporated and the title pyrimidine compound was obtained by crystallization from dichloromethane / petroleum ether, m.p. 195-199 ° C. The assay sample was crystallized from methanol to give off-white prisms, m.p. 197-200 ° C.

Example 7 7-Phenyl-5H-pyrimido [5,4-d] 2 / benzazepin-2-amine To a solution of the pyrimidine compound of Example VII (3.1 g, 0.0103 mol) in 60 mL of glacial acetic acid was added 1 teaspoon of Raney nickel. , and the solution was hydrogenated for 8.5 hours. The reaction mixture was filtered through celite, the filtrate was evaporated and the residue was partitioned between dichloromethane (50 ml) and dilute ammonium hydroxide (30 ml). The organic layer was dried over sodium sulfate and evaporated. The residual oil was refluxed in 75 ml of methanol for 15 minutes, the mixture was evaporated and the residue was dissolved in 100 ml of dichloromethane. Thin layer chromatography showed that in addition to the product, there was a substantial spot with a lower Rf. This spot was apparently caused by the presence of a dihydropyrimide such as 7-phenyl-3,4-dihydro-5H or, less likely, -1,4-dihydro-5H-pyrido [5,4-d] / 2 / presence of benzazepine-2-amine because slight oxidation of the crude reaction mixture converted the product to a low Rf spot. To the above oil was added 3 g of activated manganese dioxide, and the mixture was refluxed with stirring for 30 minutes. The mixture was filtered, concentrated and chromatographed on 100 g of Florisil. The column was eluted with 300 ml of dichloromethane, 500 ml of ether and 1.5 liters of ethyl acetate. The ethyl acetate fraction was evaporated, the resulting oil was crystallized from ether and recrystallized from dichloromethane / ether to give white rods, m.p. 239-242 ° C. The filtrates and ether fractions of the column were evaporated and chromatographed on silica gel thin layer plates in ethyl acetate / methanol (20: 1) to give more product. The analytical sample was obtained as white crystals by crystallization from ether, m.p. 201-205 ° C, the re-solidified product was obtained as rods, m.p. 240-243 ° C.

Example 8 9-Chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] [2] benzazepine 8-Chloro-1- (2-chlorophenyl) -3,4-dihydro- To a solution of 4- (dimethylamino) methylene / -5H-2-benzazepin-5-one (3.5 g, 10 mmol) in a mixture of methanol (140 mL) and methylene chloride (140 mL) was added 5.5 equal portions over 5 hours. g (58 mmol) of acetamidine hydrochloride and 15 ml (62 mmol) of 4,12-molar methanolic sodium methoxide solution. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting amber oil was dissolved in 10 mL (10 mmol) of a 1 M methanolic solution of methanesulfonic acid, from which the salt was precipitated as yellow prisms by the addition of ether, m.p. 193-197 ° C. Recrystallization from a mixture of methanol and ether gave yellow prisms, m.p. 197-198 ° C.

Example 9 9-Chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] 2H-benzazepine 8-Chloro-1- (2-chlorophenyl) -3,4-dihydro-4- [ To a solution of (dimethylamino) methylene / -5H-2-benzazepin-5-one (7.2 g, 20 mmol) in a mixture of methanol (270 mL) and methylene chloride (270 mL) was added 21 g in 3 equal portions over 3 hours. 68832 (200 mmol) of formamidine acetate and 32.5 ml (135 mmol) of a 4,12 molar solution of sodium methoxide in methanol. The solution was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting amber oil was purified by chromatography (100 g silica gel, eluent methylene chloride / ethyl acetate 1: 1). The product obtained (m.p. 122-124 ° C) was recrystallized from ether to give pale yellow prisms, m.p. 122-125 ° C.

Example 10- 9-Chloro-7- (2-chlorophenyl) -2-isopropyl-5H-pyrimido [5,4-d] - (2H-benzazepine 1- (2-chlorophenyl) -3,4- dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one (3.5 g, 10 mmol) in isobutyramidine hydrochloride (4.8 g, 40 mmol), 4,12 molar A mixture of a solution of sodium methoxide in methanol (10 ml, 41 mmol) and methanol (100 ml) was stirred at room temperature for 2 hours, diluted with water and extracted with methylene chloride. solid, mp 127-129 ° C. Recrystallization from a mixture of ether and petroleum ether gave colorless rods, mp 127-129 ° C.

Example 11 2-Amino-9-chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine 8-Chloro-1- (2-chlorophenyl) -3,4-dihydro To a solution of 4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one (3.6 g, 10 mmol) in 100 mL of methanol was added 14.4 g (80 g) of 80 equal portions over 90 minutes. mmol) of guanidine carbonate and 20 ml (82 mmol) of a 4,12 molar solution of sodium methoxide in methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting yellow oil was crystallized from methylene chloride to give a white solid, m.p. 240-241 ° C. Recrystallization from a mixture of ether and methylene chloride gave colorless needles, m.p. 240-241 ° C.

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Example 12 7- (2-Chlorophenyl) -2-methyl-5H * -pyrimido [5,4-d] 2H-benzazepine methanesulfonate 1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) ) To a solution of methylene / -5H-2-benzazepin-5-one (4.5 g, 14 mmol) in a mixture of methanol (180 mL) and methylene chloride (180 mL) was added 7.2 equal portions over 7.2 h. g (76 mmol) of acetamidine hydrochloride and 18 ml (80 mmol) of a 4.46 molar solution of sodium methoxide in methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride extract was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting amber oil was dissolved in a mixture of isopropanol (15 mL) and methanesulfonic acid (1.3 g, 14 mmol), and the isopropanol was evaporated under reduced pressure.

The residue was crystallized from a mixture of ether and methylene chloride to give a pale yellow solid, m.p. 147-151 ° C recrystallization from a mixture of ether and methylene chloride gave the compound hemihydrate as yellow prisms, m.p. 159-160 ° C.

Example 13 2-Methyl-7-phenyl-5H-pyrimido [5,4-d] benzazepine dihydrochloride 1-Phenyl-3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepine To a solution of -5-one (4.5 g, 15 mmol) in a mixture of methanol (180 mL) and methylene chloride (180 mL) was added 9.0 g (95 mmol) of acetamidine hydrochloride and 22.5 mL (0 mL) of 5 equal portions over 3 hours. , 1 mol) of a 4.46 molar methanolic solution of sodium methoxide. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting oil was dissolved in an excess of 6% HCl-methanol solution, and the solvent was evaporated under reduced pressure. The residue was crystallized from a mixture of ether and methylene chloride to give a white solid, m.p. 211-221 ° C. Recrystallization from a mixture of methanol and ether gave yellow flakes, m.p. 217-227 ° C.

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Example 14 9-Chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] [2H] benzazepine-6-oxide 9-Chloro-7- (2-chlorophenyl) - 2-methyl-5H-pyrimido [4,5-d] [2] benzazepine (2.0 g, 5.6 mmol) and 85% m-chloroperbenzoic acid (2.2 g, 10.8 mmol) in 100 ml of methylene chloride was stirred at room temperature for 21 hours. The methylene chloride solution was washed with cold dilute aqueous NaOH, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Purification by plug filtration of 25 g of silica gel, 1000 ml of eluent: ether / methylene chloride, (1: 1) gave a colorless substance, m.p. 215-216 ° C.

Example 15 9-Chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] [2] benzazepine-3,6-dioxide 9-Chloro-7- (2-chlorophenyl) - 2-methyl-5H-pyrimido [4,5-d] [2] benzazepine (3.8 g, 10.7 mmol) and 85% m-chloroperbenzoic acid (9.6 g, 47 mmol) a solution in 400 ml of methylene chloride was stirred at room temperature for 55 hours. The methylene chloride solution was washed with cold dilute aqueous Na 2 H, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. Purification by plug filtration (25 g silica gel, 400 ml eluent: ether / methylene chloride, 1: 1, and then 200 ml eluent methylene chloride / methanol, 9: 1) gave a colorless solid, m.p. 241-243 ° C.

Example IX

8-chloro-1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one 8-chloro-3,4-dihydro-1-one A mixture of (2-chlorophenyl) -5H-2-benzazepin-5-one (18.6 g, 61 mmol) and dimethylformamide dimethylacetal (149 mL) was heated at about 50 ° C for 12 hours.

The mixture was evaporated to dryness under reduced pressure. The residue was crystallized from a mixture of ether and methylene chloride to give the final product as a yellow solid, m.p. 170-171 ° C. Recrystallization from ether gave yellow prisms, m.p. 17 DEG-171 DEG C.

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Example X

1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one 1- (2-chlorophenyl) -3,4-dihydro-5H- A mixture of 2-benzazepin-5-one (3.4 g, 12.5 mmol) and dimethylformamide dimethyl acetal (28 mL) was refluxed for 2 hours. The mixture was evaporated under reduced pressure and the resulting solid residue was triturated with ether to give a tan solid, m.p. 155-157 ° C. Recrystallization from a mixture of methylene chloride and ether gave yellow prisms, m.p. 158-159 ° C.

Example XI

3,4-Dihydro-1-phenyl-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one 3,4-Dihydro-1-phenyl-5H-2-benzazepin-5-one (5.2 g, 22 mmol) and dimethylformamide dimethylacetal (43 ml) was refluxed for 4 hours. The mixture was evaporated under reduced pressure. The residue was crystallized from ether to give a yellow solid, m.p. 131-33 ° C. Recrystallization from ether gave yellow prisms, m.p. 131-132 ° C.

Example 16 9-Chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] benzazepine-2-thiol 8-chloro-1- (2-chlorophenyl) -3,4- dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one (2.8 g, 7.8 mmol), thiourea (2.8 g, 37 mmol) and 4.0 A mixture of molar sodium methoxide in methanol (8.0 mL, 32 mmol) was stirred at room temperature for 18 hours. The mixture was 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 evaporated under reduced pressure to give a yellow solid, m.p. 238-239 ° C. Recrystallization from tetrahydrofuran gave yellow crystals, m.p. 232-234 ° C.

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Example 17 9-Chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] benzyl azepine 8-chloro-3,4-dihydro-1- (2-fluorophenyl) -4- ((dimethylamino) methylene) -5H-2-benzazepin-5-one (34.2 g, 0.1 mol), formamidine acetate (62.4 g, 0.6 mol) and sodium methoxide (35 g, 0 mol). A mixture of 63 mol) in 700 ml of methanol was stirred at room temperature for 3 hours while passing nitrogen through the solution.

The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting red oil was suspended in boiling hexane, and the hexane solution was decanted. The final product was obtained by cooling and filtering the precipitate. Recrystallization from cyclohexane gave off-white crystals, m.p. 12 3-12 5 ° C.

Example 18 9-Chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] 2H-benzazepine-6-oxide 9-Chloro-7- (2-fluorophenyl) -5H-pyrimido] A solution of 5,4-dH / 2 / benzazepine (3.2 g, 10 mmol) and 85% m-chloroperbenzoic acid (3 g, 15 mmol) in 100 mL of methylene chloride was stirred at room temperature for 4 hours. The reaction mixture was washed with excess ice-cold dilute sodium hydroxide solution, dried over anhydrous sodium sulfate and filtered through hyflo. The filtrate was evaporated to dryness under reduced pressure. The residue was crystallized from a mixture of methylene chloride and ether to give the crude product, m.p. 185-186 ° C. Recrystallization from a mixture of methylene chloride and ether gave the pure product, m.p. 187-188 ° C.

Example 19 2-Amino-9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine-6-oxide 8-chloro-1- (2-fluorophenyl) -3 To a solution of 4-dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one 2-oxide (7.0 g, 20 mmol) in 200 mL of methanol was added over 2 hours. 28 g (150 mmol) of guanidine carbonate and 38 ml (150 mmol) of a 4.09 molar solution of sodium methoxide li 32 688 32 in equal doses. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The resulting red solid was crystallized from a mixture of methanol and ethyl acetate to give the title compound as fine yellow needles, m.p. 320-323 ° C.

Example XII

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

Method A. A mixture of 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one (7.2 g, 25 mmol) and dimethylformamide dimethylacetal (50 mL) was refluxed. for an hour. The mixture was evaporated to dryness under reduced pressure. The resulting tan crystals were recrystallized from ether to give yellow prisms, m.p. 228-233 ° C.

Method B. Crude 8-chloro-3,4-dihydro-1- (2-fluorophenyl) -5H-2-benzazepin-5-one (10 g, 35 mmol) and dimethylformamide dimethyl acetal (10 g, 84 mmol) in 10 ml of dimethylformamide was stirred at room temperature for 12 hours. The resulting precipitate was filtered and washed successively with ethanol and ether to give tan crystals that were identical in all respects to the authentic sample.

Example XIII

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 was prepared by the same method as 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4 - [(dimethylamino) methylene] - 5H-2-Benzazepin-5-one (Method A). It was obtained as yellow prisms, m.p. 180-183 ° C.

Example XIV

8-Chloro-1- (2-fluoro-phenyl) -3,4-dihydro-5H-2-benzazepin-5-one-2-oxide 8-Chloro-1- (2-fluoro-phenyl) -3,4- A mixture of dihydro-5H-2-benzazepin-5-one (6.4 g, 22 mmol) and m-chloroperbenzoic acid (6.4 g, 34 mmol) in 350 mL of methylene chloride was stirred at room temperature 33,63832 for 2 hours. The methylene chloride solution was washed with saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The resulting yellow oil was crystallized from a mixture of ether and petroleum ether to give off-white crystals, m.p. 166-168 ° C. Recrystallization from a mixture of ether and methylene chloride gave colorless prisms, m.p. 168-170 ° C.

Example XV

8-Chloro-1- (2-chlorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one 2-oxide 8-chloro-1- (2-chlorophenyl) -3,4-dihydro -5H-2-Benzazepin-5-one 2-oxide was prepared in a similar manner to 8-chloro-1- (2-fluorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one 2- oxide. It was obtained as yellow prisms, m.p. 184-187 ° C.

Example XVI

8-chloro-1- (2-fluorophenyl) -3,4-dihydro-4- (dimethylamino) methylene] -5H-2-benzazepin-5-one 2-oxide 8-chloro-1- (2- A mixture of fluorophenyl) -3,4-dihydro-5H-2-benzazepin-5-one 2-oxide (3.4 g, 11 mmol) and dimethylformamide dimethyl acetal (26 mL) was stirred at room temperature for 12 hours. The mixture was diluted with ether and the precipitate was collected. The yellow solid obtained, m.p. 175-178 ° C, recrystallized from a mixture of ether and ethyl acetate to give yellow needles, m.p. 193-194 ° C.

Example XVIII

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 was prepared in a similar manner to 8-chloro-1- (2-fluorophenyl) -3, 4-dihydro-4 - / (dimethylamino) methylene / SH-2-benzazepin-5-one-2-oxide. It was obtained as yellow prisms, m.p. 196-198 ° C.

Example 20 9-Chloro-7- (2-chloro-phenyl) -2-methyl-5H-pyrimido [5,4-d] [2] benzazepine-6-oxide 8-Chloro-1- (2-chloro-phenyl) - 4 - [(dimethylamino) methylene] -3,4-dihydro-5H-2-benzazepin-5-one 2-oxide (1 g, 2.8 mmol), 34,68832 acetamidine hydrochloride (1.0 g, 11 mmol) and a solution of 4,46 molar sodium methoxide in methanol (2.0 mL, 9.9 mmol) in 20 mL of methanol was stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was recrystallized from a mixture of ether and methylene chloride to give a colorless solid, m.p. 215-216 ° C.

Example 21 9-Chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] 2H-benzazepine-6-oxide 9-Chloro-7- (2-chlorophenyl) -5H-pyrimido [5 A mixture of 1,4-d / 2-benzazepine (6.8 g, 20 mmol), 85% m-chloroperbenzoic acid (6 g, 30 mmol) in 200 mL of methylene chloride was stirred at room temperature for 4 hours. The mixture was washed with excess ice-cold sodium hydroxide solution, dried over anhydrous sodium sulfate and filtered through hyflo. The filtrate was evaporated to dryness in vacuo. The residue was crystallized from a mixture of methylene chloride and ether to give the crude product, m.p. 228-229 ° C. Recrystallization from a mixture of methylene chloride and ether gave the title product, m.p. 216-217 ° C.

Example 22 9-Chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] 121-benzazepine 8-chloro-1- (2-chlorophenyl) -3,4-dihydro-4 - [(dimethylamine) -no) methylene / -5H-2-benzazepin-5-one (90.5 g, 0.25 mol), formamidine acetate (100 g, 0.96 mol) and formamide (1 L) were heated on a steam bath for 16 hours . The mixture was cooled to 0 ° C and the resulting precipitate was filtered, washed with water and dried to constant weight. The product was obtained as off-white crystals, m.p. 12-121 ° C.

Example 23 9-Chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] 2H-benzazepine-6-oxide 8-Chloro-1- (2-fluorophenyl) -3,4-dihydro 4 - [(Dimethylamino) methylene] -5H-2-benzazepin-5-one (0.4 g, 1.1 mmol) 35 688 32 formamidine acetate (1.0 g, 9.6 mmol) and formamide (20 ml) the mixture was heated on a steam bath for 6 hours. The mixture was poured onto ice and extracted with methylene chloride, the extract was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was crystallized by adding a mixture of ether and methylene chloride to give off-white crystals, m.p. 186-18 8 ° C.

Example 2 4 9-Chloro-7- (2-chlorophenyl) -5H-pyrimido [5,5-d] 2H-benzazepine-6-oxide 8-chloro-1- (2-chlorophenyl) -3.4 -dihydro-4 - [(dimethylamino) methylene] -5H-2-benzazepin-5-one 2-oxide (0.4 g, 1.1 mmol) and formamidine acetate (1.0, 9.6 mmol) the mixture in 20 ml of formamide was heated on a steam bath for 7 hours. The mixture was poured onto ice and extracted with methylene chloride, the extract was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was triturated with ether to give an off-white solid, m.p. 215-217 ° C.

Example 25 9-Chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] 2H-benzazepine 9-Chloro-7- (2-chlorophenyl) -5H-pyrimido [5,4-d] // 2 / A mixture of benzazepine-6-oxide (0.5 g, 1.3 mmol) and phosphorus trichloride (1.0 mL, 10 mmol) in 20 mL of methylene chloride was refluxed for 3 hours. The mixture was cooled, poured onto ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride solution was washed with water, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was crystallized by the addition of ether to give colorless prisms, m.p. 121-123 ° C.

Example 26 9-Chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] 2H-benzazepine 9-Chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] A mixture of 2H-benzazepine-6-oxide (0.5 g, 1.5 mmol) and phosphorus trichloride (1.0 mL, 10 mmol) in 20 mL of methylene chloride was refluxed for 2 hours. The mixture was poured onto ice, basified with ammonium hydroxide and extracted with methylene chloride. The methylene chloride extract was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The residue was crystallized from ether to give off-white crystals, m.p. 122-124 ° C.

Example 27 9-Chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] 2H-benzazepine-2-thiol-6-oxide 8-chloro-1- (2-fluorophenyl) - 3,4-dihydro-4 - [(dimethylamino) methylene)] - 5H-2-benzazepin-5-one 2-oxide (1.5 g, 4 mmol), thiourea (1.5 g, 20 mmol) ) and a 4 molar methanolic solution of sodium methoxide (5 ml) in 30 ml of methanol was stirred at room temperature for 5 hours. The 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. The residue was triturated in methylene chloride to give an orange solid. Recrystallization from methylene chloride gave orange crystals, m.p. 323-325 ° C (decomposes).

Claims (8)

37 63832 A process for the preparation of pharmaceutically useful pyrimido-η 5, -d7 / _-2-benzazepines of the general formula I,. R1 <0, n \ _N ^ - M f if> x. ^ ^ (O) u 'wherein R1- is hydrogen, lower alkyl, amino, di-lower alkylamino, mercapto or lower alkyl mercapto, X is hydrogen or halogen , Y is hydrogen or halogen, n is 0 or 1, where the groups called "lower" mean a group containing up to 7 carbon atoms, provided that when n is 1, then p is 1 and R · * "does not mean mercapto and not lower alkyl mercapto, and for the preparation of their pharmaceutically acceptable acid addition salts, characterized in that a) for the preparation of a compound of formula I wherein n is 0, a compound of general formula IV is obtained CH-R AJ ^ = / 1> °> B o 21 wherein p, X and Y are as defined above and R is di-Alem-p1-alkylamino, to react with a compound of general formula 38 688 32 NH RC 'V ^ nh2 wherein R1 is as defined above, or b) to prepare a compound of formula I wherein R1 is amino or di-lower alkylamino and n is 0, reacting a compound of formula IV with cyanamide, or c ) to prepare a compound of formula I wherein p is 0, R · * · is hydrogen, lower alkyl, amino or di-lower alkylamino and n is 0 »1. cyclize a compound of general formula II R11 V = NQ II ch2-nh2 x'° n YS 0 wherein X and Y are as defined above and R 1 is hydrogen, lower alkyl, amino or di-lower alkylamino, or 2. dehydrogenating a compound of general formula III R 11; (XHN)) x IY as ^ 88 32 wherein X, Y and R have the same meaning as above, and if desired d) deoxidizing the compound of general formula II wherein R 1, X and Y are as defined above, or if desired e) oxidizing a compound of general formula Ie rfi. Wherein R 1, Y and X are as defined above, and / or if desired f) the compound of formula I is converted into a pharmaceutically acceptable acid addition salt. A process for the preparation of a compound of formula I according to claim 1, wherein p is 1, R 1 is amino, n is 0, X is hydrogen, fluorine, chlorine or bromine and Y is hydrogen, fluorine, chlorine or bromine, characterized in that that the compound is prepared according to embodiment a), wherein X and Y • 21 have the meanings given above in this claim, R is dimethylamino, p is 1 and Rx is amino. 40 68832 A process according to claim 1 for the preparation of compounds of formula I comprising hydrogen, lower alkyl, amino, di-lower alkylamino, mercapto or lower alkyl-mercapto, provided that when p is 1, then R 1 is hydrogen. , lower alkyl, amino or di-lower alkylamino, or pharmaceutically acceptable acid addition salts thereof, characterized in that the compound is prepared according to embodiment (c1), (c2), (e) or (f); or according to embodiment (b), wherein R is dimethylamino and p is 0; 21 or according to embodiment (a), wherein R is dimethylamino and R 1 is hydrogen, mercapto, lower alkyl, amino, or di-lower alkylamino, provided that p is 0 when R is mercapto, or when R 1 is amino, X is hydrogen or halogen, and Y is hydrogen or halogen. Process according to Claim 1, characterized in that a compound of the formula I is prepared in which p is 0, n is 0, R 1 is hydrogen, lower alkyl, amino or di-lower alkylamino, X is halogen, preferably chlorine and Y is hydrogen, chlorine or fluorine. Process according to Claim 1, characterized in that 9-chloro-7- (2-chlorophenyl) -5H-pyrimidoZ,5,4-d7Z 2 -benzazepine is prepared. Process according to Claim 1, characterized in that 9-chloro-7- (2-fluorophenyl) -5H-pyrimido [5,4-d] [2] benzazepine is prepared. Process according to Claim 1, characterized in that 9-chloro-7- (2-chlorophenyl) -2-methyl-5H-pyrimido [5,4-d] Z-27benzazepine is prepared. Process according to Claim 1, characterized in that 9-chloro-N, N-dimethyl-7- (2-fluorophenyl) -5H-pyrimidoZ-5.4-47 / 2.7benzazepine-2 is prepared. -amine. Il 68832 41