HU195649B - Process for producing oxazepinone derivatives condensed with aromatic ring and their sulfur analogs - Google Patents

Abstract

Aromatic or heterocyclic oxazapines (or thiazepines) of formula (I) and their salts are prepared by, (a) the halogenation of the cpd. of formula (Nb) to produce the cpd. of formula (III) or its free base, (b) fusing the produced cpds. to produce the cpds. of formula (IIa), (C) reacting the produced halogen cpds. with the cpd. of formula ZH. The new cpds. of formula (I) are useful as antihistaminic agents.

Description

The present invention relates to novel aromatic ring-fused 2,3-dihydro-1,4-oxazepin-5 (4H) -ones and their sulfur-containing analogs, which are useful as antihistamines and antiallergics.

K. Schenkcr, U.S. Patent No. 505,850 (C.A. 75, 98600s), discloses 3-aryl, 4-benzoxazepin-5 (4H) -one substituted on the nitrogen atom of the oxazeping ring with an aminoalkyl group.

A. Lévai and R. Bognár describe the conversion of flavanones to bezoxazeplenes substituted at the 2-position by a phenyl group (Top. Flavanoid Chem. Biochem. Proc. Hung. Bioflavanoid Symp. 4th Ed., 1973 (Pub. 1975 / 119-23). ) (CA 85, 79098η) Thion derivatives were prepared by treatment with phosphorus pentasulfide.

The present invention relates to oxazepinces and thiazepines of the formula (I) and their pharmaceutically acceptable salts, wherein:

A is a 6 or 10 membered aromatic ring having two carbon atoms attached to the oxazepine or thiazepine moiety, which may be benzene, naphthalene or pyridine ring in any of the four possible positions and the pyridine ring is optionally substituted with a halogen atom, and a benzene ring with a lower alkoxy group or a halogen atom;

B and E are oxygen or sulfur, which may be the same or different;

n. is 2 or 3;

R is hydrogen, lower alkyl or phenyl (lower alkyl) when n is 2 and lower alkyl when n is 3;

Z is -NR'R ² , 1H-pyrazol-1-yl or 1H-imidazol-yl, wherein R ¹ and R ² are hydrogen, C 1-6 alkyl, phenyl or phenyl (lower alkyl) - or R * and R ² together with the adjacent nitrogen atom form a heterocyclic ring which is 1-pyrrolidinyl, 2,5-dimethylpyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 1-piperidinyl -, piperidin-1-yl, 4-morpholinyl, 1-piperazinyl, 4- (4-methyl) substituted at the 4-position with a phenyl and a HO group or a bis (4-halophenyl) methyl group. alkyl-substituted) -piperazin-1-yl or 4-phenyl-1,2,3,6-tetrahydropyridin-1-yl, provided that when R is hydrogen, then Z cannot be - NR ¹ R ² wherein R ¹ and / or R ^{2 are} hydrogen; and Z cannot be -NH ₂ if n = 2; and with the proviso that when n = 3, Z can only be -NH ₂ or -N (CH ₃ ) ₂ .

Oxazepine and thlazepine intermediates in the preparation of compounds of formula I are also novel compounds of formula II wherein A, Β, E and R are as defined above for formula (I), except that R is nein is hydrogen, n is -2 and

X is chlorine, bromine or cyano, and also acid addition salts thereof.

Λ Intermediates for the preparation of compounds of formula II are the new compounds of formula 111 wherein

A, E, R and n have the same meaning as given in formula (II) and

X is chlorine or bromine.

Also novel intermediates are the compounds of formula IVa used in the preparation of compounds of formula IVb, wherein

A, E, R and n have the same meaning as in formula II,

Q is -CN, -CONH ₂ , -COOR ³ (wherein R ³ is hydrogen), or an alkali metal ion or a carboloxy group;

unless A is phenyl or substituted phenyl and E is oxygen.

The terms used in the definition of formulas and in the specification and claims have the following meanings;

"Lower alkyl" means a straight or branched chain group containing up to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, a chair. butyl, hello. butyl. The term "lower alkoxy" has the formula -O (lower alkyl).

The term "halogen", unless otherwise specified, means fluorine, chlorine, bromine or iodine.

The term "pharmaceutically acceptable salts" includes acid addition salts, hydrates, alcoholates and quaternary salts of the compound of formula (I) that are physiologically harmless to warm-blooded organisms. Acid addition salts may be formed with strong or weak acids. Strong acids include hydrochloric acid, sulfuric acid, phosphoric acid. Examples of weak acids are fumaric acid, maleic acid, succinic acid, oxalic acid, citric acid, tartaric acid, cyclohexanecarboxylic acid.

Suitable quaternary salts are, for example, salts with lower alkyl halides and lower alkyl sulfates.

"Sulfurizing reagent" means any reagent or mixture of reagents which converts oxazepinones and thiazepinones to oxazepine or thiazepinthiones, such as 2,4-bis (4-methoxyphenyl) -1,2,3,4-dithia. -diphosphetane-2,4-disulfide or a mixture of phosphorus pentasulfide and an alkali metal sulfide or a mixture of phosphorus pentasulfide and a suitable solvent such as acetonitrile, toluene or pyridine. With the "sulfurizing agent", azepinones are sulfurized to azepinions.

The compounds of the present invention exhibit antihistamine activity in guinea pigs. As a test method, a modified version of the procedure developed by Tozzi et al., Agcnts and Actions, Vol. 4/4, 264-270, 1974, was used as follows.

Tcngcrimal pigs in individual cages 18-24

We were fasted for 195,649 hours. They received unlimited quantities of water. On the day of the study, the animals were injected intraperitoneally in groups of three, containing 30 mg / kg of the test compound in the appropriate medium. After 30 minutes, 1.2 mg / kg histamine (twice the LD ₉₉ value) was injected into a marginal ear vein. Guinea pig survival at 24 hours was considered as positive evidence of antihistatin activity. When a vehicle other than water is used for the test compound, its effect is determined by a control assay with the same amount of vehicle. Dose response curves can be used to determine the dose that protects 50% of the animals from death (PD _S0 ). The non-sedative properties of the compounds are described in additional pharmacological experiments.

The novel process of the invention comprises the following steps:

Step 1: A compound of Formula IVb: wherein

A and E are as defined above for formula (1),

R is lower alkyl or phenyl (lower alkyl);

R ³⁴ is hydrogen or an alkali metal cation; and n is 2 - chlorinated or brominated to give a compound of formula (III) or a free base thereof, wherein

X is chlorine or bromine,

A, E, R and n have the same meaning as in the parent compound,

Examples of halogenating reagents include:

a) Thionyl halides

b) triphenylphosphine and a carbon tetralialogenide

c) phosphorus pentahalide

(d) phosphorus trihalides; and

e) triphenylphosphine dihalides;

preferred halogenating reagents are thionyl halides.

Step 2: If necessary, the carboxylic acid halide derivative of Step 1 is neutralized and then cyclized to give the oxazepinone or thiazepinone 11a, wherein

A, E, R, X and n are as defined above and the two carbon atoms of ring A have the same moiety as oxazepine or thiazepine.

Step 3: Optionally, the compound prepared in Step 2 is reacted with a sulfurizing reagent to give an oxazepination or thiazeplione of formula IIb wherein

A, E, R, X and n have the same meaning as in step 2.

Step 4: Optionally, some of the compounds prepared in Step 2 (where R is lower alkyl) are reacted with an alkali metal cyanide to give a compound of formula (He):

A and E have the same meaning as in Step 2.

Step 5 (Process a): The halogen compound prepared in Step 2 or 3 is reacted with a compound of formula ZH wherein

Z is as defined above for formula (I) to ^this ring (la) compounds of the formula obtained, in which

A, E, Z have the same meaning as in step 2,

R. 'is lower alkyl or phenyl (lower alkyl), n' is 2, and

And B is oxygen or sulfur.

Step 6: A compound prepared in Step 5 wherein

B is an oxygen atom, optionally reacted with a sulfurizing agent, preferably phosphorus pentasulfide, dissolved in pyridine, to give a compound of formula (Ib) wherein

A, E, R, n and Z have the same meaning as in step 5.

Process b): cyano compound of formula prepared in step 4 (IIc) is reduced to the primary amine of formula (I _c .i _a) in which

A, if desired, E and R are as defined in step 4, a - primary amine (I-la _c) an amine having a - b) from the produced

A, E, and R have the same meaning as in Step 4, with formaldehyde and formic acid.

The resulting products are covered by the general formula (Id) in which

A, E and R are as defined in Step 4, Z is -NR ¹ R ² , wherein R ¹ and R ² are as defined above for Formula (I).

The resulting azepinone or thiazepinone is optionally sulfated to give the corresponding thion as in step 6.

If desired, one obtained in step 5 or 6

- a compound of formula (le) in which

A, E have the same meaning as in Step 2, and Z has the same meaning as in Formula I, with the proviso that only

NR'R ² , wherein neither R 'nor R ² is hydrogen, is reacted with sodium and ammonia to give a compound of formula (If)

195,649

A, E have the same meaning as in step 2, and Z has the same meaning as above.

The free base prepared by any of the above methods may optionally be reacted with a pharmaceutically acceptable acid or quaternary halide or sulfate-forming reagent to give a pharmaceutically acceptable salt of the compound.

Compounds of formula I wherein n is 2 are preferred for antihistamine activity. and Steps 6 and a salt formation step wherein the resulting compounds contain an ethyl side chain. The process of the present invention is illustrated in the following Scheme A-F.

(I _a), the compounds described in (I '), (I _c i), (I _{c. 2),} (Ic-7), Oc-la), Od), (I _e) and (If) below each is included in the formula (I) and (H _a), (II ,,), (II _c), (IIj) and compounds in the general formula (II _c) are all included in the general formula (II).

Articles 1-4 also represent a new procedure. described process steps, which products of formula (II _a), (IIb) and (II _C) compounds, all included in the formula (II): wherein.

The present invention therefore relates to novel aromatic 1,4-oxazepinones and thiazepinones and their sulfur-containing analogues having antihistamine activity.

Schemes A and B show the preparation of all intermediates.

In Scheme A:

a) R cannot be hydrogen

b) n is 2, x is halo (chloro or bromo), W is arylsulfonyloxy, alkylsulfonyloxy or X,

M is an alkali metal ion,

Q is a -CONH ₂ , -CN or -COOR ³ group in which

R ³ is hydrogen, M, or an ester-forming group.

Hydrolysis is performed when Q is not carb or -COOM.

** Sketch of the splitting and formation of joints required for rearrangement (based on hypothesis).

In Scheme B, an alternative method for the preparation of pyridocyclic compounds (halogenated intermediate IIa):

X is chlorine, bromine or cyano,

E and R are as defined in formula (I)

Scheme C illustrates the preparation of final products wherein R is not hydrogen, n is 2. Z is as defined for formula (I), η = 1 or 2.

Scheme D illustrates the preparation of compounds having a propyl group substituted at the 2-position with an amino group. R is not hydrogen and the starting compound contains a cyano group.

Scheme E illustrates the conversion of omega-substituted propyl derivatives at the omega position to tertiary amines.

Scheme F illustrates the preparation of unsubstituted azepinitrogen containing compounds (R = H). Z cannot be R ¹ and / or R ^{J is} hydrogen.

1-18. There are examples of the preparation of _(IV) and (IV ,,) compounds or the compounds used in the preparation of these starting materials. 19-53. Examples 1 to 5 (see also Table 1) illustrate the preparation of compounds of Formula 11 which are substituted by halogenated alkyl or cyanoalkyl. The compounds of formula (III) are formed in the reaction mixture; these are generally not isolated.

Examples 54-139 illustrate the preparation of compounds of formula (I). The following examples are not intended to limit the scope of the invention.

According to the invention, the. The following processes and steps for the preparation of the compounds of formulas (I), (II) and (111) and summarized hereinbelow are described below:

In step 1 (see Scheme A), the compound of formula IVb, which is a carboxyl or carboxylate group with an alkali metal ion at the ortho position to the ether linkage, is substantially pure (or preferably in the reaction mixture, obtained by hydrolysis of a precursor containing a carbamoyl, cyano or ester carboxylated group in the same ortho position without isolation of the carboxylic acid or its salt from the reaction group) with a suitable halogenating agent such as those described above, preferably thionyl chloride or triphenylcarbonyl with tetrachloride. The halogenation is carried out in a suitable organic solvent, preferably by refluxing the solvent or the halogenating agent, for example thionyl chloride. Temperatures suitable for chlorination vary over a wide range, for example from room temperature to 100 ° C (or above), but preferably between 50 ° C and 80 ° C, since these temperatures include the reflux temperature of chloroform and thionyl chloride. If excess halogenating agent is used as a solvent, it is convenient to evaporate it. If chloroform is used as a solvent, it is possible but not necessary to evaporate it. Thus, at the end of step 1, either a solution consisting of a solvent and a compound of formula (III) or an evaporation residue consisting of a compound of formula (III) is obtained. In each case, the composition is confirmed by infrared analysis.

In step 2, the halogenated compound of formula (111), if present in a non-solution form, is dissolved in an organic solvent, preferably chloroform, and usually neutralized or basified, preferably with a tertiary amine such as triethylamine, and then and heating at a temperature such as the reflux temperature of the triethylamine sufficient to form a bond between the carbonyl group and the basic nitrogen atom and to break the cyclic amine bond to form the compound of formula (Ha)

2- (2-chloro or -bromoalkyl) -oxazepine or -thiazepine. If the tendency to cyclization is high enough, then neutralization or alkalization can be omitted. Compounds of formula (Ha) may be isolated by conventional means such as partitioning between an organic solvent or mixture of solvents and an aqueous solution of an acid or base, followed by drying, evaporation and recrystallization from the appropriate solvent,

In step 3, the compound of formula (IIa) is optionally converted to the oxazepinion or thiazepinion of formula (IIb) by heating with a sulfurizing reagent in a suitable organic solvent, such as toluene. The thion of formula IIb can be isolated by conventional means, preferably by partitioning between an organic solvent and a dilute alkaline solution and then recrystallization from a suitable solvent such as ethanol.

In step 4, an oxazepinone or thiazepinone of formula (IIa) is reacted with potassium cyanide in a hot, non-proton-free solvent, in the presence of a phase transition catalyst such as tetrabutylammonium bromide. The resulting cyano compound is extracted with a suitable solvent, such as ethyl acetate, and the solution is dried and evaporated. The evaporation residue is recrystallized from a suitable solvent, such as ethyl acetate / isopropyl ether or pure ethyl acetate. As will be seen, the resulting compound either contains a cyanoethyl side chain (2), which further enables the side chain to be extended to an aminopropyl group.

In step 5, the oxazepinone (IIa) or thiazepinone (IIa) obtained in step (2) or the oxazepinthion (thiazepinone) (IIb) obtained in step (3) with pyrazole, imidazole or an amine of formula NHR ¹ R ² and R ² is as defined above for formula (I) to give a compound of formula (Ia) or (Ib). The latter reaction is preferably carried out with excess amine, such as volatile methylamines. The free bases of the compounds (Ia) and (Ib) are isolated in the conventional manner by removing the volatile components, partitioning the residue between a dilute alkaline solution and a solvent such as chloroform or methylene chloride and evaporating the solution. The free base can be converted into the pharmaceutically acceptable salt with the appropriate acid and the lower alkyl halide or sulfate into the quaternary salt and recrystallized by conventional methods. The free base can be recovered from the acid addition salt, usually in a purer form, by redistributing the salt between an aqueous solution of a base and the appropriate solvent and then evaporating. As shown in Scheme A, the resulting intermediate may have an aminoethyl group (n = 2).

If desired, a sixth step - produced in Step 5 - compound wherein B is oxygen, sulfurized so as to dry ^and heated at reflux for several hours phosphorus pcutaszulfiddal pyridine. The resulting thion is isolated by cooling the solution, partitioning between an aqueous solvent such as chloroform and an aqueous solution of a base, followed by conventional isolation techniques.

In process b), an oxazepinone or thiazepinone of formula (IIc) prepared in Step 4 is reduced, preferably using hydrogen and a Raney nickel catalyst at about 60 ° C. The resulting primary aminopropyl compound (n = 3) is isolated by conventional means, preferably in the form of an acid addition salt, which can then be converted to the free base by partitioning between a suitable solvent and an aqueous solution of a base, followed by drying and evaporation of the organic layer.

In the optional step of process b) (see Scheme E), a primary amine is converted. This method provides compounds of formula (1) in which n-3. The preparation of dimethylamino derivatives by reacting primary amines with formaldehyde and formic acid is a conventional method for the preparation of tertiary dimethylamines.

During debenzylation, a compound of formula (I) is used

A 4-beryl-oxazepinone or thiazepinone derivative in which R is benzyl and wherein Z is not -NH ₂ or -NHR ¹ or -NHR ² , respectively, into the corresponding 4-substituted (R = H) oxazepinone or is converted to thiazepinone by reaction with sodium and ammonia, and the resulting compound can be isolated as described in Example 125.

The salt-forming or base-forming step depends on whether the compound of formula (I) is present in the form of a pharmaceutically acceptable salt, or is intended to be converted to another salt or to the preparation of the free base. To form the free base, any salt of the compound of formula (I) is partitioned between a suitable organic solvent, such as chloroform, and a dilute aqueous solution of a base. The organic layer is dried and evaporated to give the free base, which is then optionally reacted with an acid as described above to give the desired salt.

As stated above, the preferred compounds containing the ethyl side chain at position 2 are prepared by the aforementioned 1-3, 5, 6 and, optionally, salt or base formation steps of the process for the preparation of the compounds of formula (I).

Example 1

2- (l-benzyloxy-3-yl) benzaldehyde

To a suspension of 4.3 g (0.11 mol) of sodium amide in 60 ml of anhydrous toluene was added 19.3 g (0.11 mol) of 1-benzyl-3-pyrrolidinol while maintaining the temperature at 35 ° C. The beginning5

Stir at 195,649 g for 3 hours at room temperature. To the mixture was added dropwise 19 g (0.1 mol) of o-tolulenesulfonyl chloride while maintaining the temperature at 20-30 ° C with ice-bath cooling. Stirring was continued at room temperature for 2.5 hours and the mixture was allowed to stand overnight. The toluene solution was washed twice with water, dried over sodium sulfate and evaporated.

In another vessel, a suspension of 5.4 g (0.1 mol) of sodium methoxide in 50 ml of dimethylformamide was added a solution of 13.6 g (0.1 mol) of salicylamide in 75 ml of dimethylformamide at a rate such that the temperature was 50 ° C. After stirring for 15 minutes, the sulfonate prepared above was dissolved in 25 ml of dimethylformamide and added dropwise to the reaction mixture, which was then heated at reflux for 5 hours. The material was partitioned between ethyl acetate (500 mL) and water (500 mL). The ethyl acetate solution was extracted with dilute hydrochloric acid, the acidic solution was made basic with dilute sodium hydroxide, and then extracted with ethyl acetate. The organic layer was dried, evaporated, and the residue was recrystallized twice from ethyl acetate / isopropyl ether. Yield: 12.5 g (42%), m.p. 120.5-122 ° C.

Elemental analysis results based on the formula Ci ₈ H ₂₀ N ₂ O ₂ :

Calculated: C, 72.95; H, 6.80; N, 9.46; Found: C, 73.23; H, 6.78; N, 9.56.

Example 2

2- (l-methyl-3-pyrrolidinyl) -benzaniid

To 85.6 g (2.2 mol) of sodium amide in 1.5 L of anhydrous toluene was added 202 g (2 mol) of 1-methyl-3-pyrrolidinol at a rate such that the temperature did not rise above 50 ° C. The mixture was then heated at 70 ° C for 4.5 hours. After cooling, 381 g (2 moles) of o-sulfol sulfonyl chloride are added dropwise while maintaining the temperature at 2030 ° C in an ice bath. The mixture was stirred at room temperature for 2.5 hours and then washed with water. The toluene solution was dried over sodium sulfate and evaporated. Dissolve the residue in 500 ml of dimethylformamide and add a reaction mixture prepared as follows: To 1 liter of dimethylformamide was added 119 g (2.2 moles) of sodium methoxide and 274 g (2.0 moles) of salicylamide, the mixture was treated as described in Example 1. Yield: 170 g (38%), m.p. 116-118 ° C.

Elemental analysis results based on the formula Ci ₂ H ₁₆ N ₂ O ₂ :

Calculated: C 65.43 H7.23 N 12.72 Found: C 65.28 H7.28 N 12.77

Example 3

2- (l-benzyloxy-3-yl) benzoic acid

To a solution of 20.3 g (0.52 mol) of sodium hydroxide in 600 ml of ethanol and 400 ml of water is added 150 g (0.51 mol) of 2- (1-benzyl-3-pyrrolidinyloxy) -benzainide and the mixture is stirred for 48 hours. is heated to reflux. The mixture was then concentrated to half its original volume in a rotary evaporator and the residue was removed by extraction with ethyl acetate to remove the remaining amide. The aqueous layer was filtered and the filtrate was adjusted to pH 6.5 with hydrochloric acid. The filtrate was evaporated in a rotary evaporator, the residue was dissolved in isopropyl alcohol, the resulting mixture was filtered and the filtrate was evaporated. The residue weighs 85.7 g and consists essentially of the title compound.

Example 4

- [(1-Methyl-3-pyrrolidinyl) oxy] 2-naphthalenecarboxamide g (0.67 mol) 1-methyl-3-pyrrolidinyl and 74 g (0.73 mol) triethylamine in 700 ml of anhydrous benzene of methanesulfonyl chloride (74 g, 0.63 mol) was added dropwise with cooling. After stirring for 45 minutes at room temperature, the reaction mixture is filtered, the filtrate is concentrated under reduced pressure and the residue is dissolved in 100 ml of dimethylformamide.

In another flask, to a suspension of sodium hydride (10.8 g, 0.45 mol) in dry dimethylformamide (75 ml) was added dropwise 3-hydroxy-2-naphthalenecarboxamide (84 g, 0.45 mol) dissolved in dimethylformamide (400 ml). . The sulfonate solution prepared above was added dropwise and the reaction mixture was heated at reflux for 16 hours with stirring. The cooled solution was diluted with 1000 mL water and extracted with 2 x 500 mL chloroform. The chloroform solution was washed with water and extracted with 2 x 500 mL of 3N hydrochloric acid. The aqueous extracts were made basic with 50% sodium hydroxide solution and then extracted three times with 500 ml of chloroform. After drying over magnesium sulfate, the chloroform is evaporated under reduced pressure to give

27.4 g (22%) of a light yellow solid are obtained. This was recrystallized from ethyl acetate. Mp 128-130 ° C.

Elemental analysis results based on the formula Ci ₆ H _lg N ₂ 0 ₂ :

Calculated: C, 71.09; H, 6.71; N, 10.36. Found: C, 70.88; H, 6.68; N, 10.37.

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195,649

Example 5

Oxalate salt of 3 - ((1-methyl-3-pyrrolidinyl) oxy] 2-naphthalenecarboxylic acid

To a solution of 21.6 g (0.54 mol) of sodium hydroxide in 500 ml of water was added 74 g (0.27 mol) of 3 - [(1-methyl-3-pyrrolidinyl) oxy] -2-naphthalenecarboxamide. The solution was heated at reflux for 16 hours, then cooled and adjusted to pH 6.8 with concentrated hydrochloric acid. The resulting solid was filtered and the pH of the syrup was adjusted to 6.02. The syrup was evaporated under reduced pressure, the residue was boiled with 200 ml of isopropyl alcohol and filtered. The filtrate was again evaporated under reduced pressure to give 69 g (94%) of an amorphous solid. An aliquot of this material was dissolved in isopropanol and treated with oxalic acid. The oxalate salt is recrystallized from a mixture of ethanol and water. Mp: 209-212 ° C.

Elemental analysis results based on the formula Ci7H ₁₈ NO ₅ :

H, 5.74; N, 4.43. Found: C, 63.83; H, 5.68; N, 4.37.

Example 6

Sodium 2 - [(l-methyl-3-pyrrolidinyl) oxy] -3-pyridinecarboxylate

To a suspension of 6.4 g (0.13 mol) of 50% sodium hydride in mineral oil in 50 ml of dimethylsulfoxide is added dropwise 1-methyl-3-j-irrolidinol (6.4 g, 0.063 mol). During the addition the temperature rises from 25 ° C to 31 ° C. After 10 minutes, 10 g (0.063 mol) of 2-chloronicotinic acid dissolved in 50 ml of dimethyl sulfoxide are added dropwise, causing the temperature to rise again. From the time when the temperature reaches 55 ° C, the temperature is periodically maintained at this temperature by the addition of an ice bath. The mixture was then heated at 5560 ° C for 1.5 hours, then cooled and filtered. The cake was slurried in 100 mL of ethyl acetate and filtered again. The solid was recrystallized from a mixture of ethyl acetate and methanol. Yield: 5 g. The substance decomposes at 240 ° C. NMR analysis showed the material to contain 1/3 molar sodium acetate as impurity.

Elemental Analysis: Calculated for C "H ₁₃ N ₂ O ₃ Na.l / C ₂ H ₃ O 3 Na ₂ O: Calculated: C, 51.62 H5,20 N, 10.32 Found: C 51.81 H5,15 N 10, 39

Example 7

4-chloro-2 - [(l-methyl-3-pyrrolidinyl) oxy] benzamide

To a solution of triethylamine (55.5 g, 0.55 mol) in anhydrous benzene (500 ml) was added dropwise 1-methyl-3-pinolidinol (50.5 g, 0.50 mol) at a temperature of 25 ° C and 35 ° C. ° C. Methanesulfonyl chloride (57 g, 0.50 mol) was added dropwise to the mixture at a temperature between 20 ° C and 50 ° C. The reaction mixture was stirred for 1 hour at room temperature, then filtered and the precipitate washed with 250 ml of hot benzene. The filtrate and washings were combined, concentrated in vacuo and the residue dissolved in 200 mL of dimethylformamide.

In a further vessel, a solution of 19.6 g (0.41 mole) of sodium hydride in 100 ml of dimethylformamide is added dropwise under cooling with a solution of 70 g (0.41 mole) of 4-chlorosalicylamide in 200 ml of diineyl formanide at such a rate. The resulting reaction mixture was added dropwise to the sulfonate salt prepared as above and the mixture was heated at reflux for 19 hours. The mixture was cooled and diluted with 1 liter of water. The diluted mixture was extracted with chloroform (3 x 300 mL). The chloroform extracts were combined and extracted with 2 x 500 mL of 3N hydrochloric acid. The combined aqueous extracts were basified with 50% sodium hydroxide solution and extracted with 3 x 500 mL ethyl acetate. The combined ethyl acetate extracts were dried over magnesium sulfate and evaporated under reduced pressure to give 46.5 g (45%) of a beige solid. Mp: 122-123 ° C

Example 8

5-bromo-2 - [(l-methyl-3-pyrrolidinyl) oxy] benzamide

1-Methyl-3-pyrrolidinol (101 g, 1.0 mol) and triethylamine (111 g, 1.1 mol) were dissolved in anhydrous benzene (1000 ml) and methanesulfonyl (114 g, 1.0 mol) was added dropwise with cooling. chloride. The reaction mixture was stirred for 1 hour at room temperature and then filtered. The filtrate was concentrated under reduced pressure and then dissolved in 100 ml of dimethylformamide.

To a suspension of sodium hydride (30 g, 0.63 mol) in dimethylformamide (100 ml) was added dropwise 5-bromosalicylamide (137 g, 0.63 mol) in dimethylformamide (750 ml) dropwise. The sulfonate prepared as above was added dropwise, and the reaction mixture was refluxed for 18 hours.

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195 649 Boil. The cooled solution was diluted with 1000 mL water and extracted with 3 x 500 mL chloroform. The chloroform extracts were washed with water and extracted with 4X500 mL of 3N hydrochloric acid. The aqueous layer was basified with 50% sodium hydroxide solution and extracted with chloroform. The chloroform extracts were washed with water, dried over magnesium sulfate and concentrated under reduced pressure to give 52 g (28%) of a yellow solid. The solid was recrystallized from ethyl acetate / chloroform. 160162 ° C.

Elemental analysis results for C | ₂ I1 | Based on N ₂ BrO ₅ wherein _z;

Calculated: C 48.18 H5.05 N9.36 Found: C 48.02 H5.01 N9.22

Example 9

5-chloro-2 - [(l-methyl-3-pyrrolidinyl) oxy] -benzamidhemihídrát

Sodium hydride (2.4 g, 0.41 mol) was suspended in dimethylformamide (50 ml), and a solution of 5-chlorosalicylamide (17 g, 0.1 mol) in dimethylformamide (50 ml) was added dropwise with cooling, while maintaining the temperature. do not rise above 20 ° C. After the addition of salacylamide, 16.7 g (0.1 mol) of 3-bromo-1-methylpyrrolidine dissolved in 50 ml of dimethylformamide are added dropwise. The reaction mixture is heated at reflux for 19 hours. After cooling, the solution was diluted with water (250 mL) and extracted with chloroform (2 x 250 mL). The chloroform layer was extracted with 3X500 mL of 3N hydrochloric acid. The aqueous extracts were made basic with 50% sodium hydroxide solution and extracted with ethyl acetate. After drying over magnesium sulfate and evaporation of the ethyl acetate under reduced pressure, a beige solid (6 g, 23%) was obtained, which was recrystallized from ethyl acetate. Mp 126-128 ° C.

Elemental analysis for C24II32N4Cl2O5:

N, 10.62 Found: C, 54.87; H, 6.12; N, 10.69.

Example 10 1 - [(1-Methyl-3-pyrrolidinyl) oxy] naphthalene-2-carboxamide

Sodium hydride (27.6 g, 0.69 mol) in 50% mineral oil was suspended in dimethyl sulfoxide (250 mL), and l-hydroxy-2-naphthalenecarboxamide (118 g, 0.63 mol) dissolved in dimethyl sulfoxide (250 mL) was added dropwise. . The reaction is exothermic and the temperature rises above 60 ° C.

In another flask, 69.7 g (0.69 mole) of l-methyl-3-pyrrolidine and 77 g (0.76 mole) of triethylamine are dissolved in 500 ml of hydrogen benzene and 79 g (0.69 mole) are added dropwise while cooling in an ice bath. methanesulfonyl chloride. The mixture was stirred for 15 minutes and then filtered. The cake is washed with 500 ml of benzene, the benzene filtrates are combined and evaporated to about 200 ml in a rotary evaporator. The residue is added dropwise at 75 [deg.] C. with stirring to a solution of dimethyl sulfoxide prepared as above containing sodium salt of 1-hydroxy-2-naphthalenecarboxamide. The temperature was maintained at 75 ° C for 18 hours by external heating. The resulting solution was cooled and an equal volume of water was added. The mixture was extracted three times with chloroform. The washings were combined and evaporated and the residue partitioned between ethyl acetate and dilute hydrochloric acid. The acidic layer was made basic with sodium hydroxide and extracted twice with ethyl acetate. The ethyl acetate washings were combined, dried over sodium sulfate and evaporated. The residue in ethyl acetate and recrystallized from iso-octane ^20. Yield: 55 g (32%) of a solid, part of which is recrystallized from ethyl acetate / isooctane, m.p. 122-129 ° C.

Elemental analysis results from the formula Ε _{! Ή} Η, _Β Ν ₂ Ο ₂ :

Calculated: C, 71.11; H, 6.71; N, 10.36. Found: C, 70.96; H, 6.71; N, 10.31.

Example 11

5-Methoxy-2- (1-methyl-3-pyrrolidinyl) oxy] benzamide

1-Methyl-3-pyrrolidinol (151 g, 1.5 moles) and triethylamine (166 g, 1.6 moles) were dissolved in anhydrous benzene (1500 mL) and methanesulfonyl chloride (171 g, 1.5 moles) was added dropwise with cooling. The reaction mixture was stirred for 1 hour at room temperature and then filtered. The filtrate is concentrated under reduced pressure to an orange oil.

In another flask, 72 g (1.5 mol) of sodium hydride containing 50% mineral oil were suspended in 150 ml of dimethylformamide and added dropwise under cooling with the sulfonate prepared as above and 139 g (0.93 mol) of 5- solution of inethoxysalicylamide in 600 ml of dimethylformamide. The reaction mixture was refluxed for 14 hours! at reflux. After cooling, it is diluted with 1000 ml of water and extracted with 3 x 700 ml of chloroform. The collected chloroform extracts were washed three times with 50 mL of water and 3 x 500 mL of 3N hydrochloric acid. The aqueous layer was made basic and extracted with chloroform. The chloroform extracts were washed three times with water, dried over magnesium sulfate and evaporated under reduced pressure to a viscous brown oil. This material was evaporated in vacuo to give a viscous orange oil which was dissolved in chloroform and extracted with acid; and the acidic solution was made basic and back-extracted with chloroform. The solvent was evaporated to give a dark brown oil which solidified under reduced pressure.

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Recrystallization three times from ethyl acetate gave 10 g (4%) of white crystals. Mp: 85-87 ° C.

Elemental analysis results based on the formula C ₁₃ Hi ₈ N ₂ O ₃ :

H, 7.25; N, 11.19. Found: C, 62.47; H, 7.26; N, 11.20.

Example 12

A 1: 2 fumarate salt of 3 - ((1-methyl-3-pyrrolidinyl) oxy] pyridine-4-carbonitrile in a solution of 1-methyl-3-pyrrolidinyl (0.55 mol) in anhydrous dimethylformamide (55 ml) was added dropwise. g (0.58 mol) of sodium hydride (40% in mineral oil) in 300 ml of dimethylanilide Λ The mixture was stirred at room temperature for 1 hour and then 73 g (0.53 mol) of 3-chloro-4 was added dropwise. Cyanopyridine was dissolved in 200 ml of dimethylformamide while maintaining the temperature under gentle cooling at 30-40 ° C. The solution was stirred for 3 hours, then an equal volume of water was added and the solution was acidified with dilute hydrochloric acid and extracted with isopropyl ether. It is made alkaline with sodium hydroxide and extracted five times with chloroform, the extracts are combined, dried over sodium sulfate and evaporated to a residue which is treated with 50 g of fumaric acid in 400 ml of isopropyl alcohol and 40 ml of water. The resulting crystalline material (51 g, 21%) was filtered off and one gram of sample was recrystallized from methyl isopropyl ketone. Yield: 1.5 g, m.p. 172-174 ° C.

Elemental analysis results based on the formula Ci ₉ H _{2 i} N ₃ O ₉ :

H, 4.86; N, 9.65. Found: C, 52.40; H, 4.90; N, 9.68.

/.?. example

- [(1-Methyl-3-pyrrolidinyl) oxy] naphthalene-2-carbonitrile oxalate g (0.11 mol) 1 - [(1-methylpyrrolidinyl) oxy] naphthalene-2-carboxamide and 30 g Thionyl chloride (0.32 mol) was dissolved in chloroform (150 ml) at reflux for 6 hours. The solution is poured onto ice and made basic with sodium hydroxide. The chloroform layer was separated, dried over sodium sulfate and evaporated. The residue was dissolved in hot isooctane, and after treatment with charcoal, the solution was filtered and evaporated. The residue was dissolved in isopropyl alcohol and oxalic acid was added. The precipitate was recrystallized from a mixture of isopropyl alcohol and water. Yield: 11.5 g (31%), m.p. 176-184 ° C.

Elemental analysis results using the formula ε _1Β Ι1 ₁₈ Ν ₂ 05:

Calculated for C 63.15 H5.30 N 8.18 For C 63.00 H5.29 N 8.15

Example 14

Sodium salt of 4 - ((1-iuctyl-3-pi-ι ol idyllyl) -oxy-J-pl ι idin-3-carboxylic acid

4-Chloropyridine is reacted with diisopropyl lithium amide and carbon dioxide to give the lithium salt of 3-carboxy-4-chloropyridine which is then reacted with l-methyl-3-pyrrolidinol as described in Example 6.

Example 15

Fumarate salt of 3 - [(1-methyl-3-pyrrolidinyl) oxy] pyridin-2-nbonylonyl

Reaction of 2-carboxamido-3-hydroxypyridine with phosphorus oxychloride yields 2-cyano-3-chloropyridine, which is then treated with 1-methyl-3-pyrrolidinol in the same manner as in Example 12. reaction to give the title compound.

Example 16

oxalate salt of methyl 3-pyrrolidinyl thiol acetate (ester)

To a solution of 101 g (1 mol) of 1-methyl-3-pyrrolidinol and 110 g (1.1 mol) of triethylamine in 700 ml of anhydrous benzene is added 115 (1 mol) of methanesulfonyl chloride dropwise with stirring and cooling in an ice bath. The resulting mixture was stirred for 1/2 hour and then filtered. The filtrate was concentrated to about 200 mL in a rotary evaporator, taking care not to overheat. The residue was dissolved in about 150 mL of ethanol.

In another vessel, under nitrogen atmosphere, 25.3 g (1.1 mol) of sodium were dissolved in 800 mL of 200 mL ethanol. After complete dissolution, 83.6 g (1.1 mol) of thioacetic acid are added slowly and the resulting solution is stirred for a further 10 minutes. The ethanolic methanesulfonate solution prepared above was then added and the resulting solution heated at 60 ° C for 20 hours. The mixture was then cooled to 25 ° C, filtered and concentrated in a rotary evaporator. The residue was dissolved in isopropyl ether and filtered to remove a small amount of solid. The filtrate was concentrated and the residue was distilled to give the free base of the title. Yield 70 g, b.p. 95-105 ° C / 15 mm Hg.

7 g of the free base are dissolved in isopropyl alcohol, treated with oxalic acid and the resulting salt is recrystallized from isopropyl alcohol to give the title product (8.4 g). Mp 108-111 ° C.

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Example 77. 1-methyl-2-pyridine thiol oxalate.

1-Methyl-3-pyridine thiolacetate ester (0.39 mole) dissolved in absolute methanol (200 ml) was treated with a 2 mm portion of sodium, and the resulting solution was distilled at a pressure of 1 atm at 100 ° C. A vacuum is then applied and the pressure is slowly reduced to 100 mmHg. The residue was distilled at 130 ° C to give 25 g (56%) of a distillate boiling at 95-100 ° C / 100 mm Hg. The product is the free base of the title compound. A 4 g sample was treated with oxalic acid in isopropyl alcohol to give 5.5 g of the oxalate salt. Mp: 80-82 ° C.

Example 18

2 - [(1-Methyl-3-pyrrolidinyl) -thio] -pyridine-3-carboxylic acid g (2 mol) - 60% sodium hydride mixed with mineral oil was suspended in 800 ml of anhydrous dimethylformamide and stirred at 60 ° C under a stream of nitrogen a solution of 157.0 g (1 mol) of z-chloronicotinic acid and 117 g (1 mol) of l-methyl-3-pyrrolidinethiol in 300 ml of dimethylformamide is added dropwise at a temperature of 60-67 ° C. C stay. The mixture was heated at 65 ° C for 6 hours, allowed to stand at room temperature overnight, and then filtered. The resulting solid was suspended in isopropyl alcohol and bubbled with hydrogen chloride gas until it reached pH 6.2. The mixture is boiled and filtered. The solid was dissolved in water (2 L) and extracted with isopropyl ether. The pIl is adjusted to 6.0, the solution is concentrated to 800 nU and placed in a refrigerator. The resulting solid (85 g) was filtered to give a mixture of about 85% of the title compound plus 15% of sodium chloride. A sample of this material was recrystallized once from ethanol and then twice from a mixture of isopropyl alcohol and water. The product obtained by recrystallization decomposes to about 225 ".

Example 79

2- (2-Chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one

To a solution of sodium hydroxide (54 g, 1.35 mol) in water (800 ml) was added 2 - [(1-methyl-3-pyrrolidinyl) oxy] -benzamide (148 g, 0.67 mol) and refluxed for 18 hours. The solution was then adjusted to pH 7 with hydrochloric acid, filtered and evaporated. The residue was dissolved in 400 ml of isopropanol and filtered. The filtrate is evaporated, 300 ml of thionyl chloride are added to the crystallized residue, the mixture is refluxed for 0.5 hours and then concentrated in vacuo. The residue was dissolved in chloroform (300 ml) and the solvent was evaporated in vacuo. The residue was redissolved in chloroform and refluxed with 150 ml of triethylamine for 1 hour. The solution was evaporated and the residue was partitioned between ethyl acetate (400 ml), isopropyl ether (400 ml) and dilute hydrochloric acid (500 ml). The organic layer was washed twice with water and once with dilute sodium hydroxide solution, dried over sodium sulfate and concentrated. The residue was crystallized from a mixture of isoptopanol and water.

Yield: 75 g (47%). Melting point: 97-107 ° C.

Elemental analysis results for C | ₂ H _I4 NO ₂ C1 formula:

Calculated: C 60.13 H 5.89 N5.84 Found: C 60.35 11 5.91 N5.65

Example 20 Benzyl 2- (2-chloroethyl) -2,3-dihydro-1,4-benzoxazepin-5 (4II) -one

To 2 - [(1-benzyl-3-pyrrolidinyl) oxy] benzoic acid (85.7 g, 0.29 mol) was added thionyl chloride (150 mL). The solution was allowed to stand for 15 minutes, then refluxed for 30 minutes and evaporated in vacuo. The residue was dissolved in chloroform (500 mL) and triethylamine (101 g, 1 mol) was added slowly with stirring. The solution was heated at reflux for 1 hour and then concentrated in vacuo. The residue was partitioned between ethyl acetate / isopropyl ether 1: 1 and dilute hydrochloric acid. The organic layer was washed with dilute sodium hydroxide solution and evaporated. The residue was recrystallized five times from a mixture of isopropyl ether and ethyl acetate. Yield: 23.8 g (26%). M.p .: 145.0-147 ° C.

Analysis results for CisHi ₈ NO ₂ C1:

Calculated: C 68.46 H5.74 N4.44 Found: C 68.47 H 5.89 N4.32.

Example 27

2-2- (Chloroethyl) -2,3-dihydro-4-methylnaphth [2,3-f], 14] oxazepin-5 (4H) -one

To 21.6 g (0.54 mole) of sodium hydroxide in 500 ml of water was added 74 g (0.27 mole) of 3 - ((1-methyl-3-pyrrolidinyl) oxy] naphthalene-2-carboxamido and the mixture was stirred for 16 hours. The solution was adjusted to pH 6.8 with concentrated hydrochloric acid, filtered and evaporated, the residue was boiled with 200 ml of isopropyl alcohol and the filtrate was evaporated under reduced pressure and the residue was dissolved in chloroform (59 g). 0.50

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After addition of 195,649 moles of thionyl chloride, the solution was heated at reflux for 4 hours. After cooling, 67 g (0.67 mol) of triethylamine are added dropwise. The mixture was washed twice with 3N hydrochloric acid solution, twice with water, twice with 10% sodium hydroxide solution, twice with water, and finally dried over magnesium sulfate. Evaporation of the chloroform under reduced pressure gave 44 g (58%) of a dense, dark brown oil. The material was purified by high performance liquid chromatography (ethyl acetate: hexane = 1: 1) and recrystallized from isopropyl alcohol to give a brown crystalline solid. Mp: 101-102 ° C.

Elemental analysis results based on the formula Ci ₆ H ₁₆ NC1O ₂ :

Calculated: C 66.32 115.57 N 4.83 Found: C 66.19 H 5.63 N4.77

Example 22

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5- (4H) -one hydrochloride in 1 g of chloroform 150 g (0, Sodium 2 - [(1-methyl-3-pyrrolidinyl) oxy] pyridine-3-carboxylate (61 mol) was suspended and hydrochloric acid was bubbled through until pH 6 was reached. Then 350 g (1.34 mol) triphenylphosphine and 350 g (2.3 mol) carbon tetrachloride are added with stirring, and the resulting cloudy solution is refluxed for 1.5 hours, then 100 ml of ethanol are added and the mixture is heated. removed. The solution was stirred under cooling for 1 hour and then 200 ml of isooctane was added. It is then extracted four times with a total of 800 ml of dilute hydrochloric acid. The acidic extracts were combined, basified with sodium hydroxide and extracted with chloroform. The chloroform layer was separated, dried over sodium sulfate and evaporated. The residue was dissolved in a mixture of 500 ml of isopropyl alcohol and 500 ml of isopropyl ether and acidified with ethereal hydrochloric acid. 82 g (49%) of crystals are obtained, part of which is recrystallized from isopropyl alcohol. Mp: 149-153 ° C.

Elemental analysis results based on the formula ChH _m N ₂ O ₂ C1 ₂ :

H, 5.09; N, 10.11. Found: C, 47.57; H, 5.18; N, 10.00

Example 23

8-Chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one

To a solution of 10.4 g (0.26 mol) of sodium hydroxide in 150 ml of water was added 32 g (0.13 mol) of 4-chloro-2 '- ((1-methyl-3-pyrrolidinyl) oxy] benzamide, and the mixture was heated at reflux for 24 hours.

Adjust to 6, then filter and concentrate the filtrate. The residue is boiled with 100 ml of isopropyl alcohol and the mixture is filtered. The filtrate was evaporated and refluxed with 98 g (0.83 mol) of thionyl chloride for 1 hour. The excess thionyl chloride was evaporated under reduced pressure. The residue was dissolved in chloroform (70 ml) and the solvent was evaporated under reduced pressure. The residue was dissolved in chloroform (75 mL) and triethylamine (40 mL) was added portionwise. The solvent was evaporated under reduced pressure to give a dark brown solid. This was dissolved in ethyl acetate and the resulting solution was washed twice with 200 mL of water and twice with 250 mL of 20% sodium hydroxide solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 21 g (59%) of a dark brown solid which was recrystallized from isopropyl alcohol to give the title compound. Mp: 85-87 ° C.

Elemental analysis results based on the formula Ci ₂ H, ₃ NCl ₂ O ₂ :

Found: C, 52.57 114.78 N5.ll. Found: C, 52.57 H4.77 N5, O4

Example 24

7-Bromo-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one

To a solution of sodium hydroxide (9.6 g, 0.24 mol) in water (200 ml) was added 5-bromo-2 ((1-diethyl-3-pyrrolidinyl) oxy] benzamide (37 g, 0.12 mol) and After refluxing for 1 hour, the pH of the mixture was adjusted to 6.7 with concentrated hydrochloric acid, the solution was evaporated under reduced pressure, the residue was refluxed with isopropyl alcohol (250 ml), the mixture was filtered, and the filtrate was evaporated. , 28.3 g (0.24 mole) of thionyl chloride are added to the solution, The mixture is refluxed for 1/2 hour and then cooled in an ice bath to 15 DEG C. 26.6 g (0.26 mole) is added dropwise. triethylamine at a rate not to rise above 25 ° C. The reaction mixture was stirred for 1 hour at room temperature and then washed with 3N hydrochloric acid, 15% aqueous sodium hydroxide and finally with water, and the chloroform layer was dried over magnesium sulfate. Concentration under reduced pressure gave 23 g (60%) of a brown solid. Part of this was recrystallized from a mixture of ethyl acetate and isopropyl ether. Mp .: 92-94 ° C.

Elemental analysis for C ₂ H ₁₃ O ₂ NBrC10 aiapj tendon:

Calculated: C, 42.24 114.11 N, 4.40; C, 45.61; H, 4.17; N, 4.42

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Example 25

7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-5-4benzoxazepin (4I1) -one

5-Chloro [(1-methyl-3-pyrrolidinyl) oxy] benzamide (113 g, 0.44 mol) was dissolved in glacial acetic acid (500 ml) and hydrogen chloride gas was bubbled through it for 15 minutes while cooling in an ice bath. 142 g (1.38 mol) of butyl nitrile are then added in one portion and the reaction mixture is stirred for 16 hours at room temperature and then for 6 hours at reflux. The acetic acid was evaporated under reduced pressure, tetrachloroethane was added to the residue and evaporated, and the latter two operations were repeated.

The residue was dissolved in chloroform, 163 g (1.38 mol) of thionyl chloride was added and the mixture was heated at reflux for 22 hours. The reaction mixture was cooled in an ice bath, and 152 (1.5 moles) of triethylamine was added dropwise at such a rate that the temperature was maintained at 25-30 ° C. The reaction mixture was diluted with chloroform (200 mL), washed with 3N hydrochloric acid, water, 10% sodium hydroxide, and again with water. Chloroform was evaporated under reduced pressure to give 40 g (33%) of a black gum.

An aliquot of this residue was purified on a silica gel column eluting with ethyl acetate to give a beige crystalline solid. Mp .: 101-103 C.

Elemental analysis results based on the formula Ci ₂ Hi ₃ NC1 ₂ 0 ₂ :

Calculated: C, 52.57; H, 4.78; N, 5.11; Found: C, 52.63; H, 4.63;

Example 26

2- (2-Chloro-ethyl) -2,3-dihydro-4-methyl-naphth [2,1-f] [1,4] oxazepin-5 (4H) -one in acetic acid 8 g (0 (03 mol) of 1 - [(1-diethyl-3-pyrrolidinyl) oxy] naphthalene-2-carboxamide was bubbled through with hydrogen chloride gas for about 2 minutes. The solution was cooled in a bath of yoghurt and slowly added 6.1 g (0.06 mole) of n-butyl nitrile under the surface of the liquid (about 10 minutes). The solution was kept at 25 ° C for 18 hours and then heated in a water bath for 3 hours. The solution was evaporated in a rotary evaporator, the residue was dissolved in 60 ml 1,1,2,2-tetrachloroethane and the solvent was evaporated at a boiling point of 0.5 mmHg.

The residue was dissolved in chloroform (75 mL), thionyl chloride (7 g, 0.06 mol) was added and refluxed for 12 hours. The solution was extracted with water followed by dilute sodium hydroxide solution (the aqueous extract was acidic), dried over sodium sulfate and evaporated. The residue was recrystallized twice from a mixture of isopropyl ether and ethyl acetate. Yield: 3.2 g (37%). Mp .: 109-111 'C.

Elemental analysis results based on the formula Ci ₆ H ₁₆ NO ₂ C1:

H, 5.57; N, 4.84. Found: C, 66.15; 11, 5.56; N, 4.76.

Example 27

2- (2-chloroethyl) -2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5- (4H) -one

Dissolve 19.2 g (0.48 mol) of sodium hydroxide in 500 ml of water, add 60 g (0.24 mol) of 5-methoxy-2 - [(1-methyl-3-pyrrolidinyl) oxy] benzamide and the mixture. Reflux for 24 hours. The reaction mixture was cooled and adjusted to pH 6.8 with concentrated hydrochloric acid. The mixture was concentrated under reduced pressure and the residue was refluxed in isopropyl alcohol for 1 hour. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in chloroform (500 mL) and thionyl chloride (114 g, 0.96 mol) was added. The mixture was refluxed for 48 hours and then cooled in an ice-acetone bath. Then, 97 g (0.96 mol) of triethylamine are added dropwise at such a rate that the temperature does not drop above 25 ° C. The reaction mixture was washed with water, 3N hydrochloric acid, water, 15% sodium hydroxide solution and water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a black solid. The material was purified on a silica gel column using ethyl acetate as eluent. After isolation, 15 g (23%) of a beige material are obtained. Mp 98-100 ° C.

Elemental analysis results based on the formula Cj ₃ Hi ₆ NC1O ₃ :

H, 5.98; N, 5.19. Found: C, 57.53; H, 6.00; N, 5.16.

Example 28

2- (2-Ethyl) _{-2,3-dihydro-4-methyl-s} 4benzoxazepin-5 (4H) thione ~

18.5 g (0.0834 moles) of phosphorous sulfide are milled with 18.5 g of potassium sulfide and 100 g (0.417 mol) of 2- (2-chloroethyl) -2,3-dihydro are added. A solution of -4-methyl-1,4-benzoxazepin-5 (4H) -one in anhydrous toluene. The mixture is refluxed for 24 hours and then filtered. The filtrate was partitioned between chloroform and dilute sodium hydroxide solution. The chloroform layer was evaporated and the residue was recrystallized several times from ethanol. Yield: 55 g (52%). Mp: 105-108 ° C.

Elemental analysis results for C | Based on ₂ H ₁₄ NSOCI formula:

Calculated: C 56.35 H 5.52 N5.48 S 12.54 Found: C 56.55 H 5.47 N 5.49 S 12.55

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Example 29

2- (2 _: chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5- (4H) -thio g (0.25 mol) 2 - (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one hydrochloride was dissolved in 1500 ml of chloroform, added

41.5 g (0.19 mol) of phosphorus phthalosulfide are added and the mixture is refluxed for 18 hours, filtered and the filtrate is extracted with dilute sodium hydroxide solution. The chloroform layer was evaporated and the residue was dissolved in boiling isoptopyl alcohol (250 mL). Upon cooling 28 g (44%) of a yellow solid precipitated. Part of this is recrystallized from isopropyl alcohol. M.p .: 134-136 ° C.

Elemental analysis based on the formula CnH ₁₃ N ₂ C10S:

Calculated: C 51.46 H5.10 N 10.81 Found: C 51.35 H5.21 N 10.72

Example 30

2- (2-chloroethyl) -2,3-dihydro-4-methylnaphtho [2,3-f] [1,4] oxazepine-5- (4H) -thione

16.6 g (0.06 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylnaphth [2,3f] [1,4] oxazepine-5 are dissolved in 150 ml of anhydrous toluene. (4H) -one and 8.6 g (0.045 mol) of phosphorus pentasulfide and 0.6 g of potassium sulphide are added. fid ground mixture. The reaction mixture was stirred at reflux for 24 hours. The mixture was filtered hot while the filtrate was concentrated under reduced pressure to give a yellow solid (6.5 g, 35%) which was recrystallized from ethanol. Mp: 166-168 ° C.

Elemental analysis according to formula C ₁₆ H _{) 6} NC1OS:

Calculated: C 62.84 H5.27 N4.58 Found: C 62.29 H5.48 N4.47.

Example 31

8-Chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5- (4H) -thione g (0.16 mol) 8-chloro-2 - (2-Chloroethyl-2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one) is dissolved in 400 ml of anhydrous toluene and 23 g (0.12 mol) of phosphorus pentasulfide and 23 g are added. The reaction mixture was refluxed for 24 hours, the mixture was filtered hot, and the filtrate was concentrated under reduced pressure to give 25.5 g (55%) of an orange oil which solidified at room temperature. recrystallized, mp 105-106 ° C.

Elemental analysis using the formula Ci ₂ lluNCl ₂ OS:

H, 4.52; N, 4.83. Found: C, 49.63; H, 4.53; N, 4.75.

Example 32

7-Bromo-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5- (4H) -thione

7-Bromo-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepyl-5 (4'L) -one (11.0 g, 0.035 mol) was dissolved in dry toluene (150 mL) and added. A milled mixture of 13.4 g (0.07 mol) of phosphorus pentasulfide and 13.4 g of potassium sulfide. The reaction mixture was heated at reflux for 5 hours under nitrogen, then filtered hot, and the filtrate was concentrated under reduced pressure. The residue was dissolved in chloroform. The chloroform solution was washed twice with dilute sodium hydroxide solution, dried over magnesium sulfate and concentrated under reduced pressure to give 8.5 g (72%) of a yellow solid, which was recrystallized from ethanol. Mp: 118-120 ° C.

Elemental analysis calculated for C ₂ H ₁₃ NBrC10S formula:

Calculated: C 43.07 H 3.92 N4.18 Found: C 43.08 H 3.88 N 4.12

Example 33 (2-Chloroethyl) -2,3-dihydro-4-methylnaphth [2,1-f] [1,4] oxazepine-5- (4H) -thione

2- (2-Chloroethyl) -2,3-dihydro-4-methyl-naphtho [2,1f] [1,4] oxazepin-5 (4H) -one (20.2 g, 0.07 mol) in 200 ml of anhydrous toluene and a milled mixture of 9.55 g of phosphorus pentasulfide and 9.5 g of potassium sulfide is added. The reaction mixture was heated at reflux for 7 hours and then filtered hot. The product crystallizes from the s: ground product during cooling. This was recrystallized from chloroform to give 18 g (84%) of a yellow crystalline solid. Mp: 167-170 ° C.

Elemental analysis results based on the formula Ci ₆ Hj ₆ NC1OS:

H, 5.27; N, 4.58. Found: C, 62.85; H, 5.20; N, 4.55

Example 34

2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [4,3-f] ll, 4] oxazepine-5 (4H) -one hydrochloride

3 - ((1-methyl-3-pyrrolidinyl) oxy] pyridine-4-carbonitrile

49 g (0.11 mol) of its 1.2 fumarate salt was partitioned between chloroform and saturated potassium carbonate solution. The aqueous layer was extracted twice with chloroform. The chloroform extracts are combined,

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195,649 were dried and evaporated. The residue was dissolved in 125 ml of t-butanol and 34 g (0.6 mol) of particulate potassium hydroxide was added. The reaction mixture was stirred for 88 hours at room temperature and then diluted with 150 ml of toluene. The mixture was filtered and the filtrate was evaporated. The residue was dissolved in chloroform with cooling and the pH was adjusted to 6.0 by the addition of hydrochloric acid gas. The mixture was evaporated and 400 ml of anhydrous toluene were added to the residue. Then evaporate in a rotary vacuum evaporator (steam heating under reduced pressure) until any water present is completely removed. The residue was dissolved in chloroform (400 ml) and triphenylphosphine (63 g) was added followed by carbon tetrachloride (70 g). The solution was stirred at reflux for 2 hours and then triphenylphosphine (30 g) was added. After heating at reflux for another hour, another 70 g of carbon tetrachloride and 63 g of triphenylphosphine are added and reflux is continued for another 4 hours. The solution was extracted with dilute sodium hydroxide solution and evaporated. The residue was partitioned between toluene and dilute hydrochloric acid. The toluene layer was extracted five times with dilute hydrochloric acid. The acidic extracts were combined, basified with sodium hydroxide and extracted with chloroform. The chloroform layer was dried over sodium sulfate and evaporated. The residue was chromatographed on a 7 x 25 cm silica gel column with acetone. After evaporation, the free base of the title compound was isolated: 5.8 g (20%). A portion of this is dissolved in isopropyl alcohol, followed by addition of ethereal hydrochloric acid and isopropyl ether. The resulting crystals were filtered off and dried. M.p .: 188-190 ° C.

Elemental analysis using the formula CuH _m N ₂ O ₂ C1 ₂ :

calcd: C47.67 H5.09 N 10.11 Found: C 48.33 II 5.22 N 9.73

Example 35

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] oxazepin-5 (4H) -one hydrochloride

In the procedure of Example 22, sodium 2 - [(1-methyl-3-pyrrolidinyl) oxy] pyridine-3-carboxylate is equimolar to sodium 4 - [(1-methyl-3-pyrrolidinyl) oxy] pyridine. Substitution with 3-carboxylate affords the title compound.

Example 36

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [2,3-f] [1,4] oxazepin-5 (4H) -one hydrochloride

In the procedure of Example 34, 3 - [(1-methyl-3-pyrrolidinyl) oxy] pyridine-4-carbonitrile fumarate was equimolar to 3 - [(1-methyl-3-pyrrolidinyl) oxy] pyridine-2- with carbonitrile fumarate to give the title compound.

Example 37

7-Chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5- (4H) -thione g (0.07 mol) 7-chloro-2- (2 -chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one is dissolved in 200 ml of toluene and 9.55 g (0.05 mol) of phosphorus pentosulfide are added. and 9.5 g of a ground mixture of potassium sulfide. The reaction mixture was filtered and the filtrate was evaporated to give a yellow solid which was recrystallized from absolute ethanol. Yield: 12.5 g (68%). Mp .: 102 104 ®C.

Elemental analysis results based on the formula Ci ₂ H ₁₃ NC1 ₂ OS:

H, 4.52; N, 4.83. Found: C, 49.62; H, 4.55; N, 4.76.

Example 38

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [4,3-f] [1,4] oxazepine-5 (4H) -thione g (0.021 mol) 2- (2 -chloroethyl) -2,3-dihydro-4-octylpyrido [4,3-f] [1,4] oxazcpin-5 (4'-one) and 5.1 g (0.0126 mole) of 2,4-bis ( 4-Methoxyphenyl) -1,3,2,4-diphosphetane-2,4-disulphide was dissolved in 100 ml of anhydrous toluene at reflux for 2.5 hours and extracted three times with sodium bicarbonate solution. The residue was chromatographed on a silica gel column using ethyl acetate (high performance liquid chromatography) as the product-containing fraction was evaporated and the residue was recrystallized from ethyl alcohol to give the title compound (0.6 g, 11%).

Example 39

2- (2-Chloroethyl) -2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepine-5- (4H) -thione

2- (2-Chloroethyl-2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5 (4H) -one) (10.3 g, 0.04 mol) was dissolved in chloroform (200 mL) and A stirred mixture of phosphorus pentasulfide (7 g, 0.03 mol) and potassium sulfide (5.7 g) was stirred under nitrogen at reflux for 5 hours, then filtered while hot, and the filtrate was evaporated under reduced pressure. Recrystallization from ethanol gave 7.4 g (65%) of product, mp 98-100 ° C.

Elemental analysis results based on the formula Ci ₃ H _lf NCiO ₂ S:

Calculated: C 54.64 H5.65 N4.90; Found: C 54.57 H5.67 N4.85.

Example 41

If, in the procedure of Example 20, 2- (1-benzyl-3-pyrrolidinyloxy) -benzoic acid is t-f (1-ethyl-3-pyrrolidinyl) -1427

195 649 equimolecular amounts of oxy] benzoic acid, 2 - [(1-isopropyl-3-pyrrolidinyl) oxy] benzoic acid give the following compounds:

- (2-chloroethyl) -2,3-dihydro-4-ethyl-1,4-benzoxazepin-5- (4H) -one,

- (2-chloroethyl) -2,3-dihydro-4-isopropyl-1,4-benzoxazepin-5 (4H) -one.

Examples 42, 43

If, in the procedure of Example 22, sodium 2 - [(1-methyl-3-pyrrolidinyl) oxy] pyridine-3-carboxylate

2 - [(1-ethyl-3-pyrrolidinyloxy] -3-pyridine carboxylate, 2-1- (1-isopropyl-3-pyrrolidinyl) oxy] -3-pyridine carboxylate.

equimolecular amount, the following compounds are obtained:

- (2-chloroethyl) -2,3-dihydro-4-ethylpyrido [3,2-b] 1,4] oxazepin-5 (4H) -one hydrochloride,

- (2-chloroethyl) -2,3-dihydro-4-isopropylpyrido [3,2-f] [1,4] -oxazepin-5 (4H) -one hydrochloride.

Example 44

2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-F) [1,4] thiazepin-5- (4H) -one

I

A mixture of 80.75 g (0.34 mol) of 2 - [(1-methyl-3-pyrrolidinyl) thio] pyridine-3-carboxylic acid, 500 ml of chloroform, 200 g of carbon tetrachloride and 178 g (0.68 mol) of triphenylphosphine Stir at reflux for 2.5 hours. The resulting solution was extracted once with 500 mL of 3 x 125 mL of IN hydrochloric acid. The acidic extracts were combined and extracted with isopropyl ether. The aqueous layer was made basic and extracted three times with chloroform. The combined chloroform extracts were dried over sodium sulfate and evaporated. Part of the residue was purified by silica gel column chromatography and ethyl acetate using high pressure liquid chromatography. The resulting compound was recrystallized from a mixture of isopropyl ether and isopropyl alcohol. Mp: 97-100 ° C.

Elemental analysis based on CnH, ₃ N ₂ OSCl:

Calculated for C 51.46 H5.10 N 10.91 Found: C 51.63 H5.12 N 10.85

Example 45

2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [3,2-f] (1,4] thiazepine-5 (4H) -thione

4.3 g (0.017 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] thiazepin-5 (4H) -one, A mixture of 100 ml of toluene and 4.8 g (0.012 mol) of 2,4-bis (4-methoxyphenyl), 3,2,4-dithiadiphosphetane-2,4-disulfide was refluxed for 3 hours and then diluted with sodium hydroxide. extracted twice with hydroxide solution. The organic layer was evaporated and the residue was purified by high performance liquid chromatography (silica gel, ethyl acetate: hexane = 1: 1). Yield: 2 g, m.p. 160-162 ° C.

Elenal analysis results for C _U H ₁₃ N ₂ S ₂ C1:

Calculated for C 48.43 114.80 N 10.27: C 48.46 114.81 N 10.51

Example 46

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5- (4H) -one g (1.1 mol) - 60% sodium hydride mixed with mineral oil is suspended in 800 ml of dimethylformamide, preheated to 55 ° C, and thereto is added 79 g (0.5 mol) of 4-chloronicotinic acid and 52 g (0.52 g) of mole) of I-methylpyrrolidin-3-ol in 150 ml of dimethylchloramide to keep the temperature between 55 ° C and 70 ° C. The mixture is kept at 60 ^D C for 4 hours and then filtered hot. The filtrate was evaporated in a rotary evaporator at 5 mmHg in a water bath. The residue was dissolved in water (600 mL) and extracted with isopropyl ether. The aqueous layer was adjusted to pH 6 with hydrochloric acid and the solution was concentrated in a rotary evaporator (5 mm Hg, water bath). The residue was suspended in chloroform (800 ml) and triphenylphosphine (188 g, 1.1 mol) was added followed by carbon tetrachloride (250 ml). The mixture is slowly cooled to 60 ° C where the reaction becomes exotene, so the temperature is maintained at 60-65 ° C in an ice bath for about 20 minutes. The ice-cooling is then removed, the mixture is refluxed for 3.5 hours and then cooled. The solution was extracted with water (600 mL) followed by IN hydrochloric acid (2 x 200 mL). The acidic layer was made basic with sodium hydroxide and extracted three times with chloroform. The chloroform was evaporated and the residue was purified by silica gel column chromatography using ethyl acetate as eluent. Yield: 30 g (25%). Both mass spectroscopy and NMR confirmed that the title compound was obtained.

Example 47

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] oxazepine-5- (4H) -thione monohydrochloride g (0.06 mol) 2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] oxazepin-5 (4H) -one is dissolved in 200 ml of anhydrous toluene and 15 g (0.037) are added. moles) of 2,4-bis (4-methoxyphenyl) -1,3,2,4-dithiaphosphetane-2,4-disulfide. The mixture was refluxed for 2.5 hours and the toluene solution was decanted. The residue was partitioned between dilute sodium hydroxide solution and chloroform. The chloroform portion was dried and concentrated

-1 529

Stir 195,649. The residue was chromatographed on a high performance liquid chromatography (Waters 500) column using silica gel and ethyl acetate as eluent. The fraction containing the molecular weight 257 was evaporated. The residue is dissolved in isopropyl alcohol and treated with hydrochloric acid and the crystalline material is filtered off. Yield: 0.1 g (0.6%) of the hydrochloride salt. Mp: 168-171 ° C.

Elemental analysis according to the formula C _U H ₁₄ N ₂ OSC1:

calculated. C, 45.06; H, 4.8; N, 9.55. Found: C, 45.15;

Example 48

2,3,4,5-tetrahydro-4-methyl-5-oxo-pyrido [3,2-f] [l, 2-propionitrile 4joxazepin

100 g (0.415 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrrolidin-3,2-l'j | The 1,4] oxyzcpin-5 (4ll) -one hydrochloride was partitioned between 200 mL of dilute aqueous sodium hydroxide and 200 mL of chloroform. The organic layer was set aside and the aqueous layer was extracted with chloroform (3 x 50 mL). The organic layers were combined, dried over sodium sulfate and evaporated in a rotary evaporator (70 ° C, water air pump). The residue (89 g, 0.37 mol), the free base of the starting hydrochloride salt, was dissolved in toluene (150 ml) and tetrabutylammonium bromide (9 g, 0.027 mol) was added. 100 ml of saturated potassium cyanide solution are then added and the mixture is heated to reflux with mechanical stirring. After 2 hours, additional tetrabutylammonium bromide (0.009 mol) and saturated potassium cyanide solution (20 ml) were added and stirring was continued at reflux for 0.75 hours. The contents of the reaction vessel were then extracted with ethyl acetate (3 x 50 mL). (Note: chloroform may be used instead of ethyl acetate.) The organic layer is dried over sodium sulfate and then concentrated to 1/3 of its original volume in a rotary evaporator (70 ° C, water air pump). During cooling, crystallization begins. The crystals were filtered off and washed several times with ethyl acetate and isopropyl ether. 30 g (35%) of an off-white crystalline solid are obtained. Mp: 104105 ° C. A small amount was recrystallized from ethyl acetate. Mp: 104-105 ° C.

Elemental analysis results based on the formula Ci ₂ Hj ₃ N ₃ O ₂ :

H, 5.67; N, 18.17. Found: C, 62.06; H, 5.65; N, 17.97.

Example 49

2- (2-Chloroethyl) -4-ethyl-2,3-dihydropindo [3,2-f] [1,4-oxazepin-5- (4'L) -one hydrochloride

81.45 g (2.036 mol) of a 60% sodium hydride dispersion in sodium hydride are suspended in 500 ml of dimethylsulfoxide 16, heated to 50 ° C and 142 g (0.905 mol) of 2-chlorine are added dropwise with stirring. of nicotinic acid and 99 g (0.86 mol) of N-ethyl-3-pyrrolidinol in 500 ml of dimethylsulfoxide at a rate such that the temperature remains between 50 ° C and 60 ° C (cooling may be necessary). After the addition is complete the mixture

Stir at 50-60 ° C for 1.5 hours and allow to cool. The precipitate was filtered off, washed with ethyl acetate and dried.

The dry sodium salt (172.53 g, 0.62 mol) was suspended in 1 liter of chloroform. Hydrogen chloride gas was bubbled through the suspension until the pH on the pH meter reached 5.76. At this time, triphenylphosphine (365.5 g, 1.395 mol) and carbon tetrachloride (365.5 g) were added and heated to reflux with stirring. After 45 minutes, the IR showed 95% complete reaction. An additional 100 g (0.38 mol) of triphenylphosphine and 100 g of carbon tetrachloride are added to the reaction mixture and refluxed for a further 45 minutes. The IR test then shows that the reaction is over 99% complete. After cooling, the solution is extracted several times with dilute hydrochloric acid (1.5 L total). The aqueous layer was basified with concentrated sodium hydroxide solution and extracted with chloroform (3 x 250 ml). The aqueous layer was dried over sodium sulfate and evaporated in a rotary evaporator (70 ° C, water air pump). The residual oil was dissolved in isopropyl alcohol (500 mL) and acidified with hydrogen chloride gas. During cooling, an oil appears; the volume is reduced to 1/3 of the original. Upon cooling, 60 g (0.241 mol) (28%) of a light brown crystalline solid are precipitated. Mp: 153-155 ° C.

Elemental analysis results based on the formula Ci ₂ HieN ₂ O ₂ Cl ₂ :

Found: C, 49.50; H, 5.53; N, 9.62. C 49.64 H5.62 N9.32

Example 50

2- (2-Chloroethyl) -4-ethyl-2,3-dihydropyrido [3,2-f] 1,4] oxazepln-5- (4H) -thione Hydrochloride

About 50 g of 2- (2-chloro-ethyl) -4-ethyl-2,3-dihydropyridido] -3,2-f [1,4] oxazepin-5 (4H) -one hydrochloride was partitioned between 50 ml of dilute aqueous sodium hydroxide solution and 50 ml of chloroform. The organic layer was discarded and the aqueous layer was extracted with 2 x 50 mL methylene chloride. The organic layers were combined, dried over sodium sulfate, filtered and evaporated in a rotary evaporator (70 C, water air pump) to give 39 g (0.153 mol) of free base. This

It is dissolved in 1.2 L of chloroform and 33.9 g (0.153 mol) of phosphorus pentasulfide are added with stirring. The resulting mixture was heated at reflux for 16 hours. After cooling, the reaction mixture was filtered, washed with dilute sodium hydroxide solution (3 x 300 mL), dried over sodium sulfate and evaporated to a yellow viscous oil in a rotary evaporator (70 ° C, water pump). The shoulder

-1 631

195,649 were dissolved in about 200 ml of isopropyl alcohol and acidified with hydrogen chloride gas. On cooling, 20 g (43%) of crystalline material are precipitated, m.p. 133-135 ° C.

Elemental analysis results based on the formula Ci ₂ Hi ₆ N ₂ OSC1 ₂ :

Calculated: C 46.91 H5.25 N9.12 Found: C 47.33 H5.38 N9.10

Example 57

7-Chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5- (4H) -one g (0.136) mole) 2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f], 4-oxazepin-5 (41l) -one hydrochloride was dissolved in 150 ml of dimethylformamide and heated to reflux. Sulfuryl chloride (20 g, 0.148 mol) was then added dropwise over 40-50 minutes. After the addition was complete, the reaction mixture was stirred at reflux for 30 minutes. After cooling, the vessel was partitioned between 150 mL water and 150 mL benzene. The benzene layer was discarded and the aqueous layer was extracted with additional 2 x 50 mL benzene. The benzene extracts were combined and washed with dilute aqueous potassium hydroxide solution (2 x 50 ml) followed by dilute aqueous hydrochloric acid (2 x 50 ml). The benzene layer was dried over sodium sulfate and concentrated in a rotary evaporator (70 ° C, water air pump) to give 2.61 g of crude product. Recrystallization from isopropyl ether gave 1.25 g (12.6%) of an off-white crystalline solid. Mp 78-79 ° C.

Elemental analysis using the formula CnH ₁₂ N ₂ O ₂ Cl ₂ :

Found: C, 48.02; H, 4.40; N, 10.18;

Example 52

-chloro-2- (2-chloroethyl) -2,3-dihydio-4-methylpyrido [3,2-f] [1,4] oxazepine-5- (4H) -thione

6.0 g (0.022 mol) of 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) We suspended in 200 ml of toluene. To this suspension was added 2,4-bis (4-methoxyphenyl-1,3-dithia-2,4-diphosphetane-2,4-dulphide sulfide) and the mixture was heated at reflux for 2 hours with vigorous stirring. nein is completely consumed, an additional 3.0 g of 2,4-bis (4-nictoxyphenyl) 1,3-dithia-2,4-diphosphetane-2,4-disulfide is added and refluxed for a further 2 hours. The solution was then decanted and washed with dilute aqueous sodium hydroxide solution (50 mL) and dilute hydrochloric acid (50 mL).

The crude oil was recrystallized from isopropyl alcohol to give 3.5 g (54%) of a pale yellow crystalline solid. M.p .: 125-127 ° C.

Elemental analysis using the formula CnH ₁₂ N ₂ OSCI ₂ :

calculated. C45.37 H4.15 N9.62 found. C 45.40 H4.20 N9.71

Example 53

2- (2-chloroethyl) -2,3-dihydro-4-benzyl-pyrido [3,2-f] [l, 4] oxazepine-5 (4H) -one

The title compound is obtained in the first part of Example 124 in the form of a crude product.

Example 54

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepln-5 (4H) -one hydrochloride g (0.1 mol) 2- (2-chloro) ethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one dissolved in 250 ml of ethanol was added 9 g (0.2 mol) of dimethylamine in a steel bomb. The mixture was heated at 100 ° C for 18 hours, then concentrated in vacuo and partitioned between ethyl acetate and dilute sodium hydroxide. The ethyl acetate layer was evaporated and the residue, which essentially consists of the free base of the title product, was dissolved in a mixture of methyl isobutyl ketone and isopropanol. The solution was acidified with hydrogen chloride gas to give the title product. M.p .: 188-197 ° C.

Example 55

2-] 2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one

The total amount of the hydrochloride salt obtained in Example 54 was partitioned between chloroform and dilute sodium hydroxide solution, and the chloroform layer was evaporated. The residue was recrystallized several times from isopropyl ether to give 6 g (21%) of free base, m.p. 56-76 ° C.

Elemental analysis Calcd Ci4H ₂₀ N ₂ O ₂ wherein:

Calculated: C 67.72 H8.12 NI 1.28 Found: C 67.35 H8.16 N 11.09

Example 56

2,3-Dihydro-4-methyl-2- [2- (4-morpholinyl) ethyl] -1,4-benzoxazepin-5 (4H) -one fumarate salt 1: 1 g (0.084 mol) 2- (2-chloro) Ethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4'L) -one is added with 50 ml of morpholine. The solution was refluxed for 5 hours

-1 733

195 649, then evaporated in vacuo. The residue was dissolved in chloroform, washed with dilute sodium hydroxide solution, dried over sodium sulfate and evaporated in vacuo. The residue, which is essentially the free base of the title product, is reacted with 10.5 g (0.09 mol) of fumaric acid in a mixture of isopropanol and water. The resulting solid was recrystallized from a mixture of isopropanol and water to give 21.5 g (64%) of melting point 199-201 ° C.

Analysis results for C ₂₀ H ₂₆ N ₂ 0 ₂ :

Calculated: C 59.10 H 6.45 N 6.89 Found: C 58.95 H 6.25 N6.88

Example 57

4-Benzyl-2,3-dihydro-2- [2- (4-morpholinyl) ethyl] -1,4-benzoxazepin-5 (4H) -one

To 200 ml of morpholine was added 30 g (0.095 mol) of 4-benzyl-2- (2-chloroethyl) -2,3-dihydro-1,4-benzoxazepin-5 (4H) -one. The solution was refluxed for 3 hours and then concentrated in vacuo. The residue was partitioned between dilute sodium hydroxide solution and chloroform. The chloroform layer was dried over sodium sulfate and concentrated in vacuo. The resulting solid was recrystallized three times from a mixture of isopropyl ether and ethyl acetate.

15.2 g (43%) of a solid are obtained. Mp .: 9799 'C.

Elemental analysis according to formula C ₂₂ H ₂₆ N ₂ O ₃ :

Calculated: C, 72.10; H, 7.15; N, 7.64. Found: C, 72.25; H, 7.22; N, 7.64.

Example 58

1: 1 fumarate salt of 4-benzyl-2,3-dihydro-2β-methylamino-ethyl] -1,3-benzoxazcpin-5 (4'1) -one

Monomethylamine (5.95 g, 0.19 mol) was dissolved in ethanol (200 ml) and treated with 4-benzyl-2- (2-chloroethyl) -2,3-dihydro-1 (30 g, 0.095 mol) in a steel bomb. 4benzoxapein-5 (4H) -one. The mixture was heated at 100 ° C for 16 hours. The solution was concentrated in vacuo and the residue partitioned between chloroform and dilute sodium hydroxide solution. The chloroform layer is evaporated and the residue, which contains essentially the free base of the title compound, is dissolved in isopropanol and reacted with fumaric acid to give the fumarate salt. The salt is dried at 100 ° C in vacuo until the remaining isopropyl alcohol is removed. Mp 178-181 ° C.

Elemental analysis according to formula C ₂₃ I1 ₂₆ N ₂ O ₆ :

H, 6.15; N, 6.57. Found: C, 64.87; H, 6.20; N, 6.62.

Example 59

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxa7.epin-5 (411) -thionic hydrochloride (1: 1)

To a solution of dimethylamine (7.2 g, 0.16 mol) in absolute ethanol (350 ml) was added 2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4,4 g (0.08 mol). Benzoxazepine-5 (4H) ion is added. The solution was heated in a steel bomb for 18 hours at 100 ° C and evaporated. The residue was partitioned between chloroform and dilute sodium hydroxide solution. The chloroform layer was dried over sodium sulfate and evaporated. The solid, which is essentially the free base of the title compound, is reacted with hydrochloric acid dissolved in ethanol to give the hydrochloride salt. This was recrystallized once from ethanol and dimethylformamide and then three times from ethanol to give 7.5 g (28%). Mp: 233-236 ° C.

Elemental analysis establish the Ci4H SOCl ₂ IN ₂ O:

Calculated: C 55.90 H 7.04 N 9.32 Found: C 55.72 H 7.26 N 8.94

Example 60

4-benzyl-2- [2-dimethylamino-Aminobenzyl) ethyl] -2,3-dihydro-5-4benzoxazepin (4-yl) -one monohydrate

Following the procedure of Example 54, 4-benzyl-2- (2-chloroethyl) -2,3-dihydro-1,4-benzoxazepin-5 (4H) ontone was reacted with dimethylamine to give the title compound as a residue. free base of the compound. This is recrystallized from ethanol / water to give the product, m.p. 75-77 ° C.

Analysis results for C ₂₀ H ₂₆ N ₂ O ₃ :

Calculated: C 70.13 H 7.65 N 8.21 Found: C 70.02 11 7.53 N 8.25

Example 67

2,3-Dihydro-4-methyl-1- [2- (4-morpholinyl) ethyl] -1,4-benzoxazepine-5 (4H) -thio-hydrochloride (1: 1)

20.4 g (0.08 mol) of 2,3-dihydro-4-methyl-2- (2-chloroethyl) -1,4-benzoxazepine-5 (4H) -thione in 60 ml of morpholine are heated at reflux for 5 hours, then evaporate. The residue was partitioned between dilute sodium hydroxide solution and chloroform. The chloroform layer was dried over sodium sulfate and evaporated to yield essentially the free base of the title compound. The hydrochloric acid salt was prepared in a solution of methyl isobutyl ketone and dimethylformamide (hydrochloric acid gas) by recrystallization from ethanol / diethylphenyl to give 14 g (31%) of a solid, m.p .: 253-256 ° C.

-1 835

195,649

Elemental analysis using the formula C _t6 II ₂₃ N ₂ SÜ ₂ Cl:

Calculated: C 56.04 H6.76 N8.17 Found: C 55.73 H 6.63 N 7.97

Example 62

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylnaphth [2,3-f] [1,4] oxazepin-5 (4H) -one

1: 1 oxalate salt

To a steel bomb, 5.0 g (0.017 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylnaphth [2,3-f] [1,4] oxazepin-5 (4H) -one, of absolute ethanol and 3.78 g (0.034 mol) of dimethylamine were added as a 40% aqueous solution. The bomb was heated at 100 ° C for 16 hours. The volatiles were removed under reduced pressure and the residue was partitioned between chloroform and 15% aqueous sodium hydroxide. The chloroform layer was washed twice with water, dried over magnesium sulfate and evaporated under reduced pressure to give 2.7 g (54%) of a viscous yellow oil, essentially the free base of the title compound. The oil was dissolved in isopropyl alcohol and treated with oxalic acid, and the resulting oxalate salt was recrystallized from a mixture of ethanol and water. Melting point: 192-194 ° C.

Analysis results for C ₂₀ H ₂₄ N ₂ O ₆ :

calculated. C 61.84 H 6.23 N7.21 Found: C 61.41 H 6.27 N 7.09

Elenal analysis results using the formula C'isIhsNjOs:

Calculated for C 53.90 H5.90 N9.92: C 53.76 H 6.02 N9.96

Example 64

2- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thionic fumarate (1: 1) ) · Ethanol (2: 1)

A steel bomb was charged with 32.8 g (0.29 mol) of a 40% aqueous solution of dimethylamine, 100 ml of ethanol and 15 g (0.058 mol) of 2- (2-chloroethyl) -2,3-dihydro-4 -methyl-pyrido [3,2-f] [l, 4] oxazepine-5 (4H) -thione. The mixture was heated at 100 ° C for 18 hours with gentle stirring. The solution was cooled and partitioned between dilute sodium hydroxide solution and chloroform. The chloroform layer was dried over sodium sulfate and evaporated. The residue, which is essentially the free base of the title product, is dissolved in isopropyl alcohol and reacted with 7 g of fumaric acid. The fumarate salt was recrystallized from isopropyl alcohol to give 19 g (86%). Mp: 105-129 ° C. 14 g of this are crystallized from ethanol to give 10.5 g of yellow crystals. Mp: 103-108 ° C. The NMR spectrum showed that the crystals contained 1/2 mol of ethanol.

Elemental analysis using the formula C36Hs ₂ N ₆ 0nS ₂ :

H, 6.48; N, 10.39. Found: C, 53.07; H, 6.53; N, 10.23.

Example 63

Fumarate salt of 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one g To a 40% aqueous solution of dimethylamine (0.8 mol) in a steel bomb was added 25 g (0.09 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3 2-f | [l, 4] oxazepine-5 (4H) -one hydrochloride. The mixture was heated at 100 ° C with gentle stirring for 15 hours and then partitioned between dilute sodium hydroxide solution and twice with chloroform. The chloroform layers were combined and evaporated. The residue, consisting essentially of the free base of the title product, was dissolved in isopropyl alcohol (200 mL) and oxalic acid (9 g) was added. The oxalate salt was recrystallized from 95% ethanol to give 18 g. The oxalate salt is then converted to the free base by partitioning between chloroform and dilute sodium hydroxide solution and evaporating the chloroform layer. The residue, which is the free base of the title product, is dissolved in isopropyl alcohol and reacted with fumaric acid to give 13 g (34%) of a white solid. Mp 146-148 ° C. (Base frame: Formula (1))

Example 65

Fumarate salt of 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione

A steel bomb was charged with 113 ml (1.0 mol) of 40% aqueous dimethylamine solution, 326 ml of ethanol and 48.4 g (0.189 mol) of 2- (2-chloroethyl) -2,3-dihydro-4 -methyl-pyrido [3,2-f] [l, 4] oxazepine-5 (4H) -thione. The mixture was heated at 100 ° C for 14 hours. The ethanol is removed in a rotary evaporator with little water remaining. The residue was dissolved in methylene chloride (200 mL) and washed with 20% aqueous potassium carbonate (3 x 100 mL). The combined aqueous layers were extracted with methylene chloride (3 x 150 mL). The methylene chloride solutions were combined and treated with activated carbon. The activated carbon was filtered off and the filtrate was evaporated until an oil remained. This oil was dissolved in isopropyl alcohol (215 mL) and heated slowly to a solution of fumaric acid (21.9 g, 0.19 mol) in boiling methanol (150 mL).

63.4 g (88%) of crystals are obtained. This was recrystallized from 200 mL of hot ethyl alcohol. The crystalline material is filtered off, triturated at room temperature in isopropyl ether and filtered again.

-1 937

195,649

Dry overnight at 85 ° C in vacuo to give 72.45 g (79%) of crystalline material. M.p .: 130-133 ° C.

Anal Calcd for C ₇ LL2 _{3 3} N ₅ O S O:

Calcd. C, 53.53 116.08 NI 1.02; Found: C, 53.23; H, 11.11; N, 10.64. The residue is evaporated at 0.22 mmHg at 182 ° C to give 4.3 g of product. .

Elemental analysis results based on the formula Ci ₃ H ₁₈ N ₂ O ₂ :

Found: C, 66.64 117.74 NI 1.96. Found: C 66.48 117.69 N 11.88

Example 66

4-Benzyl-2,3-dihydro-2- [2- (4-morpholinyl) ethyl] -1,4-benzoxazepln-5 (4H) -thione

A fine mixture of 2.9 g (0.013 mol) of phosphorus pentasulfide and 2.9 g of potassium sulfide is suspended in 75 ml of anhydrous toluene and 12 g (0.033 mol) of 4-benzyl-2,3-dihydro-2- [2 - (4-morpholinyl) ethyl] -1,4-benzoxazepin-5 (4H) -one. The mixture was stirred at reflux for 10 hours and then filtered. The filtrate was evaporated and the residue was recrystallized from a mixture of isopropyl ether and toluene to give 2.54 g (20%). Mp: 236-238 ° C.

Elemental analysis for C22H26N2O2S:

Calculated: C 69.08 H 6.85 N 7.32 Found: C 69.60 H 6.96 N7.15

Example 7

Fumarate salt of 2,3-dihydro-4-methyl-2- [2- (methylamino) ethyl] -1,4-benzoxazepin-5 (4H) -one

Following the procedure described in Example 58, 50 g (0.21 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one Reaction with monomethylamine (13.0 g, 0.42 mol) in 400 mL of ethanol to give the free base of the title product. This was then reacted with fumaric acid to give 17 g (23%) of the title compound after isolation and recrystallization from ethyl alcohol. Mp: 154-156'C.

Elemental analysis results based on the formula CiJ ^ NjO ^:

Calculated: C 58.27 11 6.33 N8.00 Found: C 58.34 H 6.52 N 7.82

Example 68

2,3-Dihydro-4-methyl-2- [2- (methylamino) ethyl] -1,4-benzoxazepin-5 (4H) -one

2,3-Dihydro-4-methyl-2- [2- (methylamino) ethyl] 1,4-benzoxazepin-5 (4H) -one fumarate is converted to the free base by diluting with sodium hydroxide solution and chloroform. between. The chloroform layer

Example 69

2,3-Dihydro-2- [2- (4-hydroxy-4-phenylpiperidino) ethyl] -4-methyl-1,4-benzoxazepine-5 (4H) -thione (and its hydrochloride salt)

10.7 g (0.078 mol) of potassium carbonate, 13.7 g (0.078 mol) of 4-hydroxy-4-phenylpiperidine and 19.8 g (0.078 mol) of 2- (2-chloroethyl) -2, 3-Dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione is suspended in 200 ml of n-butanol and refluxed overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue is dissolved in a mixture of ethanol and ligroin and shaken with hydrochloric acid gas to give the hydrochloride salt which is then recrystallized from a mixture of ethanol and dimethylformamide. The hydrochloric acid salt is converted to the free base by partitioning between chloroform and dilute sodium hydroxide solution and then evaporating the chloroform. This was recrystallized twice from isopropyl alcohol to give 9.27 g (30%) of the free base. Op: 142-148 ^e C.

Elemental analysis results based on the formula C2 ₃ H ₂₈ N2 0 ₂ S:

Calculated for C 69.66 H 7.12 N 7.07 Found: C 69.78 H7.18 N7.00

Example 70

2,3-Dihydro-4-methyl-2- [2- (4-phenyl-1,2,3,6-tetrahydropyridino) ethyl] -1,4-benzoxazepine-5 (4H) -thione

24.3 g (0.176 mol) of potassium carbonate, 11.5 g (0.059 mol) of 4-phenyl-1,2,3,6-tetrahydropyridine and 15 g (0.059 mol) of 2- (2-chloroethyl) - 2,3-Dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione is suspended in enough n-butanol to form a thick slurry and refluxed for 72 hours. The reaction mixture was filtered hot, the filtrate cooled to room temperature and filtered again. The latter filtrate was evaporated and the residue was dissolved in ethyl acetate. On cooling, the crystallization material was recrystallized from ethyl acetate to give 7 g (31%) of product. Mp: 153-155 ° C.

Elemental analysis for C23H26N2OS:

Calculated: C, 72.98; H, 6.92; N, 7.40. Found: C, 73.36; H, 7.01; N, 7.47.

-2 039

195,649

Example 71

1: 1 hydrochloric acid salt of 8-chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione

To a solution of 9.8 g (0.04 mol) of 8-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4ll) -thione in 50 ml of absolute ethanol let's mix 10 in! 40% aqueous dimethylamine solution and heated in a steel bomb for 16 hours at 100 ° C. The ethanol was evaporated under reduced pressure and the residue was partitioned between chloroform and 10% sodium hydroxide solution. The chloroform was evaporated under reduced pressure to give an amorphous solid. This was dissolved in 6N hydrochloric acid and the solution was washed with ethyl acetate. The aqueous layer was basified with 50% sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was evaporated under reduced pressure to give a viscous oil, which is essentially the free base of the title compound. This is dissolved in absolute ethanol and reacted with ethereal hydrochloric acid. The hydrochloric acid salt was recrystallized from ethanol to give 30 g (25%) of product. M.p .: 196-199 ° C.

Example 72

Oxalate salt of 8-chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-ethyl-1,4-benzoxazepin-5 (4H) -one g (0.037 mol) 8- a solution of chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one in 50 ml of absolute ethanol was mixed with 10 ml of a 40% aqueous solution of dimethylamine and heated in a steel bomb for 16 hours at 100 ° C. The solution was concentrated under reduced pressure, the residue was dissolved in chloroform and the solution was washed twice with 15% sodium hydroxide solution. The chloroform layer is dried over magnesium sulfate and concentrated under reduced pressure to an oil which is essentially the free base of the title product. The oil was dissolved in absolute ethanol and reacted with oxalic acid. The oxalate salt was recrystallized from ethanol to give 4 g (38%) of product. Mp: 198-201 ° C.

Elemental analysis calculated for C ₆ H _2I C10 _{N2 O6:}

Calculated: C 51.55 H5.68 N7.51 Found: C 51.07 H 5.69 N 7.43

Example 73

Oxalate salt of 7-bromo-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylbenzoxazepin-5 (4H) -one

3.0 g (0.01 mol) of 7-bromo-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one in 50 ml of absolute ethanol and 2.2 ml of a 40% aqueous solution of dimethylamine are added. The reaction mixture was heated at 100 ° C for 16 hours in a steel boiler and then concentrated under reduced pressure. The residue was partitioned between chloroform and 15% sodium hydroxide solution. The chloroform layer was separated and extracted with 3N aqueous hydrochloric acid. The acidic layer was diluted with 50% aqueous sodium hydroxide solution and extracted with chloroform. Chloroform was evaporated under reduced pressure to give 2.4 g (73%) of a brown viscous oil, consisting mainly of the free base of the title compound. The oil was dissolved in isopropyl alcohol and reacted with oxalic acid. The oxalate salt was recrystallized from a mixture of isopropyl alcohol and water to give the title compound. Mp: 192-194 ° C,

Elemental analysis using the formula C ₆ H ₂ iO ₆ BrN ₂ :

Calculated: C 46.06 H 5.07 N6.71 Found: C 46.00 H5, I0 N 6.68.

Example 74

Oxalate salt of 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylnaphth [2,1f] [1,4] oxazepin-5 (4H) -one g ( 0.028 mole) of 2- (2-chloroethyl) -2,3-dihydro-4-methylnaphtho [2,1f] [1,4] oxazepin-5 (4H) -one and 6.2 g (0.055 mole). % dimethylamine in 100 ml of ethanol was heated in a steel bomb for 18 hours at 100 ° C. The resulting solution was partitioned between methylene chloride and dilute sodium hydroxide solution. The methylene chloride layer was dried over sodium sulfate and evaporated. The residue, which consists mainly of the free base of the title compound, is dissolved in isopropyl alcohol and treated with 2.6 g of oxalic acid. The oxalate salt recrystallized from an aqueous isopropyl alcohol solution had a melting point of 206-209 ° C.

Elemental analysis based on the formula C ₂ H ₂ 4 N ₂ O ₆ :

H, 6.23; N, 7.21. Found: C, 61.61; H, 6.26; N, 7.13.

Examples 75-77

If 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one hydrochloride is used in the procedure of Example 63,

2- (2-chloroethyl) -2,3-dihydro-4-methyl-pyrido [4,3-f] [l, 4] oxazepine-5 (4H) -one hydrochloride,

2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] oxazepin-5 (4H) -one hydrochloride or

Equivalent to 2- (2-chloro-ethyl) -2,3-dihydro-4-methylpyrido [2,3-f] [1,4] oxazepin-5 (4H) -one hydrochloride, the? The following compounds are obtained:

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrrolo [4,3-f] [1,4] oxazepin-5 (4H) -one fumarate .

- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-methylpyrid

-2 141

195,649 do [3,4-J [1,4] oxazepin-5 (4II) -on fumarate and

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [2,3-f] [1,4] oxazepin-5 (4H) -one fumarate.

Example 78

2: 3 hydrochloric acid salt of 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [4,3-f] [1,4] oxazepine-5 (4H) -thione

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [4,3-f] [1,4] oxazepine-5 (4H) -thione (0.5 g, 0.002 mol) in 20 ml of ethyl alcohol and 2 ml of 40% aqueous dimethylamine solution are added. The mixture was heated in a steel bomb for 14 hours at 100 ° C. The resulting solution was filtered and concentrated. The residue is dissolved in isopropyl alcohol and a few drops of ethereal hydrochloric acid are added. The hydrochloride salt crystals were dissolved in ethyl alcohol, refluxed while the ethyl alcohol was replaced with isopropyl alcohol. Yield: 0.3 g (47%). The product decomposes above 200 ° C.

Elemental analysis according to formula C ₂₆ H ₄₁ N ₆ 0 ₂ S ₂ Cl ₃ :

Calculated: C 48.78 116.46 N 13.13 Found: C 49.34 H 6.47 N 13.03

Example 79

2- [2- (diethylamino) ethyl] -2,3-dibidro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thionic oxalate (1: 1) hemihydrate

2- (Chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione is dissolved in ethanol and heated with diethylamine to give a salt. followed by the title compound.

Example 80

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylnaphth [2,3-f] [1,4] oxazepine-5 (4H) -thionoxalate (1: 1) hemihydrate g (0.05 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylnaphth [2,3-f] [1,4] oxazepine-5 (4H) -thione 50 Dissolve in 20 ml of absolute ethanol and add 10 ml of 45% aqueous dimethylamine solution. The solution was heated in a steel bomb for 16 hours. The ethanol was evaporated under reduced pressure and the residue was partitioned between chloroform and 15% aqueous sodium hydroxide. The chlorophoric layer was separated and extracted with 3N aqueous hydrochloric acid. The acidic layer was basified with 50% aqueous sodium hydroxide solution and extracted with chloroform. The chloroform solution was concentrated under reduced pressure, the residue was dissolved in isopropyl alcohol and treated with oxalic acid. The salt was recrystallized from a mixture of isopropyl alcohol and water to give the title compound. Mp .: 115-118 ° C.

Elemental Analysis: Calculated for C40H _5o OiiS ₄ N ₂ O:

Calculated: C, 58.09; H, 6.09; N, 6.77. C, 58.42; H, 5.85; N, 6.70

Example 81

Oxalate salt of 7-chloro-2- (2- (dimethylethylanoylethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one

7-Chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxoxazepin-5 (4ll) -one (9.0 g, 0.033 mol) was dissolved in absolute ethanol (50 mL) and added. 7 g (0.066 mol) of 45% aqueous dimethylamine solution. The solution was heated in a stainless steel bomb for 14 hours at 100 ° C. The reaction mixture was concentrated under reduced pressure and the residue partitioned between chloroform and 15% aqueous sodium hydroxide. The chloroform layer was separated and concentrated under reduced pressure to give a viscous brown oil. This is dissolved in isopropyl alcohol and oxalic acid is added. Recrystallization from a mixture of isopropyl alcohol and water gave 7.0 g (57%) of the oxalate salt. Mp .: 199-200 'C.

Elemental analysis according to formula C ₁₆ H ₂₁ N ₂ O ₆ C1:

Calculated: C 51.55 H5.68 N 7.51 Found: C 51.52 H 5.72 N 7.44

Example 82

2- [2- (dimethy) ethyl] _-2> 3-dihydro-4-methyl-pyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione-methyl iodide

3.8 g (0.01 mol) of 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-ethylpyrido [3,2-f] (1,4) oxazepine-5 (4H) -thionfumarate (1: 1) ethanol (2: 1) was partitioned between chloroform and dilute sodium hydroxide solution, the chloroform extract was dried over sodium sulfate and evaporated to a residue which was dissolved in 15 ml of methyl isobutyl ketone. Methyl iodide (1.4 g, 0.01 mol) in isobutyl ketone (15 mL) was recrystallized from 50% ethanol / 50% methyl isobutyl ketone to give 2.5 g (78%) of product. 221-225 'C.

Elemental analysis results based on the formula Ci ₄ H ₂₂ N ₃ OSJ:

Calculated for C 41.28 H5.44 N 10.31 Found: C 41.29 H5.51 N 10.30

Example 83

7-Chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl, 4-benzoxazepine-5 (4H) -thionoxalate (1: 1) hemihydrate

7-Chloro-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione (8.0 g, 0.027 mol) was dissolved in 50 ml of absolute ethanol, and 6 ml (0.054

-2 243

195,649 moles) of a 40% aqueous solution of dimethylamine. The solution was heated in a steel bomb at 90 ° C for 14 hours. The ethanol was removed under reduced pressure and the residue was partitioned between chloroform and aqueous sodium oxide solution. The chloroform layer is evaporated to a viscous yellow oil which is dissolved in isopropyl alcohol and reacted with oxalic acid. The oxalate salt precipitates immediately. The mixture is heated and a little water is added to dissolve the salt. A white crystalline powder is obtained. Mp: 150-151 ° C.

Found: C, 48.30 H5.57 N7.04; Found: C, 48.74 H5.34 N, 6.95.

Example 84

2- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-methylnaphth [2,1-f] [1,4] oxazepine-5 (4H) -thionic acid 1: 1 salt

Dissolve 15.0 g (0.05 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylnaphthyl [1,1] f] [1,4] oxazepine-5 (4H) -ion in 50 ml of absolute ethanol. , and 10 g of 40% aqueous dimethylamine solution are added. The resulting solution was heated in a steel bomb for 40 hours at 100 ° C and then concentrated under reduced pressure. The residue was partitioned between chloroform and 15% aqueous sodium hydroxide. The chloroform layer was evaporated and the residue partitioned between chloroform and 3N hydrochloric acid. The aqueous layer was basified with 50% sodium hydroxide solution and extracted with chloroform. The chloroform extract was evaporated, the residue was dissolved in isopropyl alcohol and ethereal hydrochloric acid was added. The precipitate was recrystallized from a mixture of isopropyl alcohol and water to give 3.0 g (20%) of product. Mp: 238-240 ° C.

Elemental analysis for C18H23N2CIOS:

Calculated for C 61.61 116.61 N 7.98. C 61.80 H 6.61 N7.91

Examples 85, 86

When 2- (2-chloro-ethyl) -2,3-dihydro-4-methylethylpyrido [3,2-f] [1,4] oxazepine-5 (4H)

- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione, or

- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [2,3-f] [1,4] oxazepinion is replaced by the following equivalents:

- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] oxazepine-5 (411) -thionic fumarate or

- [2- (Dimethyl-amino) -ethyl] -2,3-dihydro-4-methyl-pyrido [2,3-f] [1,4] oxazepine-5 (4H) -thionic fumarate.

Example 87

2- (2- (Dimethylamino) ethyl] -2,3-dihydro-7-methoxy-4-methyl-1,4-hexoxynzpcin-5 (4II) -one oxalate (1: 1) hemihydrate

2- (2-Chloroethyl) -2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5 (4H) -one (3.0 g, 0.011 mol) was dissolved in absolute ethanol (50 mL) and added. 3.0 g of 40% aqueous dimethylamine solution. The reaction mixture was heated in a stainless steel bomb for 16 hours at 100 ° C, then cooled and evaporated under reduced pressure. The residue was partitioned between chloroform and 15% aqueous sodium hydroxide. The chloroform layer is evaporated and the residue, i.e. the free base, is dissolved in isopropyl alcohol and reacted with oxalic acid. The resulting oxalate salt was recrystallized from a mixture of isopropyl alcohol and water to give 1.9 g (45%) of the title salt. Mp 176-178 ° C.

Analytical results for C34ll _{5 (} ) N4O ( ₅ ):

Calculated: C, 54.10; H, 6.67; N, 7.42; Found: C, 54.29; H, 6.59;

Example 88

Monohydrate of the 1: 1 oxalate salt of 7-bromo-2- (2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione (0.04 mol) 7-Bromo-2- (2-chloroethyl) -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione is dissolved in 50 ml of absolute ethanol and 8 ml of 45% aqueous solution are added. The solution was heated in a steel bomb for 16 hours at 100 [deg.] C. The ethanol was evaporated under reduced pressure and the residue partitioned between ethyl acetate and 3N aqueous hydrochloric acid. The residue, the free base of the title product, was dissolved in isopropyl alcohol and reacted with oxalic acid to give the title salt by recrystallization from 95% ethanol, m.p. 155-157 ° C.

Elemental Analysis: Calculated for C32H ₄₆ N ₂ O ₄ Br 2S2 ₁ wherein:

Calculated: C 42.58 H5.14 N6.12 Found: C 42.93 H4.79 N 6.19

89, p

If, in the procedure of Example 81, 7-chloro-2- (2-chloro-ethyl) -2,3-dihydro-4-methyl-1,4-b-enzoxazepln-5 (4H) -one

- (2-chloroethyl) -2,3-dihydro-4-ethyl-1,4-benzoxazepin-5 (4H) -one, oxazepin-5 (4H) -one,

- (2-chloroethyl) -2,3-dihydro-4-isopropyl-1,4-benzoxazepin-5 (4H) -one,

-2 345

195,649 equimolecular amounts to give the following compounds:

- [2- (dimethylamino) ethyl] -2,3-dihydro-4-ethylbenzoxazepin-5 (4H) -one oxalate,

- [2- (dimethylamino) ethyl] -2,3-dihydro-4-isopropyl-1,4-benzoxazepin-5 (4H) -one oxalate.

is dissolved in propyl alcohol and treated with hydrochloric acid. The hydrochloride salt obtained weighed 1.5 g (77%). Mp: higher than 250 ° C.

Elemental analysis for C ₁₃ H ₂₁ N ₃ OSCI ₂ :

H, 6.27; N, 12.42. Found: C, 45.68; H, 6.18; N, 12.35.

Examples 91 and 92

When 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one hydrochloride is used in the procedure of Example 63.

- (2-chloroethyl) -2,3-dihydro-4-ethylpyrido [3,2-f] | 1,4] oxazepine-5 (4-yl) -one hydrochloride,

- (2-Chloroethyl) -2,3-dihydro-4-isopropylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one hydrochloride, the following compounds are substituted: we get:

- [2- (dimethylamino) ethyl] -2,3-dihydro-4-ethylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one fumarate,

- [2- (dimethylamino) ethyl] -2,3-dihydro-4-isopropylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one fumarate. Ra.

93-96. example

When the morpholine is replaced by an equimolar amount of pyrrolidine, piperidine, piperazine or 4-methylpiperazine in Example 56, the following compounds are obtained:

2,3-dihydro-4-methyl-2- (2- (1-pyrrolidinyl) ethyl] -1,4-benzoxazepin-5 (4H) -one urea,

2,3-dihydro-4-methyl-2- (2- (1-piperazinyl) ethyl] -1,4-benzoxazepin-5 (4H) -one fumarate,

2,3-dihydro-4-methyl-2- (2- (1-pierazinyl) ethyl] -1,4-benzoxazepin-4 (4H0-one fumarate or

2,3-Dihydro-4-methyl-2- (2- (4-methylpiperazin-1-yl) ethyl) -1,4-benzoxazazpin-5 (4H) -one fumarate.

Example 97

2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] -1,4] thiazepin-5 (4H) -one dihydrochloride

1.5 g (0.0058 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido (3,2-f] [1,4] thiazepin-5 (4H) -one A solution of 20 ml of dimethylamine is stirred in a closed vessel for 72 hours at 25 [deg.] C. The excess dimethylamine is evaporated, the residue is partitioned between chloroform and dilute sodium hydroxide solution, and the chloroform layer is evaporated and free base of labeled compound - iso24

Example 98

Oxalate salt of 2- (2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] thiazepine-5 (4H) -thione

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] thiazepine-5 (4H) -thione (1.5 g, 0.005 mol) in 40 ml of dimethyl -amine was stirred for 96 hours in a closed vessel at 25 ° C. The dimethylamine is then evaporated and the residue is partitioned between methylene chloride and dilute sodium hydroxide solution. The methylene chloride layer was evaporated and the residue, treated with 0.4 g of oxalic acid, the free base of the title compound, dissolved in 30 ml of a 90: 100 mixture of isopropyl alcohol and water. The resulting crystals were recrystallized from the same solvent to give 1 g of product. M.p .: 191-193 ° C.

Elemental analysis results based on the formula Ci ₅ H ₂₁ N ₃ S ₂ O4:

H, 5.70; N, 1.33. Found: C, 48.49; H, 5.84; N, 10.99.

Example 99

Oxalate salt of 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido (3,4-f) [1,4] oxazepin-5 (4H) -one hemihydrate g (0.02 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] oxazepin-5 (4H) -one in 25 ml of dimethylamine The solution was dissolved in chloroform and the solvent evaporated in vacuo to remove excess dimethylamine and dilute sodium hydroxide solution and The ethyl acetate solution was evaporated and then 3 g (0.033 mol) of oxalic acid in 50 ml of isopropyl alcohol and enough water to keep the resulting salt solution in reflux were obtained. recrystallization to yield 5.3 g (60%), mp 179-181 ° C.

Elemental analysis results based on the formula Γ ^ ΙΗηΝλΟ ^:

calculated. C, 46.48; 115.52; N, 9.58. C, 46.58; H, 5.7; N, 9.61

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Example 100

Oxalate salt of 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] oxazepine-5 (4H) -thione

2- [2- (Dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] oxazepin-5 (4H) -one has a 1: 2 ratio. A sample of 4 g (0.009 mol) of the hemihydrate of its oxalate salt was partitioned between dilute sodium hydroxide and chloroform. The aqueous layer was extracted three times with chloroform, and the combined extracts were dried over sodium sulfate and evaporated. The residue was dissolved in anhydrous toluene (200 mL) and evaporated to dryness in vacuo. The residue was dissolved in anhydrous pyridine (10 mL), phosphorus pentasulfide (2.8 g, 0.01 mol) was added and refluxed for 20 hours. The cooled mixture was partitioned between chloroform and dilute sodium hydroxide solution and the aqueous layer was extracted three times with chloroform. The combined chloroform extracts were dried over sodium sulfate and evaporated. To 1 g of the residue is added 0.6 g of oxalic acid in 10% water in isopropyl alcohol and the resulting crystals are filtered off. Yield of oxalate salt: 0.37 g. Mp: 111-114 ° C.

Elemental analysis results based on the formula Ci ₇ H ₂₃ N ₃ SO ₉ :

Calculated: C 45.84 H5.20 N9.43 Found: C 45.46 H5.38 N9.28

Example 101

Hemihydrate of the oxalate salt of 2- (3-aminopropyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one g (0) (22 mol) of 2,3-dihydro-4-methyl-5 (4H) -oxopyrido [3,2-f] [1,4] oxazepine-2-propionitrile was dissolved in 150 ml of ethanol and about 1.5 g of wet Add Raneynikkel. The mixture was hydrogenated in a Parr apparatus at 60 ° C and 2.8 atm. The mixture was cooled, filtered and the filtrate evaporated. To the residue was added 3.9 g of oxalic acid dissolved in 130 ml of boiling isopropyl alcohol containing 2 ml of water. The hot solution was filtered and allowed to cool. The resulting solid was recrystallized from ethanol. The yield of the olxalate hemihydrate salt was 3 g (43%). Mp 126-134 ° C.

Elemental analysis according to formula C ₂₈ H ₄₀ N ₆ O ₇ :

Calculated: 0 50.30 H6.03 N 12.57 Found: 0 50.46 H5.71 N 12.21

Example 102

2,3-dihydro-4-methyl-2- [2- (4-morpholinyl) ethyl] pyrido [3,2-f] [1,4] oxazepin-5 (4H) -one

The 1: 1 maleate salt of g (0.58 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] -1,4,4] oxazepine-5 (4H) ) -one hydrochloride was dissolved in morpholine (30 ml) and stirred at room temperature overnight. Dilute sodium hydroxide solution (50 mL) was added and the resulting mixture was extracted with chloroform (3 x 30 mL). Chloroform was removed in a rotary evaporator using a water-air pump. The remaining inorpholine is removed in vacuo at 50 ° C (rotary evaporator). To the remaining 15.5 g (0.053 mol) of the free base are added 1 liter of isopropyl alcohol and 9.24 g (0.080 mol) of maleic acid. The mixture is heated to boiling and the clear solution is cooled to 20 ° C and maintained at this temperature for several hours. 16 g (68.1%) of crystals are obtained, which is recrystallized from isopropyl alcohol. Mp: 163-165 ° C.

Elemental analysis results based on the formula Ci ₉ I1 ₂₅ N ₃ O ₇ :

Calculated: C 56.01 H6.18 N 10.31 Found: C 55.71 H6.21 N 10.18

Example 103

Fumarate salt of 2,3-dihydro-4-methyl-2- [2- (1-pyrrolidinyl) ethyl] pyrido [3,2-f] [1,4] oxazepin-5 (4H) -one g (0.058 mol) of 2- (2-chloroethyl) -2,3-dihydro-4mcylpyrido [3,2-f] 1,4-Oxazcpin-5 (41 L) -one hydrochloride was dissolved in 65 ml of pyrrolidine and the solution was stirred at 80 ° C for 3 hours. It is then cooled to room temperature and 50 ml of dilute sodium hydroxide solution are added. The resulting solution was extracted with chloroform (3 x 30 mL) and concentrated in vacuo. The residue was dissolved in boiling isopropyl alcohol (500 mL) and fumaric acid (9.2 g, 0.079 mol) was added. The solution was filtered hot, the filtrate cooled to 20 ° C and maintained at this temperature for several hours. The resulting crystalline material (14 g, 47.8%) was filtered off and recrystallized from isopropyl alcohol. Mp 147-149 ° C.

Elemental analysis according to formula C ₂₃ H ₁₀ N ₃ H ₂₉ :

Calculated: C, 54.43; H, 5.76; N, 8.28. Found: C, 54.38; H, 5.83; N, 8.27.

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Example 104

2- [2- (dibutylamino) ethyl] -2,3-dihydro-4-methyl-pyrido [3,2-f] [l, 4] oxazepine-5 (4H) -one

The 1: 1 maleate salt of 2- (2-chloroethyl) -2,3-dihydro-4-methyl) -1-pyrido [3,2-f] [1,4] oxazepine-5 (4H) (0.058 mol). ) -on-hydrochloride is dissolved in 30 ml of dimethylformamide and 30 ml of di-n-butylamine. The solution was stirred for 3 hours at 90 ° C and then for 2.5 hours at 100 ° C. The solution was cooled and dilute sodium hydroxide solution (50 mL) was added. The resulting mixture was extracted with chloroform (3 x 50 mL) and the chloroform was removed in a rotary evaporator at 50 ° C using a water pump. The residual dimethylformamide and di-n-butylamine were removed under high vacuum at 50 ° C in a rotary evaporator. The rest

To the free base (13.8 g, 0.041 mol) was added isopropyl alcohol (900 ml) and oxalic acid (5.6 g, 0.062 mol) and the solution was heated to reflux. The clear solution was kept at 20 ° C overnight and filtered to give 13.6 g (56.5%) of crystalline material which was recrystallized from isopropyl alcohol. M.p .: 195-196 ° C.

Elemental analysis for C ₂₁ H ₃₃ N ₃ O ₆ :

H, 7.85; N, 9.72. Found: C, 59.37; H, 7.91; N, 9.86.

Example 105

Oxalate salt of 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one g (0.058 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4 [oxazepin-5 (4H) -one hydrochloride in 30 ml of diethyl amine, and the suspension is stirred for 72 hours at room temperature. Mass spectroscopy then showed that the reaction was 33% complete. The mixture was heated at reflux for 6 hours and then the diethylamine was removed in a rotary evaporator (70 ° C using a water air pump). The residue was dissolved in chloroform (100 mL) and washed with dilute sodium hydroxide (2 x 30 mL). The organic layer was evaporated in a rotary evaporator (70 ° C, water air pump). The residue was dissolved in boiling isopropyl alcohol and oxalic acid was added. After cooling, 18.6 g (87.7%) of a light brown crystalline solid are obtained. Mp 150-155 ° C. A sample of this is recrystallized three times from isopropyl alcohol. Mp: 156-157 ° C.

Elemental analysis results based on the formula Ci ₇ H _2s N ₃ O ₆ :

Calculated for C 55.57 H6.86 N 11.43 Found: C 55.28 H 6.85 NI 1.27.

Example 106,

2,3-dihydro-4-methyl-2- [2- (1-piperidinyl) ethyl] pyrido [3,2-f [[1,4] oxazepin-5 (4H) -one. Oxalate salt 1: 1 g (0.015 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one hydrochloride Dissolve in 30 ml of piperidine and heat at 80 ° C for 20 minutes with stirring. The piperidine is removed in a rotary evaporator (85 ° C, vacuum pump) and the residue is dissolved in 50 ml of chloroform. The organic layer was washed with dilute aqueous sodium hydroxide solution (2 x 20 mL) and evaporated in a rotary evaporator (80 ° C, water air pump). The resulting oil was dissolved in hot isopropyl alcohol and oxalic acid was added. After cooling, the crystals of the oxalate salt were filtered off and recrystallized from isopropyl alcohol to give 3.4 g (62%) of a light brown crystalline solid. M.p .: 133-136 ° C.

Example 107

Maleic salt of 2,3-dihydro-4-methyl-2- [2- (N-methyl-N-benzylamino) ethyl] pyrido [3,2-f [[1,4] oxazepin-5 (4H) -one ( 1: 1) 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one hydrochloride (0.015 mol) Dissolve in 30 ml of methylbenzylamine and heat to 80 ° C with stirring. After 3 hours, the excess amine was removed in a rotary evaporator (90 ° C, vacuum pump). The residual oil was dissolved in chloroform (40 mL) and washed with dilute aqueous sodium hydroxide (30 mL). The chloroform layer was evaporated in a rotary evaporator at 90 ° C using a water-air pump. The residual oil was dissolved in hot isopropyl alcohol and rnalcinic acid was added. After cooling, 4.23 g (66%) of a light brown crystalline solid are obtained. Mp .: 167-169 ° C.

Elemental analysis for C ₂₃ H ₂₇ N ₃ O ₆ :

Calculated: C 62.57 116.16 N 9.52 Found: C 62.28 H6.16 N9.24

Example 108

2- [2- (2,5-Dimethyl-1-pyrrolidinyl) ethyl] -2,3-dihydro-4-methylpyrido [3,2-lj [1,4] oxazepin-5 (4H) -one 1: 1 fumarate

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one (5.0 g, 0.021 mol) in 25 ml absolute dissolved in ethanol and 3 g (0.03 mol) of 2,5-dimethylpyrrolidine was added. The solution was stirred for 48 hours at 75 ° C. Since the reaction was not complete within this time, an additional 1.00 g (0.01 mol) of 2,5-dimethylpyrrolidine was added and the reaction continued, and after five days the reaction was still incomplete, so 2,5-Dimethylpyrrolidine (1.00 g, 0.01 mol) was added

The excess of 195,649 dimethylpyrrolidine was removed in a rotary evaporator (80 ° C, vacuum pump). The residue was dissolved in chloroform (200 mL) and washed with dilute aqueous sodium hydroxide (2 x 75 mL). The organic layer was dried over sodium sulfate, filtered, and evaporated in a rotary evaporator (70 ° C, water air pump). The residual oil was dissolved in hot isopropyl alcohol and fumaric acid was added. After cooling, 2.38 g (27.4%) of light brown crystals were obtained. Mp .: 161-162 V.

Elemental analysis for C ₂₁ H ₂₉ N ₃ O ₆ :

H, 6.96; N, 10.02. Found: C, 59.79; H, 6.93; N, 9.76.

Example 109

2,3-dihydro-4-methyl-2- [2- (2-methyl-l-pyrrolidinyl) -etiljpirido (3,2-D | [l, 4] oxazepine-5 (4H) -one

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one (3.5 g, 0.0145 mol) dissolved in ethanol (2 ml) and 2-methylpyrrolidine (5.0 g, 0.063 mol) was added. The solution was stirred at reflux for 3 hours. The ethanol is removed in a rotary evaporator (water air pump, 80 ° C). The residual oil was partitioned between dilute aqueous sodium hydroxide solution (50 mL) and chloroform (50 mL). The organic layer was set aside and the aqueous layer was extracted with chloroform (2 x 30 mL). All chloroform layers were combined, dried over sodium sulfate and evaporated on a rotary evaporator (water pump, 70 ° C). The residual oil was evaporated under high vacuum (using a vacuum pump) at 200 ° C to give 1.5 g (35.7%) of a clear, clear oil.

Elemental analysis using the formula Ci <sH ₂₃ N ₃ O ₂ :

Calculated: C 66.41 H8.01 N 14.52 Found: C 65.83 H 8.06 N 14.39

Example 110

2,3-dihydro-4-methyl-2- [2- (lH-pyrazol-l-yl) ethyl] -pyrido [3,2-f] (l, 4] oxazepine-5 (4H) -one

Sodium hydride (1.2 g, 0.05 mol) was suspended in dimethylformamide (15 ml) and added dropwise to a solution of pyrazole (3.1 g, 0.045 mol) in dimethylformamide (15 ml). The resulting solution was then added with 9.12 g (0.038 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] (1,4) oxazepine-5 (4H). ), 30 ml of dimethylformamide was added, and the vessel was sealed and stirred overnight As the reaction was not complete, 3.12 g (0.045 mol) of pyrazole were added to the reaction solution overnight. The reaction is still incomplete, so another suspension of sodium hydride (0.5 g,

0.021 mole of active ingredient) and 1.5 g (0.022 mole) of pyrazole in 10 ml of dimethylformamide are added and the mixture is stirred again overnight. The reaction is completely complete so far. Dimethylformamide was removed in a rotary evaporator (80 ° C, vacuum pump), the residue was dissolved in chloroform (100 ml), washed with dilute aqueous sodium hydroxide (1X50 ml), dried over anhydrous sodium sulfate and dried in a rotary evaporator (70 ° C). evaporated. The resulting material was purified by high performance liquid chromatography over silica gel (95: 5 v / v ethanol: methanol). The product-containing fractions were concentrated in a rotary evaporator (70 ° C, water vapor pump). Upon cooling, crystallization begins. The crystals are filtered off and recrystallized from ethanol. Yield: 1.5 g (1.4.5%). Mp 132-134 ° C.

Elemental analysis according to formula C _{) 4} Hi ₆ N ₄ O ₂ :

Calculated: C, 61.75; 11.92; N, 20.58; Found: C, 61.35; H, 5.89; N, 20.67.

Example 777

2,3-Dihydro- [2- (11-imidazol-1-yl) ethyl] -4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one

9.12 g (0.038 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one in 30 ml of din dissolved in ethyl formamide and 5.66 g (0.083 mol) of imidazole was added. The solution was heated at 130 ° C for 18 hours. The dimethylformamide was removed in a rotary evaporator at 80 ° C using a vacuum pump and the residue was dissolved in 100 ml of chloroform. The chloroform solution was washed with dilute aqueous sodium hydroxide solution (30 mL), dried over sodium sulfate, and evaporated to an oil in a rotary evaporator (70 ° C, water air pump). Crystallization was initiated by addition of ethanol. 1.5 g (14.5%) of white crystals are obtained. Mp: 150-152 ° C.

Elemental analysis results based on the formula CmHh ^ Oj:

Calculated: C 61.75 11 5.92 N 20.58 Found: C 61.36 H 5.92 N 20.60

Example 112

Oxalate salt of 2- [2- (dimethylamino) ethyl] -4-ethyl-2,3-dihydropyrido [3,2-f] [1,4] oxazepin-5 (4H) -one 6 ml (0.021 mol) of 2- (2-chloroethyl) -4-ethyl-2,3-dihydropyrido [3,2-f] 11,4-oxazcpin-5 per ml of dimethylamine cooled to 0 ° C. (411) -one hydrochloride is added. The vessel was tightly closed and the contents were stirred for 70 hours at room temperature. The solution was then cooled to 0 ° C and the stopper was removed. The dimethylamine is evaporated. The residue was taken up in 150 ml 27

-2 753

It was dissolved in chloroform (195,649) and washed with dilute aqueous sodium hydroxide (1 x 50 ml). The organic layer was dried over sodium sulfate, filtered and evaporated in a rotary evaporator (70 ° C, water air pump). After cooling down

4.5 g (61.5%) are obtained. Mp: 208 ° C.

Elemental analysis results based on the formula Ci ₆ H ₂₃ N ₃ O ₆ :

Calculated for C 54.38 116.56 Ni 1.89 Found: C 54.26 H 6.61 Ni 1.81

Example 113

2,3-dihydro-4-ethyl-2- [2- (1-pyrrolidinyl) ethyl] pyrido [3,2-f] [1,3] oxazepin-5 (4H) -one

1: 1 Oxalate salt of g (0.01 mol) of 2- (2-chloroethyl) -4-ethyl-2,3-dihydropyrido [3,2-f] [1,4] oxazepine-5 (4H) - on hydrochloride was dissolved in 30 ml of pyrrolidine and the. the solution was heated at 70 ° C for 30 minutes with stirring. After cooling, the contents of the reaction vessel were diluted with 40 ml of dilute aqueous sodium hydroxide solution and extracted with 2 x 30 ml of chloroform. The chloroform layer was dried over sodium sulfate, filtered through a rotary evaporator (70 ^rf , water air pump) and evaporated to a brown viscous oil. The oil was dissolved in hot isopropyl alcohol and oxalic acid was added. After cooling, the solid obtained is recrystallized from isopropyl alcohol to give 1.80 g (45.4%) of a light brown crystalline solid. M.p. 185-188 ° C.

Elemental analysis results based on the formula Ci ₈ H ₂₅ N ₃ O ₆ :

Calculated: C, 56.98; H, 6.64; N, 1.07. Found: C, 56.90; H, 6.67; N, 10.90.

Example 114

2,3-dihydro-4-methyl-2- [2- (4-morpholinyl) ethyl] pyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione

2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione (4.5 g, 0.018 mol) in morpholine (30 ml) The solution was stirred at 50-60 ° C for 6 hours with stirring. The morpholine is then removed in a rotary evaporator (90 ° C using a vacuum pump). The residue was dissolved in chloroform (100 mL) and washed with dilute aqueous sodium hydroxide (2 x 30 mL). The organic layer was evaporated in a rotary evaporator (60 ° C, water pump). The residue was recrystallized from ethanol to give 3.26 g (60%) of a light yellow crystalline solid. Mp 152-153 ° C.

Elemental analysis using the formula C ₁₅ H ₂ , N ₃ O ₂ S:

H, 6.89; N, 13.66. Found: C, 58.48; H, 6.92; N, 13.62.

Example 115

2- (2- (dibutylamino) ethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione

1: 1 oxalate salt

4.0 (0.016 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido, 3,2-Π (1,4] oxazcpin-5 (4II) -thione in 30 ml of di-n-butyl Suspend in aliquot and add enough dimethylformamide (about 10 mL) with stirring to dissolve.

Heat at 140 ° C for 3.5 hours. Dinbutylamine and dimethylformamide are then removed in a rotary evaporator (80 ° C, vacuum pump). The residue was diluted with 50 mL of dilute aqueous sodium hydroxide solution and extracted with 3 x 40 mL of chloroform. The chloroform was removed in a rotary evaporator (70 ° C, water pump). The residue was dissolved in boiling isopropyl alcohol and oxalic acid was added. After cooling, the resulting oxalic acid salt was filtered off from recrystallized from 5-isopropyl alcohol to give 3.2 g (47%) of a yellow crystalline solid. Mp: 208 ° C.

Elemental analysis according to formula C _{2 i} H ₃₃ N ₃ O ₅ S:

Calculated: C 57.38 117.57 N9.56 Found: C 57.04 H 7.63 N9.31

Example 116

Oxalate salt of 2- [2- (diethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione 2- (2-Chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -ion (0.016 mol) was suspended in diethylamine (30 ml) and while stirring, enough dimethylformamide (about 10 mL) was added to dissolve the suspended material. The solution was stirred at 65 ° C for 8 hours. The diethylamine was removed in a rotary evaporator at 70 ° C using a water air pump and a higher vacuum (vacuum pump) at 90 ° C was used to remove residual dimethylformamide. The residue was dissolved in chloroform (100 mL) and washed with dilute aqueous sodium hydroxide (2 x 30 mL). The organic layer was evaporated in a rotary evaporator (70 ° C, water air pump). The residue was dissolved in boiling isopropyl alcohol and oxalic acid was added. After cooling, 1.7 g (28.5%) of the oxalate salt are obtained. Mp 142-144 ° C.

Elemental analysis using the formula CnH _2s N ₃ O ₅ S:

Calculated: C, 53.25; H, 6.57; N, 10.95. Found: C, 53.14; H, 6.60; N, 10.72.

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195,649

11.7. example

2,3-Dihydro-4-methyl-2- [2- (1-pyrrolidinyl) ethyl] pyrido [3,2-f] -1,4,4-oxazcpin-5 (4H) -thione

1: 1 oxalate salt g (0.02 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) - The thion is dissolved in 30 ml of pyrrolidine and the solution is stirred at 60-80 ° C for 35 minutes. After cooling to room temperature, the reaction mixture was diluted to 50 ml with aqueous sodium hydroxide solution and extracted with 2 x 50 ml of chloroform. The organic layer was evaporated in a rotary evaporator (70 ° C, water air pump). The remaining pyrrolidine is removed at 90 ° C using a vacuum pump. The residue was dissolved in hot ethanol and added with oxalic acid. After cooling, the oxalate salt was filtered off and recrystallized twice from ethanol to give 3.55 g (45%) of product. Mp .: 141 "C.

Elemental analysis for C17H23N2O5S:

Calculated: C 53.53 H6.08 NI 1.02 Found: C 53.39 H6, II N 10.91

Example 118

2,3-Dihydro-2- [2- (1H-imidazol-1-yl) ethyl] -4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione 2: 3-ratio oxalate salt

4.5 g (0.018 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione in 35 ml of dimethyl formamide, and imidazole (2.20 g, 0.038 mol) was added. The resulting solution was heated at 130 ° C for 15 hours. Dimethylformamide was removed in a rotary evaporator at 80 ° C using a vacuum pump and the residue diluted with 50 ml of dilute aqueous sodium hydroxide solution. The aqueous solution was extracted with chloroform (1 x 50 mL), dried over anhydrous sodium sulfate, and evaporated in a rotary evaporator (70 ° C, water pump). Oxalic acid dissolved in ethanol was added to the resulting oil to give 4 g (54%) of a pale yellow crystalline solid, which was also recrystallized from ethanol. Mp: 163-167 ° C.

Elemental analysis for C17H19O7N4S:

Found: C, 48.22 H4.52 N 13.23 Found: C 48.04 H4.62 N 13.18

Example 119

2- [2- (Dimethylamino ') ethyl] -4-ethyl-2,3-dihydropyrido [3,2-f] [1,4] oxazepine-5 (4H) -thion per ml of anhydrous dimethylamine 5.00 (0.016 mol). 2- (2-Chloroethyl) -4-ethyl-2,3-dihydropyrido [3,2-f] (1,4) oxazepine-5 (4H) -thione hydrochloride is added.

The reaction vessel was sealed and stirred for 6 days at room temperature. After cooling to 0 ° C, the vessel is opened and the dimethylamine is evaporated at room temperature. The residue is dissolved in 100 ml of chloroform and washed with 1 x 30 ml of dilute aqueous sodium hydroxide solution. The chloroform layer was dried over sodium sulfate, filtered and concentrated in a rotary evaporator. The residual oil was dissolved in hot cyclohexanone. On cooling, 1.76 g (39.4%) of a pale yellow crystalline precipitate is formed. Mp: 73 ° C.

Elemental analysis results are in C14

Elemental analysis for C14H21N3OS:

Calculated: C 60.18 H7.58 N 15.03 Found: C 60.32 11 7.70 N 15.13

Example 120

2,3-Diliro-4-methyl-2- [2- (N-methyl-N-bis-isyl-amino) -ethyl] - [3,2-f] [1,4] oxazepine-5 (4H) -thione 1: 1 ratio of oxalate

4.0 g (0.0155 mole) of 2- (2-chloroethyl) -2,3-dihydro-4mMethylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione Dissolve in chloroform (10 mL) and add benzylmethylaniline (10.0 g, 0.086 mol). The solution was stirred at reflux for 24 hours, then washed with water (2 x 50 mL) and evaporated in a rotary evaporator (about 70 ° C, water air pump). The residue was evaporated by molecular distillation at 165 ° C and 0.1 L of Hg. The residue was treated with oxalic acid dissolved in hot isopropyl alcohol. During cooling, excellent crystalline material is collected in two successive phases and the purity of each batch is checked. The two portions were combined to crystallize from hot isopropyl alcohol. After cooling, 3.69 g (55%) of pale yellow crystals are obtained. Mp: 163-166 ° C.

Eíenianalíziseredmények under C2 (LL25 ₃ O ₅ S wherein:

Calculated: C 58.45 H5.84 N 9.74 Found: C 58.24 H 5.92 N9.61

Example 121

Oxalate salt of 2,3-dihydro-2- [2- (methylamino) ethyl] -4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione, 1: 1.5

4.0 g (0.016 inol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyridol-3,2-F] L 1,4-oxazepine-5- (411) -thione nicetylline 30% of ethanol solution (70 ml) and stirred for 56 hours at room temperature. Since the reaction is not complete during this time, the reaction mixture is carefully heated to 55 ° C over 2 hours and then stirred at this temperature for 24 hours. The methylamine is removed by a water air pump over 1.5 hours.

-2 957

195,649

The resulting solution was concentrated in a rotary evaporator at 70 ° C using a water air pump. The residual oil was dissolved in 150 ml of chloroform and washed with 2 x 50 ml of aqueous potassium bydroxide solution. The chloroform layer was dried over sodium sulfate and concentrated in a rotary evaporator (70 ° C, water air pump). The residue was dissolved in hot ethanol and oxalic acid was added. After cooling, 2.0 g (37.5%) of yellow crystals are obtained. Mp 137-138 ° C.

Elemental analysis for C ₂₅ H ₂₀ N ₃ O ₇ S:

Calculated: C 46.63 H5.22 N 10.67 Found: C 46.47 H5.35 N 10.85

Example 122

7-Chloro-2,3-dihydro-4-methyl-2- [2- (1-pyrrolidinyl) ethyl] pyrido [3,2-f] [1,4] oxazepin-5 (4H) -one 1: 2 ratio fumarate salt

2.5 g (0.009 mol) of 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) ) -one is dissolved in 50 ml of pyrrolidine and the solution is heated at 80 ° C for 1 hour. The pyrrolidine was removed in a rotary evaporator (80 ° C using a water pump) and the residue was dissolved in 100 ml of chloroform. The organic layer was washed with water (2 x 50 mL), dried over sodium sulfate, and evaporated in a rotary evaporator (about 80 ° C, water air pump). To the residue was added fumaric acid and allowed to stand overnight. The resulting crystals were collected by filtration to give 1.25 g (23.2%). Mp: 164-166 ° C.

Elemental analysis for C ₂ 5 _{H 3 O} N ₃ 0 Cl

Found: C, 50.05 H5.04 N7.00 Found: C 50.22 H 5.14 N7.02

Example 123

7-Chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one 1: 1 ratio of oxalate

2.8 g (0.01 mol) of 7-chloro-2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) ) was added 25 ml of dimethylamine and stirred in a sealed vessel for 96 hours. The excess amine was evaporated and the residue partitioned between chloroform and dilute sodium hydroxide. The chloroform layer was dried over sodium sulfate and evaporated. To the residue was added 0.7 g of oxalic acid dissolved in isoppropyl alcohol. The resulting crystalline material is recrystallized from the same solvent. Yield: 15 g (40%) of the oxalate salt. Mp 150-156 ° C. I ¹ !

Elemental analysis results for C | ₅ II ₂ ,, N ₃ O _f , CI:

Calculated: 0 48.20 H5.39 N 11.24 Found: C 48.09 H5.47 N 11.12

Example 124

Hemihydrate of oxalate salt of 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-benzylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one g To a suspension of 60% sodium hydride in mineral oil (1.3 moles) in 500 ml of anhydrous tetrahydrofuran was added a solution of 94.2 g (0.6 mole) in 800 ml of anhydrous tetrahydrofuran, with rapid stirring, under reflux. 2-chloronicotinic acid and 100 g (0.54 mol) of 1-benzyl-3-pyrrolidinol (about 1 hour). The mixture was refluxed for a further 1.5 hours and then cooled to room temperature. About 1 liter of ethyl acetate was added, allowed to stand overnight at room temperature, and then concentrated in a rotary evaporator at 100 ° C and 50 mm Hg. The residue was dissolved in 1 L of chloroform and the pH of the solution was adjusted to 6.15 with hydrogen chloride gas. While stirring, 383 g (1.0 mol) triphenylphosphine and 383 g (2.48 mol) carbon tetrachloride are added to the solution. The mixture was refluxed for 1 hour and then ethanol (50 mL) was added. The solution was then cooled to room temperature and extracted with dilute hydrochloric acid (3 x 400 mL). The chloroform layer was extracted with dilute sodium hydroxide solution, dried over sodium sulfate and evaporated. Mass spectroscopy for 2- (2-chloroethyl) -2,3-dihydro-4- (phenylmethyl) pyrido [3,2-f] [1,4] oxazepin-5 (4H) -one (MW 316) ), triphenylphosphine (MW: 262) and triphenylphosphinoxide (MW: 278). The remaining 2/3 was dissolved in chloroform (30 mL) and added to a solution of dimethylamine in ethanol (30 g). The solution was refluxed for 4 hours and then concentrated in a rotary evaporator. The residue was partitioned between chloroform and IN hydrochloric acid. The acidic layer was made basic with sodium hydroxide and extracted with chloroform. The chloroform layer was dried over sodium sulfate and evaporated. To the residue (10 g) was added an equivalent amount of oxalic acid dissolved in a mixture of isopropyl alcohol, ethanol and isopropyl ether. The resulting crystalline material (9 g, 5%) was recrystallized from the same solvent mixture. Mp: 95-98 ° C.

Elemental analysis results based on the formula C ^ J ^ NgO ^:

Calculated: C 56.28 H5.79 N8.95 Found: C 56.61 115.76 N8.77

-3 059

195,649

Example 125

2- [2- (dimethylamino) ethyl] -2,3-dihydropyrido [3,2-f] [1,4] oxazepin-5 (41 L) -one

Oxalate salt of 2- [2- (diethylethylamino) ethyl] -2,3-dihydro-4-benzylpyrido (3,2-f) [1,4] oxazepin-5 (4H) -one Dissolve 3.0 g (0.006 mol) of the hemihydrate in about 50 ml of water, basify the solution with dilute aqueous sodium hydroxide solution, extract with 3 x 50 ml benzene, dry the combined benzene extracts over anhydrous sodium sulfate, and evaporate in a water bath. (50 mm Hg) The residue is further dried by azeotropic distillation by adding two times about 50 ml of anhydrous benzene and evaporating to dryness each time.The final residue is dissolved in 40 ml of liquid ammonia and a small amount of sodium globe is added with stirring. , while the blue color remains for 20 minutes (about 1 hour), then slowly add 3 g of sodium chloride to the solution and allow the ammonia to evaporate. The filtrate was evaporated and the residue was chromatographed on a silica gel column using a silica gel column; eluent: .75% ethyl acetate, 25% dimethylformamide. Yield: 0.1 g (7%). The chemical isonization spectrophotometer gives a peak at 236, which corresponds to a molecular weight of 235. Compound A 'H NMR spectrum CDCl containing 1% tetramethylsilane (TMS) was taken up in _3. The spectrum is consistent with the assumed structure and shows the presence of small amounts of dimethylformamide (DMF) and mineral oil.

NMR data for compound (1):

8.45 (m) H (8) and H (6)

8.00 (s)

7.85 (bs)

7.20 (doublet)

4.65 (p)

4.05 (bs)

3.50 (t)

2.95 (s)

2.90 (s)

2.60 (t)

2.65 (s)

2.05 (m) 0.7-1.7 (m) = C-H (DMF)> N-H H (7)

H (2) unknown pollutant 2H (3)

-CH ₃ (DMF)

-CH ₃ (DMF)

2H (a)

An aqueous solution of formic acid -N (CH ₃ ) ₂ 2H (β) in mineral oil was added. The resulting solution was added to a solution of 10.7 g (0.13 mol) in 37% aqueous formaldehyde inhibited with 13% methanol. The resulting solution was heated on a water bath for 5.5 hours, cooled (g) and dilute aqueous hydrochloric acid (100 mL) was added. The solution is evaporated to dryness and the residue is dissolved in 50 ml of water. The solution was neutralized with dilute aqueous potassium hydroxide solution and extracted with chloroform (4 x 50 mL). The combined chloroform extracts were dried over sodium sulfate and evaporated in a rotary evaporator. The residue is reacted with fumaric acid dissolved in hot isopropyl alcohol. The resulting 3 ', 0 g (31.8%) product is recrystallized twice from isopropyl alcohol. Op: 108—

110 ° C.

Elemental analysis based on the formula C4 ₀ H ₅₆ N <-, On:

Calculated for C 53.81 H 6.32 N 9.41 ²⁰ Found C 53.69 H6.33 N9.41

Example 127

2- [3- (Dinethylamino) -propyl] -2,3-dibydro-4-methylpyrido [3,2-b] [1,4] oxazcpin-5 (411) -thione

1: 2 oxalate salt

11.0 g (0.042 mol) of 2- [3- (dimethylamino) propyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) ontone. dissolved in pyridine (ml) and phosphorus pentasulfide (9.25 g, 0.042 mol) was added. The mixture is stirred at reflux for 3.5 hours. After cooling to room temperature, the reaction mixture is added to an equal volume of 2 M potassium hydroxide solution. The mixture was extracted several times with a total of 800 ml of methylene chloride. The organic layer was washed with dilute potassium hydroxide solution (3 x 100 mL), dried over sodium sulfate, filtered and concentrated in a rotary evaporator at 70 ° C using a water pump. The residual oil was suctioned at 90 ° C for one hour with a vacuum pump, then cooled and treated with oxalic acid in isopropyl alcohol. The precipitated crystalline material was collected in two portions (4.5 g and 3.1 g, respectively) and the two portions were recrystallized from isopropyl alcohol to give 6.5 g (34%) of a yellow crystalline solid. Mp: 136-138 ° C

Elemental analysis results based on the formula Ci ₈ H ₂₅ N ₃ O ₉ S:

Calculated: C 47.05 H5.42 N9.16 Found: C 46.76 H5.75 N9.04

Example 126

Example 128

2- (3- (dimethylamino) propyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one θθ

Hemihydrate of a 1: 1.5 ratio of fumarate salt

5.0 g (0.021 mol) of 2- (3-aminopropyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepin-5 (4H) -one were cooled in a water bath 20 g (0.38 mol) 88% - 65

7-Chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thionic fumarate ( 1: 1) hemihydrate hemiisopropyl alcoholate To a solution of 57% v / v dimethylamine in ml methanol, 2.5 g (0.009 mol) of 7-chloro-2 (2-chloroethyl) -2,3-dihydro-4 methyl piridol3,2-f] [l, 4] oxa31

-3 161

195 649 zepin-5 (41 µl) was added. The reaction vessel was sealed and allowed to stand for 16 hours. TLC indicated that the reaction was about 60% complete. The solution was gradually brought to 45 ° C. heat and keep at this temperature for 5 hours, remove methanol and excess dimethylamine in a rotary evaporator (water pump, 60 ° C), dissolve the residue in 100 ml of chloroform and wash twice with 40 ml of water. The residue was treated with fumaric acid in isopropyl alcohol to give 1.43 g (36.5%) of crystalline material, which was recrystallized from isopropyl alcohol and dried thoroughly in a drying gun. .

Elemental analysis for C37H54N6O12Cl2S2:

Calculated for C 48.04 115.98 N9.23 Found C 48.82 H5.8 N9.37

Example 129

2,3-Dihydro-4-methyl-2- [2- (ethylamino) ethyl] pyrido [3,2- f] [1,4] oxazcpin-5 (4H) -one oxalate [1: 1] ml 30% To a solution of monoethylamine in ethanolic ethanol was added 11.0 g (0.04 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1 4] oxazepine-5 (4H) on hydrochloride. The solution was gradually heated to 55 ° C over 2 hours and maintained at this temperature overnight.

The monoethylamine and ethanol were removed in a rotary evaporator (water pump, 70 ° C) and the residue was taken up in 100 ml of chloroform. The organic layer was washed with dilute aqueous sodium hydroxide solution (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and evaporated in a rotary evaporator (70 ° C, water air pump). This gives 9.0 g of a crude oil which is treated with isopropyl alcohol oxalic acid. 8.77 g (67.8%) of crystals are obtained, m.p. 14850 ° C.

Elemental analysis using the formula C ₁₄ Hic> N ₃ O ₆ :

Found: C 51.69 H5.89 N 12.92 Found: C 51.88 H5.97 N 12.96

Example 130

2,3-Dihydro-4-methyl-2- [2- (4-methyl-1-piperazinyl) ethyl] pyrido [3,2-f] [1,4] oxazepine-5 (4H) -onfumarate monohydrate [1: 2]

10.45 g (0.043 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyridoph3,2-f] [1,4] oxazepin-5 (4H) -one were prepared in 80 ml of absolute ethanol. To this solution was added 10.84 g (0.1084 mol) of N-methylpiperazine and the resulting solution was refluxed for 4 hours. At this time, 25% by weight of the starting material was still present, so another 5.0 (0.05 mol N-methylpiperazine) was added to the reaction mixture and the reflux was continued for another 2 hours. The ethanol was removed by rotary evaporation The residue was diluted with water (150 mL), the aqueous phase was extracted with chloroform (4 x 50 mL) and the organic layer was washed with water (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in a rotary evaporator (70 vacuum (95-100 [deg.] C.) for 2.5 hours The resulting residue was treated with fumaric acid in isopropyl alcohol to give 8.45 g (35.4%) of an off-white crystalline solid, m.p. 162167 [deg.] C.

Elemental analysis results based on the formula CiHm ^ Oh:

Calculated: C51.98 H6.17 N 10.10 Found: C 52.03 H6.00 N 10.17

Example 131

2,3-Dihydro-4-methyl-2- [2- (4-methyl-1-piperazinyl) ethyl] pyrido [3,2-f [[1,4] oxazepine-5 (4H) -thionfumarate lithium hydrate [1: 2]

80 g of absolute (8.0 g, 0.031 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione 9.30 g (0.093 mol) of N-methylpiperazine in ethanol are added. The reaction mixture was heated under reflux for 2 hours, and additional 5.0 g (0.05 mol) of N-methylpiperazine was added. The resulting reaction mixture was refluxed for a further 5 hours.

The ethanol is removed in a rotary evaporator (90 ° C, water air pump). The remaining N-methylpiperazin was removed at 90 ° C under vacuum for 2 hours. The residue thus obtained is taken up in 150 ml of chloroform and washed with 2 x 50 ml of water. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in a rotary evaporator (90 ° C, water air pump). The residue was further concentrated in vacuo at 90 ° C. 10.0 g of crude product are treated with isopropyl alcohol fumaric acid to give 10.0 g (57.4%) of pale yellow crystals, m.p. 184-185 ° C.

Elemental analysis of C 24 H _{33 N4} O9, _and S based on the formula:

Calculated for C 51.32 14 5.92 N 9.98 Found: C 51.56 H 5.89 N9.86

Example 132

2 - ((2- (4 (Bis (4-fluorophenyl) methyl] -1-piperidinyl) ethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine -5 (4H) -ondihydrochloride hemihydrate g (0.036 mol) 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) - is -hydrochloride-3263

195,649 doses were partitioned between dilute sodium hydroxide and chloroform. The chloroform layer was dried over sodium sulfate and evaporated in a rotary evaporator. The residue was dissolved in ethanol (50 mL) and 4- [bis (4-fluorophenyl) methyl] piperidine (10.3 g, 0.036 mol) was added. The resulting solution was refluxed for 18 hours and then concentrated in a rotary evaporator. The residue was partitioned between dilute sodium hydroxide solution and chloroform. The chloroform layer was dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on a Waters 500 HPIC (silica gel / 92% ethyl acetate / 8% triethylamine). After evaporation of the desired product, the residue is dissolved in isopropyl alcohol and treated with ethereal hydrogen chloride. The crystalline material thus obtained was 3 g (14%), m.p. 160-180 ° C.

Elemental analysis for C ₅₈ H ₆₈ N ₆ O ₅ Cl ₄ F ₄ :

Calculated: C, 60.73; H, 5.98; N, 7.33. C, 60.60; H, 6.04; N, 7.12

Example 133

2,3-Dihydro-4-methyl-2- [2- (N-methyl-N-phenylamino) ethyl] pyrido [3,2-f] [l, 4] oxazepine-5 (4H) -thione

To a suspension of (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione in 100 mL of toluene was added 11.49 g N-methylaniline (0.11 mol) and the reaction mixture was stirred and refluxed for 2 days (after about 6 hours, 23.0 g (0.22 mol) of additional N-methylaniline was added). The toluene was removed in a rotary evaporator (90 ° C, water air pump). N-methylaniline is also removed in a rotary evaporator (90 ° C, vacuum). The residue is taken up in 100 ml of chloroform and washed with 3 x 30 ml of dilute aqueous sodium hydroxide solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in a rotary evaporator (80 ° C, water air pump). Further N-methylaniline was removed under vacuum at 90 ° C for several hours. Ethyl acetate (150 mL) was added to the residue as the product crystallized. However, since most of the product remained in solution, the reaction mixture was subjected to preparative HPLC chromatography on a silica gel column using 60% hexane / 40% ethyl acetate as eluent. The contents of the vessel were evaporated and crystallized by inoculation. The chromatographed product was recrystallized from ethyl acetate / isopropyl alcohol to give 1.1 g of product, m.p. 164-165 ° C. Another product (about 2 g) was obtained by recrystallization of the crude product, m.p. 163-164 ° C. Total yield 3.1 g (26%)

Elemental analysis results based on the formula Ci ₈ II ₂ iN ₃ OS:

H, 6.46; N, 12.83. Found: C, 65.72; H, 6.51; N, 13.13.

Example 134

2- (3-Aminopropyl) -2,3-dihydro-4-methylpyrido [3,2- f] [1,4] oxazepln-5 (4'L) -thionum rumarate [1: 1] g (0.064 mol) 2- (3-Amino-propyl) -2,3-dihydro-4-methyl-pyrido [3,2-f [1,4] oxazepin-5 (4H) -one is dissolved in 50 ml of methylene chloride and added 15.24 g (0.07 mol) of di-tert-butyl dicarbonate. The solution was stirred for 30 minutes at room temperature. The protected amine was purified by high performance liquid chromatography on a silica gel column using ethyl acetate as the eluent. 15 g (0.045 mol), 70.3% of the protected amine are obtained as an oil. To a solution of the resulting oil (13.5 g, 0.04 mol) in dry toluene was added 8.16 g (0.02 mol) of 2,4-bis (4-ineloxyphenyl) -1,3 dithia-2,4-diphosphetane-2,4-disulphide. The reaction mixture was heated at 80 ° C for 2 hours. To the resulting reaction mixture was added 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide (2.0 g, 0.005 mol) and the reaction mixture was heated for an additional 1 hour. A further 4.0 g (0.01 mole) of 2,4bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide (4.0 g, 0.01 mol) was added and heating continued for 5 hours. After cooling, the toluene is decanted off, washed with dilute aqueous sodium hydroxide solution (5 x 30 mL), dried over sodium sulfate, filtered and evaporated in a rotary evaporator. Isopropyl alcohol was added to the residue to crystallize the impurity (Lawesson's reagent). The isopropyl alcohol was removed by rotary evaporation and the residue was purified by high performance liquid chromatography on a silica gel column using 1% methanol / 99% chloroform as eluent. About 6 g (0.017 mol, 42.6%) of product are obtained which is treated with a solution of acetic acid / anisole / methylene chloride (40/15/50 v / v / v) in 100 ml for 30 minutes. The solvents were removed in a rotary evaporator (70 ° C, water pump) and the residue was taken up in 150 mL of methylene chloride. This phase was washed with dilute aqueous sodium hydroxide solution (3 x 40 mL), dried over anhydrous sodium sulfate, filtered and evaporated in a rotary evaporator. The residue was treated with isopropyl alcohol fumaric acid to give 4.0 g (0.011 mol, 54%) of the salt. The salt was recrystallized from isopropyl alcohol to give the analytical sample, mp 164-166 ° C.

Elemental analysis results based on the formula Ci ₆ H _{2 i} N ₂ O ₅ :

Calculated: C, 52.30; H, 5.76; N, 1.43. Found: C, 52.43; H, 5.83; N, 11.51.

-3365 | Example 135 j

2- [2- (Dimethylamino) ethyl] -2,3-dihydropyrido [3,2-f] [1,4] oxazepine-5 (411) -thionihydrochloride monohydrate g (0.021 mol) 2- [2 - (Dimethylamino) ethyl] -2,3-dihydropyrido [3,27f] [1,4] oxazepine-5 (4H) -thione In 50 ml of pyridine was added 5.1 g (0, 046 mol) of phosphorus pentasulfide. . An exothermic reaction is initiated. When the temperature begins to decrease, the reaction mixture is heated to 70 ° C for 3.5 hours and then allowed to cool. The resulting reaction mixture was partitioned between dilute sodium hydroxide solution and chloroform while ice-cooling was applied. The aqueous phase is extracted 3 times with chloroform. The combined chloroform extracts were dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in ethanol (40 mL) and acidified with ethereal hydrogen chloride. The resulting crystalline material was recrystallized from 95% ethanol. 1.4 g (19%) of product are obtained, m.p. 172-175 ° C.

Elemental analysis calculated for C ₁₂ H ₂₁ N ₃ SO ₂ Cl ₂ : C 42.10 H6.18 N 12.28 Found: C 42.66 H 5.74 N 12.34

Example 136

2- "2- <4- [Bis (4-fluorophenyl) methyl] -l-piperidinyl> ethyl» -2,3-dihydro-4-methylpyrido [3,2-f] [l, 4] oxazepine -5 (4H) -thionoxalate hydrate [1: 1: 1] g (0.016 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [ A solution of 1,4] oxazepine-5 (4H) -thione and 4.5 g (0.016 tol) of 4- [bis (4-fluorophenyl) methyl] piperidine in 100 ml of ethanol is refluxed for 48 hours. To the reaction mixture was added 1 g of potassium carbonate and refluxed for 144 hours. The reaction mixture was evaporated and the residue partitioned between chloroform and dilute sodium hydroxide solution. The chloroform layer was dried over anhydrous sodium sulfate and evaporated. The residue was chromatographed on a Waters 500 HPLC column on silica gel using absolute ethanol as eluent. The product 507 was collected and evaporated. The residue (6 g) was treated with 1.2 g of oxalic acid in ethanol. 5 g of product are obtained, m.p. 125-138 ° C.

Elemental analysis using the formula C _{3 i} H ₃₅ N ₃ O ₆ SF ₂ :

Found: C, 60.47; H, 5.72; N, 6.82; Found: C, 60.62; H, 5.60; N, 6.68.

Example 137

2,3-Dihydro-4-methyl-2- | 2- (1H-pyrazol-1-yl) ethyl] pyrido [3,2-f] [1,4] oxazepin-5 (4'L) -thione

To a suspension of sodium hydride (2.16 g, 0.054 mol) in dimethylformamide (20 ml) was added a solution of pyrazole (2.92 g, 0.043 mol) in dimethylformamide (10 ml). Slightly exothermic reaction starts with weak hydrogen evolution. The resulting solution was then added dropwise to 10.0 g (0.039 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 ( 4H) -ion in 30 ml of dimethylformamide. The reaction vessel was sealed and stirred overnight at room temperature.

The dimethylformamide was removed in a rotary evaporator (90 ° C, 30 mm). The residue is taken up in 200 ml of chloroform and this phase is washed with water (2 x 50 ml) and then with 50 ml of aqueous sodium hydroxide solution. The organic phase was dried over sodium sulfate, filtered and concentrated in a rotary evaporator (70 ° C, 30 mm). Isopropyl alcohol is added to the residue and crystallization is promoted by cooling. The crude crystals (4.5 g) were recrystallized from isopropyl alcohol to give 3.45 g (31%) of yellow crystals, m.p. 119-121 ° C.

Elemental analysis results based on the formula Ci ₄ H ₁₆ N ₄ OS:

Calculated: C 58.31 H5.59 N 19.43 Found: C 58.01 H5.59 N 19.37

Example 138

2,3-Dihydro-4-methyl-2- [2- (1-piperidinyl) ethyl] pyrido [3,2-f] [1,4] oxazepine-5 (4H) -thionic fumarate, isopropyl alcohol-hydrated compound [1: 1: 0.5: 0.5]

5.0 g (0.019 mol) of 2- (2-chloroethyl) -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione 75 To a suspension of 20 ml of absolute ethanol was added 10 ml of piperidine and the reaction mixture was heated at 50 ° C for 4 days. The ethanol was removed in a rotary evaporator (70 ° C, 30 mm). The piperidine is removed by rotary evaporator (80 ° C _f 5 mm), then azeotroped with 2x100 ml of toluene. The syrup-like residue was taken up in 200 ml of isopropyl alcohol and heated with fumaric acid. 5.2 g (57%) of yellow crystals are obtained, m.p. 133-140 ° C.

Elemental analysis results based on the formula C ₂ i _{t 5} H ₃₂ N ₃ O ₆ S:

calculated. C 56.07 H 7.00 N9.12 Found: C 55.90 116.86 N9.17

-3 467

195,649

Example 139

6-Chloro-2,3-dihydro-4-methyl-2- [2- (dimethylamino) ethyl] pyrido [3,2- f] [1,4] oxazepin-5 (4H) -one fumarate in ml of fresh dimethyl To the amine at -10 ° C was added 4.0 g (0.015 mol) of 6-chloro-2- (2-chloroethyl) 2,3-dihydro-4-methylpyrido [4,3-f] [1 4] oxazepin-5 (4H) -one, The reaction vessel was sealed and allowed to stand at room temperature for 5 days. After cooling to -10 ° C, the vessel is opened and the dimethylamine is allowed to evaporate overnight. The residue is taken up in 100 ml of chloroform, washed with 2 x 30 ml of dilute sodium hydroxide solution, dried over anhydrous sodium sulfate, filtered and evaporated in a rotary evaporator (70 ° C for 30 min). The residue is treated with fumaric acid in isopropyl alcohol, whereupon crystallization begins. Yield: 3.8 g (76.7%) of yellow crystals.

Elemental analysis results based on the formula Ci _S H ₂₀ N ₃ O ₄ Cl:

H, 5.90; N, 12.29. Found: C, 52.67; 115.96; N, 12.01.

Table 1

Example number THE B R E X n Salt 19 benz SHE -ch ₃ 0 cl 2 20 benz SHE -CH ₂ -C ₆ H ₅ 0 cl 2 21 naphth | f 3,2 ~] SHE -ch ₃ 0 cl 2 22 pyrido [3,2-f] SHE -ch ₃ 0 cl 2 11 Cl 23 8-Cl-benz SHE -ch ₃ 0 cl 2 - 24 7-Br-benz SHE -ch ₃ 0 cl 2 - 25 7-CI-benz SHE -ch ₃ 0 cl 2 - 26 naphtho [2, l-f SHE -ch ₃ 0 cl 2 - 27 7-OCH ₃ Benz SHE -ch ₃ 0 cl 2 - 2? benz s -ch ₃ 0 cl 2 - 29 pyrido [3,2-f] s -ch ₃ 0 cl 2 - 30 naphth [2,3-f] s -ch ₃ 0 cl 2 - 31 8-Cl-benz s -ch ₃ 0 cl 2 32 7-Br-benz s -ch ₃ 0 cl 2 - 33 naphtho [2, l-f s -ch ₃ 0 cl 2 - 34 piridol4,3-f 0 -ch ₃ 0 cl 2 UCL 35 pyrido [3,4-f] 0 -ch ₃ 0 cl 2 HC1 36 pyrido [2,3-f] 0 -ch ₃ 0 cl 2 HC1 37 7-CI-benz s -ch ₃ 0 cl 2 - 38 pyrido [4,3-f] s -ch ₃ 0 cl 2 - 39 7-OCH ₃ -bcnz s clf, 0 cl 2 40 benz 0 -C ₂ II ₅ 0 cl 2 - 41 benz 0 -CH (CH ₃ ) ₂ 0 cl 2 - 42 pyrido [3,2-f 0 —C ₂ H _s 0 cl 2 HC1 43 pyrido [3,2-f] 0 -CH (CH ₃ ) ₂ 0 cl 2 HC1 44 pyrido [3,2-f 0 -C1I ₃ s cl 2 - 45 pyrido [3,2-f] s -ch ₃ s cl 2 - 46 pyrido [3,2-f] 0 -CHs 0 cl 2 - 47 pyrido [3,2-f s -ch ₃ 0 cl 2 HC1 48 pyrido [3,2-f 0 -ch ₃ 0 CN 2 - 49 pyrido [3,2-f] 0 -c ₂ h ₅ 0 cl 2 HC1 50 pyrido [3,2-f] s -ch ₅ 0 cl 2 HC1 51 7-Cl-pyrido [3,2-f 0 -ch ₃ 0 cl 2 - 52 7-Cl-pyrido [3,2-f s CH, 0 cl 2 - 53 piridol3,2-f] 0 -CH ₂ C ₆ H ₅ 0 cl 2 -

-35195 649 ι

II. spreadsheet

Example number THE B R I · z (CH,) ,, Salt (base, hydrates) 54 benz 0 -ch ₃ 0 -N (CH ₃ ), - (CH,), - HC1 55 benz 0 -ch ₃ 0 -N (CH ₃ ), - (CH,), - - 56 benz 0 -ch ₃ 0 morpholino - (CH,), - fumarate 57 benz 0 benzyl 0 morpholino - (CH,), - - 58 benz 0 benzyl 0 -NHCH ₃ - (CH,), - fumarate 59 benz s -CH ₃ 0 -N (CH ₃ ) ₂ - (CH,) - HC1 60 benz 0 benzyl 0 -N (CH ₃ ), - (CH,), - H, 0 61 benz s -ch ₃ 0 morpholino - (CH,), - HC1 62 naphth [2,3-f] 0 -ch ₃ 0 -N (CH ₃ ), - (CH,), - oxalate 63 pyrido [3,2-f] 0 -ch ₃ 0 -N (CH ₃ ) ₂ - (CH,), - 1.5 fumarate 64 pyridof 3,2-f] 0 -C1I ₃ 0 -N (CH ₃ ), -ÍCH,), - fumarate. 0.5 ethanol O5 piridol3,2-f s -ellj υ -N (C11 ₃ ), - (CH,), - fumarate 66 benz s benzyl 0 morpholino - (CH,), - - 67 benz 0 -ch ₃ 0 -NHCH ₃ - (CH,), - fumarate 68 benz 0 —Ch ₃ 0 -NHCH ₃ - (CH,), - - 69 benz s -ch ₃ 0 2 / - (CH,), - - 70 benz s -ch ₃ 0 1 / - (CH,), - - 71 8-Cl-benz s ~ ch ₃ 0 -N (CH ₃ ), - (CH,), - HC1 72 8-Cl-benz 0 -ch ₃ 0 -N (CH ₃ ), - (CH,), - oxalate 73 7-Br-benz 0 -ch ₃ 0 -N (CH ₃ ) ₂ - (CH,), - oxalate 74 naphtho [2, l-f] 0 -ch ₃ 0 -N (CH ₃ ) ₂ - (CH,), - oxalate 75 pyrido [4,3-f] 0 -ch ₃ 0 -N (CH ₃ ), - (CH,), - fumarate 76 pyrido [3,4-f] 0 -ch ₃ 0 -N (CH ₃ ), - (CH,), - fumarate 77 pyrido [2,3-f] 0 -Cl _{1 3} 0 N (C1I _3); - (CH,), - fumarate 78 pyrido [4,3-f] s -cu ₃ 0 -N (CH ₃ ), - (CH,), - 1.5 HCl 79 pyrido [3,2-f] s -ch ₃ 0 -N (C, H ₅ ), - (CH,), - oxalate, 1/2 H, 0 80 naphth [2,3-f] s -ch ₃ 0 -N (CH ₃ ), - (CH,), - oxalate, 1 / 2H ₂ O 81 7-CI-benz 0 -ch ₃ 0 -n (ch ₃ ). - (CH,), - oxalate 82 pyrido [3,2-f] s -ch ₃ 0 -N (CH ₃ ), - (CH,), - metijodid 83 7-CI-benz s -ch ₃ 0 -N (CH ₃ ) ₂ - (CH,), - oxalate, 1/2 Η, O 84 naphtha [2,1-f] s ~ ch ₃ 0 -N (CH ₃ ), - (CH,), - HC1 85 pyrido [3,4-f] s -ch ₃ 0 -N (CH ₃ ), - (CH,), - fumarate 86 pyrido [2,3-f] s -ch ₃ 0 -N (ch ₃ ) ₂ - (CH,), - fumarate 87 7-OCH ₃ Benz 0 -ch ₃ 0 -N (CH ₃ ), - (CH,), - oxalate, 1/3 H, ü 88 7-Br-benz s -ch ₃ 0 -N (CH ₃ ), - (CH,), - oxalate, H, 0 89 benz 0 -c, h ₅ 0 -N (CH ₃ ) ₂ - (CH,), - oxalate 90 benz 0 cii (cn ₃ ), 0 N (CH ₃ ), (CH,), - oxalate 91 pyrido (3,2-f] 0 -c, h ₅ 0 -N (CH ₃ ), - (CH,), - fumarate 92 pyrido [3,2-f] 0 -CH (CH ₃ ), 0 -N (CH ₃ ), - (CH,), - fumarate 93 benz 0 -ch ₃ 0 1-pyrrolidinyl - (CH,), - fumarate 94 benz 0 -ch ₃ 0 1-piperidinyl - (CH,), - fumarate 95 benz 0 -ch ₃ 0 1-piperazinyl - (CH,), - fumarate 96 benz 0 -ch ₃ 0 4-CH ₃ -piperazine l- (CH,), - fumarate 97 pyrido [3,2-f 0 -ch ₃ s -N (CH ₃ ), - (CH,), - 2 HC1 98 pyrido [3,2-f] s -ch ₃ s -N (CH ₃ ), - (CH,), - oxalate 99 pyrido [3,4-f] 0 -ch ₃ 0 -N (CH ₃ ), - (CH,), - 1/2 H, O 2 oxalate 100 pyrido [3,4-f] s -ch ₃ 0 -N (CH ₃ ), - (CH,), - 2 oxalates 101 pyrido [3,2-f] 0 -ch ₃ 0 NH, - (CH,) ₃ - 1/2 H, 0 oxalate 102 pyrido [3,2-f] 0 -ch ₃ 0 morpholino - (CH,), - maths 103 pyrido | 3,2-f 0 Cl I ₃ She 1-pyrrolidinyl - (CLL); fumarate 104 pyrido [3,2-f] 0 -Cll ₃ 0 —N (n-butyl) ₂ - (CH,), - maleate 105 pyrido [3,2-f] 0 -ch ₃ 0 -N (C ₂ H ₅ ) ₂ - (CH,), - oxalate 106 pyrido [3,2-f] 0 -ch ₃ 0 1-piperidinyl - (CH,), - oxalate 107 pyrido [3,2-f] 0 -ch ₃ 0 -N (CH ₃ ), (benzyl) ~ (C11,), ~ maleate 108 pyrido [3,2-f] 0 -ch ₃ 0 2,5-dimethyl-l- yl - (CH,), - fumarate

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Continuation of Table 77

Example number THE B R F. Z • (Cilj) n) Salt (base, hydrate) 109 pyrido [3,2-f] SHE -ch ₃ 0 2-methyl-l- pyrrolidinyl - (CH ₂ ) ₂ - 1 110 pyrido [3,2-f] SHE -ch ₃ 0 lH-pyrazol-l-yl _ (CH ₂ ) ₂ - - 111 pyrido [3,2-f] SHE -ch ₃ 0 imidazol-l-yl - (CH ₂ ) ₂ - - 112 pyrido [3,2-f] SHE -C ₂ H _s 0 -N (CH ₃ ) ₂ - (ch ₂ ) ₂ - oxalate 113 pyrido] 3,2-f] SHE ^- C ₂ h ₅ 0 1-pyrrolidinyl - (CII ₂ ) ₂ - oxalate 114 pyrido) 3,2-µl S CII-, 0 morpholino (El 1 ₂ ) ₂ - 115 pyrido (3,2-f] S -cn ₃ 0 —N (n-butyl) ₂ - (CII ₂ ) ₂ - oxalate 116 pyrido [3,2-f] S -ch ₃ 0 -N (C ₂ H ₅ ) ₂ - (ch ₂ ) ₂ - oxalate 117 pyrido [3,2-f] S -ch ₃ 0 1-pyrrolidinyl - (CH ₂ ) ₂ - oxalate 118 pyrido [3,2-f] s -ch ₃ 0 1H-Inidazol-1-yl - (CH ₂ ) ₂ - 1.5 oxalate 119 pyrido] 3,2-f] s -C ₂ H _s 0 -N (CII ₃ ) ₂ - (CH ₂ ) ₂ - - 120 pyrido [3,2-f] s -ch ₃ 0 -N (CH ₃ ) (benzyl) - (ch ₂ ) ₂ - oxalate 121 pyrido [3,2-f | s -ch ₃ 0 -nhch ₃ - (CH ₂ ) ₂ - 1.5 oxalate 122 7-Cl-pyrido (3,2-f] 0 -ch ₃ u -I-piriOiiainn - (eh ₂ ) ₂ - 2.5 fumarate 123 7-Cl-pyrido [3,2-f] 0 -ch ₃ 0 -N (CH ₃ ) ₂ - (ch ₂ ) ₂ - oxalate 124 pyrido [3,2-f] 0 -ch ₂ c ₆ h ₅ 0 -N (CH ₃ ) ₂ - (ch ₂ ) ₂ - 1.5 oxalate, 1 / 2H ₂ O 125 pyrido [3,2-f] 0 H 0 -N (CH ₃ ) ₂ _ (CII ₂ ) ₂ - - 126 pyrido [3,2-D] 0 -C1I ₃ 0 -N (cii ₃ ) ₂ (EI1 ₂ ) ₃ - 1.5 fumarate 0.5 _H2 O 127 pyrido [3,2-f] s -ch ₃ 0 -N (CH ₃ ) ₂ - (CH ₂ ) ₃ - 2 oxalates 128 7-Cl-pyrido [3,2-f s -ch ₃ 0 -N (CH ₃ ) ₂ - (ch ₂ ) ₂ - 1/2 H ₂ O, 1/2 (CH ₃ ) ₂ CHOH 129 pyrido [3,2-f] 0 -ch ₃ 0 -nhch ₃ - (CII _{2) 2} - oxalate 130 pyrido [3,2-f] 0 -ch ₃ O 4-methylpiperazin-1-yl ~ (ch ₂ ) ₂ - 2.0 fumarate, hydrate 131 pyrido [3,2-f] S ' -ch ₃ O 4-methylpiperazin-1-yl - (ch ₂ ) ₂ - 2.0 fumarate, 1/2 H ₂ C 132 pyrido [3,2-f] 0 -ch ₃ SHE (the) - (ch ₂ ) ₂ - 2.0 fumarate, 1/2 H ₂ O 133 pyrido [3,2-f] s -ch ₃ 0 —N (CH ₃ ) (C ₆ H _s ) - (CH ₂ ) ₂ - - 134 pyrido [3,2-f [ s -ch ₃ 0 -nh ₂ - (CH ₂ ) ₃ - fumarate 135 pyrido (3,2-f] s H 0 -N (CH ₃ ) ₂ - (CH ₂ ) ₂ - 211C1, H ₂ O 136 pyrido] 3,2-η s -ch ₃ 0 (the) - (CII ₂ ) ₂ - oxalate, 11 ₂ O 137 pyrido] 3,2-f] s -ch ₃ 0 1H-pyrazol-1-yl - (ch ₂ ) ₂ - - 138 pyrido [3,2-f] s -ch ₃ 0 1 -picr pitinil _ (ch ₂ ) ₂ - (fumarate, (0.5 H ₂ O, (0.5 isopropyl alcohol) 139 6-Cl-pyrido [4,3-f] She -ch ₃ 0 -N (CH ₃ ) ₂ - (CH ₂ ) ₂ - 0.5 fumarate

(a) = 4-bis (4-fluorophenyl) methyl-1-piperidinyl

1 = 4-Phenyl-1,2,3,6-tetrahydropyridinyl-12 = 4-hydroxy-4-phenylpiperidinyl-1 The following describes pharmaceutical compositions which can be administered to a living animal body at least They contain a compound of formula (I) and a pharmaceutical carrier or excipient. The compositions may be used for oral, rectal, palenteric, subcutaneous, intramuscular, intraperitoneal, intravenous or intranasal administration. Oral administration may take the form of, for example, solutions, capsules, tablets or dragees containing a pharmaceutical carrier, suitable excipients such as lactose, potato and corn starch, talc, gelatin, stearic acid, silicic acid, magnesium. stearate and polyvinylpyrrolidone.

For parenteral administration, the carrier or excipient may be a sterile liquid suitable for parenteral administration, for example, ampoules of water or arachis oil.

For rectal administration, the carrier may be, for example, cocoa butter or a ready-to-use glyceride.

The compositions may be administered into the nose, throat, or bronchial field by the administration of a gargling agent or an aerosol spray

-3 771

195,649 in the form of a spray or dry powder containing the active ingredient of the formula (I).

The compositions are preferably formulated in dosage units, each unit containing a fixed dose of the active ingredients. Preferred dosage forms of the compositions of the invention include tablets, dragees, capsules, ampoules, and suppositories. All that is required is that the active ingredient is present in an effective amount, i.e., that the appropriate effective dose is consistent with the dosage form employed.

The exact individual dosage as well as the daily dosage will, of course, be determined according to the usual medical principles under the guidance of a physician or veterinarian. The results of comparative pharmacological studies conducted in guinea pigs in parallel with other antihistamines suggest that the effective dose for adult subjects is between 2 and 8 mg for formulations containing more active substances.

Based on animal data, unit doses containing 0.03-0.10 mg / kg body weight of the active ingredient are prepared. Daily doses of from about 0.2 to about 0.6 mg / kg body weight can be used in human medicine, and it is obvious that multiple unit dosage forms can be used simultaneously. However, these considerations limit the scope of the invention in view of the uncertainty that will arise when transposing animal test results to the human medical field.

Examples of composition and preparation of unit dosage formulations:

capsules

Components Per Capsule

t. Active ingredient 4 mg

2. Lactose 150 mg

3. Magnesium stearate 4 mg

tablets

components tablet 1. Active ingredient 4 mg 2. Cereal starch 20 mg 3. Kelacid 20 mg 4. In the ferries 20 mg 5. Magnesium stearate 1.3 mg The tablets are prepared by the following procedure: 1. Components 1, 2, 3 and 4

mix.

2. To the mixture obtained in Step 1, water is added portionwise and mixed thoroughly. Water is added and mixed until the consistency of the mass allows it to be converted to a wet granulate.

3. Convert the wet mass into a granulate by passing it through an oscillating granulator having a mesh size of 2.38 mm.

4. Dry the wet granulate in an oven at 60 ° C.

5. Magnesium stearate lubricant is added to the dry granulate.

6. The granulate containing the lubricant is compressed into tablets on a suitable tablet press.

In tracheal injection per ml

1. Active ingredients 10.0 mg

2. Isotonic buffer solution to a volume of 1,0 ml

Procedure for the preparation of the above injection preparations:

1. The active ingredient is dissolved in the buffer solution.

2. The solution obtained in Step 1 is filtered under aseptic conditions.

3. Aseptically fill the sterile solution into sterile ampoules.

4. Aseptically seal the ampoules.

suppository

Components per cone

1. Active ingredient 10.0 mg

2. Polyethylene glycol 1000 1350.0 mg

3. Polyethylene glycol 4000 450.0 mg

These compositions are prepared as follows:

1. Components 2 and 3 are melted and mixed to form a uniformity.

2. In the melt obtained in Step 1, dissolve

Component 1 and mix until smooth.

3. The melt obtained in Step 2 is poured into suppository molds and cooled.

4. The suppositories are removed from the molds and packaged.

The antihistamine activity of some of the compounds of the present invention was confirmed by the following assays.

For intraperitoneal administration, the assay was performed with a modified version of the procedure of Tozzi et al., Vol. 4/4, 264-270, 1974. Guinea pigs were kept in a separate cage for 18-24 hours with water. libitum were given. On the day of the test, the animals (in groups of three) were given a formulation containing 30 mg / kg of the test compound by intraperitoneal injection. Thirty minutes later 1.2 mg / kg of histamine (= 2x

-3 873

195,649

LD ₉₉ )) was injected into the marginal ear vein and 24 hours later the antihistamine activity was evaluated by the number of surviving guinea pigs. If the composition was not filled with water, a control was performed with the same amount of material. The dose that protected 50% of the animals from death (PD _S0 ) was determined from the dose-response curve.

For oral administration, a modified version of the procedure of Toz.zi (Agents and Actions, Vol. 4 / 4,264-270, 1974) was also performed. The animals (in groups of three or more) were injected with 1.2 mg / kg (= 2x LD ₉₉ ) of the test compound 1, 3 or 6 hours after 1, 3 or 6 hours into the marginal ear vein. The control study and the results were evaluated in the same manner as described above.

The results are summarized in the tables below.

examined compound Compound (Mg / kg) Number of surviving / treated animals 3.0 3/3 30 3/3 diphenhydramine 0.3 4/6 1.0 1/5 3.0 4/6 5.0 1/2 10 3/4

Oral application

Oral application

examined compound Pre-treatment time (hours) Oral PDj ₀ and 95 per dose * Example 128 1 0.12 (0.06-0.19) 3 0.87 (0.39-2.07) 6 6.07 (2.05-10.21) diphenhydramine 1 2.83 (0.93-20.51) 3 12.97 (8.19 to 18.01) 6 38.27 (27.58 to 52.30) * Refers to free base.

examined compound Dose (Mg (kg) * Pretreatment time Number of overdone / treated animals Example 123 0.32 1 hr 1/3 1 1 hr 3/3 21.5 3h 5/5 21.5 6h 0/5 43 6 b 5/5 Example 128 1 1 hr 1/3 21.5 3h 5/5 21.5 6h 2/5

* Refers to free base.

Intraperitoneal application (30 minute preparation) Examinated Compound Compound (mg / kg) Number of overdone / treated animals Example 128 0.12 3/3 0.32 3/3 1.0 6/7

Intraperitoneal application (30 minutes pretreatment)

exams Dose Survivors / treated compound (Mg (kg) * number of animals Example 123 compound 0.32 2/3

2/3

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examined compound Dose (Mg / kg) * Number of surviving / treated animals I 3 3/3 30 3/3 Example 128 0.1 3/3 1 3/3

* Applies to free base.

Additional pharmacological experiments

Experiments have been conducted to determine whether the use of the compounds of the invention as antihistamines results in sedative (sedative) effects. The results obtained with the test compounds indicate that these compounds are non-sedative antihistamines. for comparison, diphenhydramine was used as the antihistamine, which has been shown to cause sedation. [See Douglas, WC (1980), "Hystamine and 5-hydroxytryptamine (serotonin) and their antagonists", in "The Pharmacological Basis of Therapentics", published by G. Gilman et al., 6th edition Macinilan, New York, pp. 609-641] In our current studies, sedation is defined as the normal course (pattern) of low-voltage, fast (β) cerebral cortex in electroencephalograms (EEGs) at high voltage at 1225 Hz, <50 rnV. , become synchronized, slow (α, Δ) cortical waves (1-3, 4-7 Hz,> 50 mV amplitude), and frequent periods of sleep spindle drawings dominate EEGs.

Experimental method for determining sedative effect

10 cats of both sexes were anesthetized with halothane and cannulae were placed in their trachea, left cranial vein, and right femoral artery for artificial respiration, active ingredient administration, and blood pressure monitoring. The animals' heads were fixed in a Kpf-type stereotaxic apparatus and the cranial roof was exposed over a wide area. Through the cranium, stainless steel screw electrodes (1/4 in size) were placed with the ends of the electrodes on both sides of the hard hemisphere in the frontal, parietal, and occipital (i.e., forehead, temporal, and cervical) areas. An electrode of the same type was placed in the right forehead, which served as a reference electrode for monopolar EEG displays. After the surgery was completed, the animals were intravenously administered with 20 mg of gallamine-triszethoyodide (supplemented if necessary) and halothan was discontinued. Artificial ventilation was started (10 ml room air / kg / 3 sec).

EEGs were recorded in a Grass Model 5 electroencephalograph with ECG recording (Channel II). Λζ EEGs were observed every 10 minutes for 2 to 3 minutes. Arterial blood pressure was recorded continuously using a Grass Model 79 polygraph.

In most of our experiments, 0.5 mg / kg of histamine was administered intravenously, which produced a transient hypotensive effect (less than 30 seconds). This was usually administered 10, 20 or 30 minutes before the first dose of test drug, and then 5, 10 and 20 minutes after each dose of test drug. In this way, the effect of the nthhistamine of the test substance was quantitatively observed.

At the same time as quantifying the antihistamine effect, the effect of the test substance on EEG was observed. Generally, the test compound was administered intravenously in increments of 0.1, 0, 3, 5, 5, 10, and 20 mg / kg.

Experimental results on sedative effects

Illustrative Example of Test Compounds (Compounds described in Examples 65, 123, and 128) The compound prepared in Example 65 which, when administered intravenously at 0.3 mg / kg, reduced by 50%, 1-3 mg / kg. administered intravenously, 100% reversed the antihypertensive effect of histamine. When this compound was administered intravenously at up to 20 mg / kg, no signs of sedation were observed in the experimental animals.

for comparison, diphenhydramine, which is known to have a sedative effect, was tested. Our experiments were conducted in 6 cats: dsphenhydramine 0.5 mg / kg intravenously reduced it by 50%, and 3-5 mg / kg intravenously 100% eliminated the histamine-induced antihypertensive (depressor) effect. Signs of diphenhydramine-induced sedation were already present in the EEG after intravenous administration of 0.5 mg / kg, such that there was a marked slowing of synchronized waves and, after intravenous administration of 1 to 3 mg / kg, sleep drawings were observed. To sum up, diphenhydramine exerts its antihistamine effects at doses that also produce a sedative effect. This is quite similar to what is observed when people are given diphenhydramine.

In contrast to the effects of diphenhydramine, active compounds similar to those described in Example 65 do not induce sedation at doses up to 20 mg / kg.

-4 077

195,649 and it should be noted that their antihistaminic effects occur at much lower doses. All these data indicate that the compounds of the invention are non-sedative. !

Claims (61)

A process for the preparation of the oxazepines and thiazepines fused to an aromatic ring and a pharmaceutically acceptable salt thereof, wherein A is a 6 or 10 membered aromatic ring having two carbon atoms in the oxazepine or thiazepine moiety, which may be a benzene, naphthalene or pyridine ring in any of the four possible positions, and the pyridine ring is optionally substituted with a halogen atom, and a benzene ring with a lower alkoxy group or a halogen atom; B and E are oxygen or sulfur, which may be the same or different; n is 2 or 3; R is hydrogen, lower alkyl or phenyl (lower alkyl) when n is 2 and lower alkyl when n is 3; Z is -NR * R ² , 1H-pyrazol-1-yl or 1H-imidazol-3-yl, wherein R ¹ and R ² are hydrogen, C 1-6 alkyl, phenyl or phenyl (lower alkyl). or else R ¹ and R ² together with the adjacent nitrogen form a heterocyclic ring which is 1-pyrrolidinyl, 2,5-dimethyl-1-pyrrolidin-1-yl, 2-methylpyrrolidin-1-yl, 1-piperidinyl -, piperidin-ΙΟ-, 4-morpholinyl, Ι-piperazinyl, 4- (lower alkyl substituted) at the 4-position substituted by a phenyl and a HO group or a bis (4-halophenyl) methyl group - piperazin-1-yl or 4-phenyl-1,2,3,6-tetrahydropyridin-1-yl, provided that when R is hydrogen, Z is not may be a group -NR ¹ R ² wherein R ¹ and / or R ^{2 are} hydrogen, and Z must not be -NH 1 if n = 2, and provided that when n = 3, Z is only n -NR ¹ R ² may be a group wherein R ¹ and R ² are hydrogen or two methyl groups characterized in that a compound of formula IVb wherein A and E are as defined above, R is lower alkyl or phenyl (lower alkyl), R ³ is hydrogen or an alkali metal cation; n is 2, preferably with a thionyl halide, chlorinated or brominated followed by the compound of formula (111) or its free base, wherein X is chlorine or bromine, A, E, R, and n are cyclized as defined in general formula (IVb), and if desired to form a compound of formula (11b), wherein A, E, R, η, X are as defined in formula (III), | Ij is a compound of formula (Ua) prepared by cyclization, wherein Λ, E, R, η, η, X are reacted with a sulfurizing agent of formula (III) or to produce a compound of formula (Ilc): Λ and Ii of formula (III), R is lower alkyl, are reacted with a compound of formula (IIa), wherein A, E and R are the same, n = 2 and X are as defined above, followed by a) for the preparation of compounds of formula I wherein Z, A, E, B are as defined for formula (1), R is as defined therein but different from hydrogen and n is 2, a compound of formula (IIa) or (IIb). ), wherein A, E, R and n are as defined above, and X is as defined above, with a compound of formula ZH Z is a compound of the formula (I), where appropriate, and optionally used to prepare a compound of formula (I): Z, A, E, R and n are the latter compounds of formula Ia wherein B is oxygen, A, E, R, Z, and n are as defined above, by reacting with a sulfurizing agent or, if desired, reducing a 4-benzyl compound with sodium and NH _{3 to} a compound containing R in hydrogen or b) for the preparation of compounds of formula I wherein B is n = 3, Z = -NH ₂ , A and E are as defined in process a) and R is a lower alkyl group of a cyano compound of formula Ilc Wherein the substituents are as defined above; or, if desired, for the preparation of a compound of formula (Id), wherein: Z is a group -NR ¹ R ² wherein R ¹ and R ² are methyl, R is lower alkyl, A and E are as defined in formula (IIc) - a primer of formula (I _{c , l} ) obtained above _. whereby A, E and R are reacted with formaldehyde and formic acid as defined in formula (Id) and / or if desired, the resulting compound of formula (I) is sulfurized to the corresponding thionium to afford pharmaceutically acceptable salts, if desired. a free base prepared by any of the above methods -4 179 195,649 acids or quaternary halide or sulfate salt reactants. (Priority: August 29, 1983) ^; A process for the preparation of an aromatic ring-fused oxazepine and thiazepine of formula (Ia) as defined in claim 1, and pharmaceutically acceptable salts thereof, wherein: A, B, E and Z are as defined in claim 1 R 'is C 1 -C 4 alkyl or phenyl (C 1 -C 4 alkyl); n'means 2; characterized in that a compound of formula IVb - wherein A, E, R 'and n' are as defined in the preamble, R ³ is hydrogen or an alkali metal cation, chlorinated or brominated followed by the compound of formula (111) or the free base thereof, wherein X is chlorine or bromine, A, E, R \ n 'have the meaning given above, cyclizing; and optionally preparing a compound of formula (IIb) wherein: A, E, R ', η', X are compounds of formula (III) as defined by formula (111), wherein: A, E, R ', η', X are reacted with a sulfurizing agent of formula (III); subsequently reacting a halogen compound of formula IIa or IIb wherein A, E, R ', X, n' are as defined above with a compound of formula ZH wherein Z is as defined above; optionally for the preparation of a compound of formula (Ib), wherein: A, E, R ', Z, n' have the meanings given above for a compound of formula (Ia) in which B is oxygen, A, E, Z, R ', n' are as defined above, reacted with a sulfurizing agent; and / or optionally reacting the free base of any of the compounds prepared by the above process with a pharmaceutically acceptable acid, lower alkyl halide or lower alkyl sulfate to prepare a pharmaceutically acceptable salt. (Priority: August 29, 1983) 3. A process for the preparation of the compounds of the general formula (I) and pharmaceutically acceptable salts thereof, wherein: A is a 6 or 10 membered aromatic ring having two carbon atoms in the oxazepine or thiazepine moiety, which may be a benzene, naphthalene or pyridine ring in any of the four possible positions, and the pyridine ring is optionally substituted with a halogen atom, and a benzene ring with a lower sonic alkoxy group or a halogen atom; B and E are oxygen or sulfur, which may be the same or different; R is (1-4C) alkyl or phenyl (1-4C) alkyl; n is 2; Z is -NR ¹ R ² wherein one of R ¹ and R ² is hydrogen or the other is C 1 -C 6 alkyl or phenyl (C 1 -C 4 alkyl) or R ^{1 is} hydrogen. and R ² , together with the adjacent nitrogen atom, forms a heterocyclic ring which is piperidinyl substituted with 1-pyrrolidinyl, 1-piperidinyl, 4-position in the phenyl and one in OH, or one in the bis (4-halophenyl) -ethyl group. 1-yl, 4-morpholinyl, 1-piperazinyl, 4- (lower alkyl substituted) piperazin-1-yl, or 1,2,3,6-tetrahydropyridin-1-yl; characterized in that a compound of formula IVb wherein A, E, R, n and B are as defined above, R ^{3 is} hydrogen or an alkali metal cation, chlorinated or brominated; the acid halide of formula (III) so prepared or a free base thereof, wherein X is chlorine or bromine, A, E, R, n are as defined above, cyclized; and, if desired, preparing an azepinion of formula (IIb) wherein A, E, R, η, X are the above compound of formula (Ha) obtained by cyclization, wherein A, E, R, n, X are reacted with a sulfurizing agent as described above, followed by reaction of a compound of formula (IIa) or (IIb) with an amine of formula NHR ¹ R ² , wherein R * and R ^{2 for} the preparation of a compound of formula Ib, if desired, wherein A, E, R, Z, n are as defined above for a compound of formula (I) in which B is oxygen, A, E, R, Z, n are as defined above, reacted with a sulfurizing agent and, if desired, the free base obtained by the above process is converted to a salt with a pharmaceutically acceptable acid, (lower alkyl) halide, or (lower alkyl) sulfate. 30.) A process according to claim 3 for the preparation of 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one or pharmaceutically acceptable salts thereof, to employ appropriately substituted starting materials. (E .: September 30, 1982) The process of claim 3, 2,3-dihydro-4-4281 195,649 for the preparation of ethyl-2- [2- (4-iolototinyl) ethyl] -1,4-benzoxazeplu-5 (4L) or the pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E .: September 30, 1982) 1 The process of claim 3, 4-benzyl-2,3-dihydro-2- [2- (4-morpholinyl) ethyl] -1,4-benzoxazepin-5 (4- 'H) -one or a pharmaceutically acceptable salt thereof. characterized in that the appropriate starting materials are substituted. (E .: September 30, 1982) The process of claim 3, 4-benzyl-2,3-; dihydro-2- | 2- (methylamino) ethyl] -1,4-benzoxazepin-5 (4H) -one or a pharmaceutically acceptable salt thereof, wherein the appropriately substituted starting materials are used. (E .: September 30, 1982) A process according to claim 3 for the preparation of 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione or pharmaceutically acceptable salts thereof, characterized in that the appropriately substituted starting materials are used. (E .: September 30, 1982) 9. A process according to claim 3 for the preparation of 4-benzyl-2- [2- (dimethylamino) ethyl] -2,3-dihydro-1,4-benzoxazepin-5 (4H) -one or pharmaceutically acceptable salts thereof, characterized in that the appropriately substituted starting materials are used. (E .: September 30, 1982) The process according to claim 3 for the preparation of 2,3-dihydro-4-methyl-2- [2- (4-morpholinyl) ethyl] -1,4-benzoxazepln-5 (4H) -thione or pharmaceutically acceptable salts thereof, to employ appropriately substituted starting materials. (E .: September 30, 1982) The process according to claim 3, which is 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylnaphth [2,3-f [1,4] oxazepine-5 (4H) - or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E .: September 30, 1982) The process according to claim 3, which is 2- [2- (dimethylamirio) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -. or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E .: September 30, 1982) The process according to claim 3, which is 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -. or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E .: September 30, 1982) The process according to claim 3 for the preparation of 4-benzyl-2,3-dihydro-2- [2- (4-morpholinyl) ethyl] -1,4-benzoxazepine-5 (4H) -thione or pharmaceutically acceptable salts thereof, to employ appropriately substituted starting materials. (E: Sep 30, 1982) 15. A process according to claim 3 for the preparation of 2,3-dihydro-4-methyl-2-] 2- (methylamino) -ethyl] -1,4-benzoxazepin-5 (4H) -one or pharmaceutically acceptable salts thereof, that is, the use of appropriately substituted starting materials. 5 (E .: September 30, 1982) The process according to claim 3, which is 2,3-dihydro-2- [2- (4-hydroxy-4-methyl) piperidinyl ethyl] -4-methyl-1,4-benzoxazepine-5 (4H) -thione or and pharmaceutically acceptable salts thereof 1Q substituted starting materials are used. (E .: September 30, 1982) The process according to claim 3, 2,3-dihydro-4-methyl-2] -1- (4-phenyl-1,2,3,6-tetralidro) -pyridinyl] -yl-1,4-benzoxazepine-5 (41 ) -thion or a pharmaceutically acceptable salt thereof, wherein the appropriately substituted starting materials are used. (E .: September 30, 1982) The process according to claim 3, 8-chloro-2- (2 ² θ (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazeine-5 (4I) or a pharmaceutically acceptable salt thereof, wherein the appropriately substituted starting materials are used. (E .: September 30, 1982) 9. The method of claim 3, 8-chloro-2- (2- (dimethylallyl) amino) ethyl] -2,3-diyldioxo-4-ylcyl-1,4-benzoxoxazepine-5. (4H) -one or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. ³⁰ (5: September 30, 1982) The process of claim 3, wherein 7-bromo-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione or a pharmaceutically acceptable salts thereof, characterized in that the appropriately substituted starting materials are used. (E .: September 30, 1982) A process according to claim 3, for 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylnaphth [2,1f] fl, 4] oxazole-4-yl (5 ') or and pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E .: September 30, 1982) The process of claim 3, 2- [2- (dimethyl45 amino) ethyl] -2,3-dihydro-4-methylpyrido [4,3-f] [1,4] oxazepine 5 (4H) - or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E. Sept. 30, 1982) 50 The process of claim 3, 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylnaphth [2,3-f] (1,4) oxazepine-5 (4H) - or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. 55 (E. Sept. 30, 1982) 24. The method of claim 3, 7-chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepin-5 (4H) -one or a pharmaceutically acceptable salt thereof. salts thereof, characterized in that appropriately θθ-substituted starting materials are used. (E .: September 30, 1982) 25. The process of claim 3, 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxa43 -4 383 195,649 for the preparation of zepin-5 (4II) -thionyl iodide, characterized in that the appropriately substituted starting materials are used. (E .: September 30, 1982) The process according to claim 3, which is 7-chloro-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione or a pharmaceutically acceptable salt thereof. salts thereof, characterized in that the appropriately substituted starting materials are used. (E .: September 30, 1982) The process according to claim 3, wherein 2- [2- (dimethylamino) -ethyl] -2,3-dihydro-4-methyl-naphth [2, 3] [1,4] oxazepine-5 (4H) -thione or and pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E .: September 30, 1982) 28. The process of claim 3, which is 2- [2- (dimethylamino) ethyl] -2,3-dihydro-7-methoxy-4-methyl-1,4-benzoxazepin-5 (4H) -one or a pharmaceutically acceptable salt thereof. salts thereof, characterized in that the appropriately substituted starting materials are used. (E .: September 30, 1982) 29. The process of claim 3, which is 7-bromo-2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methyl-1,4-benzoxazepine-5 (4H) -thione or a pharmaceutically acceptable salt thereof. salts thereof, characterized in that the appropriately substituted starting materials are used. (E .: September 30, 1982) 30. The process of claim 3, 2- (2- (dimethylamino) ethyl] -2,3-dihydro-4-ethylpyrido [3,2-f] [1,4] thiazepine-5 (4II). ) or a pharmaceutically acceptable salt thereof, wherein the appropriately substituted starting materials are used. (E .: September 30, 1982) 31. The process of claim 3, which is 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] thiazepine-5 (4H) -. or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E .: September 30, 1982) 32. The process of claim 1, which is 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] oxazepine-5 (4H) -. or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 33. The preferred compound of claim 1 is 2- [2- (diethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,4-f] [1,4] oxazepine-5 ( 4H) -thione or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 34. A process according to claim 1 for the preparation of 2- (3-aminopropyl) -2,3-dihydro-4-methylpyrido [3,2-f] (1,4) oxazepin-5 (4H) -one or pharmaceutically acceptable salts thereof. , characterized in that the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 35. A process according to claim 1, which is 2,3-dihydro-4-methyl-2- [2- (4-morpholinyl) methyl] pyrido [3,2-f] 1,4-oxazepin-5 (4H) -one or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) The process according to claim 1, which is 2,3-dihydro-4-methyl-2- [2- (1-pyrrolidinyl) ethyl] pyrido [3,2-f] [1,4] oxazepine-5 (4H) -. or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) The process of claim 1, wherein the compound is 2- [2- (dibutylamino) ethyl] -2,3-dihydro-4-methylpyrido (3,2-f] [1,4] oxazepin-5 (4'L) -one or and pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 38. The process of claim 1, which is 2- (2- (dimethylamino) ethyl) -2,3-dihydro-4-methylpyrido [3,2- f] [1,4] oxazepine-5 (4H) - or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) The process according to claim 1, which is 2,3-dihydro-4-methyl-2- (2- (1-piperidinyl) ethyl) pyrido [3,2-f] [t, 4] oxa7.epin-5 (4-pyridyl) methyl. l) -one or a pharmaceutically acceptable salt thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 40. The process of claim 1, 2,3-dihydro-4-methyl-2- [2- (N-methyl-N-benzylamino) ethyl] pyrido [3,2-f] [1,4] oxazepine -5 (4H) -one or a pharmaceutically acceptable salt thereof, characterized in that the appropriately substituted starting materials are used. (E .. Aug. 29, 1983) 41. The process according to claim 1, which is 2,3-dihydro-4-methyl-2- [2- (N-methyl-N-phenylamino) ethyl] pyrido [3,2-f] 1,4] oxazcpin- 5 (4ll) -one or a pharmaceutically acceptable salt thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 42. The process of claim 1, which is 2- (2- (2,5-dimethyl-1-pyrrolidinyl) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine. 5 (4H) -one or a pharmaceutically acceptable salt thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 43. The process according to claim 1, which is 2,3-dihydro-4-methyl-2- [2- (2-methyl-1-pyrrolidinyl) -c] - pyrido (3,2-f], 4] oxazepine-5 (4'-yl) ) or a pharmaceutically acceptable salt thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 44. The process of claim 1, 2,3-dihydro-4-methyl-2- [2- (1H-pyrazol-1-yl) ethyl] pyrido [3,2-f] [1,4] oxazepine-5 (4H) -one or a pharmaceutically acceptable salt thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 45. The process according to claim 1, wherein 2,3-d) hydro-2- [2- (1H-imidazol-1-yl) ethyl] -4-methylpyrido [3,2-f] 1,4-oxazpiu-5 (4ll) -one or pharmaceutically acceptable salts thereof, characterized in that the starting materials are appropriately substituted. (E.: Aug. 29, 1983) -4 485 195,649 46. The method of claim I 2-2- (dimethyl- j amino) ethyl-4-ethyl-2,3-dihydro-pyrido (3,2-f | fl, 4] oxaze- ^one pin-5 ( 4H) -one or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (Sat: Aug 29, 1983) 47. The process according to claim 1, which is 2,3-dihydro-4-ethyl-2- (2- (1-pyrrolidinyl) ethyl] pyrido (3,2-f), 4 (oxazcpin-5 (4II) -one or pharmaceutically acceptable in the preparation of its acceptable salts, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 48. The process according to claim 1, which is 2,3-dihydro-4-methyl-2- [2- (4-morpholinyl) ethyl] pyrido [3,2-f] [1,4] oxazepine-5 (4H) -. or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 49. The method of claim 1, wherein 2- [2- (dibutylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1,4] oxazepine-5 (4H) -thione or a pharmaceutically acceptable salts thereof, characterized in that the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 50. The process of claim 1, wherein the compound is 2- [2- (diethylamino) ethyl] -2,3-dihydro-4-methylpyrido [3,2-f] [1.4] oxazepine-5 (4H) -thione or and pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 20, 1983) 51. The process of claim 1, wherein 2,3-dihydro-4-methyl-2- (2- (1-pyrrolidinyl) ethyl) pyrido [3,2-f] [1.4] oxazepine-5 (4H) -thione or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 52. The method of claim 1, which is 2,3-dihydro-2- [2- (1H-imidazol-1-yl) ethyl] -4-methylpyrid [3,2-f] (1,4) oxazepine-5. (4H) -thione or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 53. The process of claim 1, wherein the compound is 2- [2- (dimethylamino) ethyl] -4-ethyl-2,3-dihydropyrido [3,2-f] [1.4] oxazepine-5 (4H) -thione or a pharmaceutically acceptable salt thereof. in the preparation of its acceptable salts, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 54. The process according to claim 1, which is 2,3-dihydro-4-methyl-2- [2- (N-methyl-N-benzylamino) ethyl] pyrido [3,2- b] (1,4) oxazepine-5 (4H) -thione or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 55. The method of claim 1, which is 2,3-dihydro-2- [2- (methylamino) ethyl] -4-methylpyrido [3,2-f] (14) oxazepine-5 (4H) -thione. or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 56. The process of claim 1, which is 7-chloro-2,3-dihydro-4-methyl-2- (2- (1-pyrrolidinyl) ethyl] pyrido [3,2-f] (1,4) -oxazepine-5 (4H). ) or a pharmaceutically acceptable salt thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 57. The method of claim 1, which is 7-chloro-2- (2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrdoo [3,2-f] [1,4] oxazepine-5. (4H) or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 58. The method of claim 1, wherein 2- [2- (dimethylamino) ethyl] -2,3-dihydro-4-benzylpyrido [3,2-f] [14] oxazepin-5 (41I) -one or and pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 59. The process of claim 1 for preparing 2- [2- (dimethylamino) ethyl] -2,3-dihydro [3,2-f] [1,4] oxazepin-5 (4H) -one or pharmaceutically acceptable salts thereof, characterized in that the appropriate substituted starting materials are used. (E.: Aug. 29, 1983) 60. The process of claim 1, wherein the compound is 2- [3,3- (dimethylamino) propyl] -2,3-dihydro-4-methylpyrido [3,2f] (1,4) oxazepine-5 (4H) -one or and pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 61. The method of claim 1, which is 2- [3- (dimethyl-nino) -propyl] -2,3-dihydro-4-methyl-pyrido (3,2 [b] (1,4) oxazepyl) -5 (4H) -thione. or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used. (E.: Aug. 29, 1983) 62. The process of claim 1, wherein 7-chloro-2- (2- (dimethylamino) ethyl] -2,3-dihydro-4-methylpyrido {3,2-f] [1,4] oxazepine-5 ( 4H) -ton or pharmaceutically acceptable salts thereof, wherein the appropriately substituted starting materials are used.